key: cord-0818939-5uuhmftx
authors: Serban, Georgeta
title: Synthetic Compounds with 2-Amino-1,3,4-Thiadiazole Moiety Against Viral Infections
date: 2020-02-19
journal: Molecules
DOI: 10.3390/molecules25040942
sha: c19f426a9602e64794abc621c69358c119448fbc
doc_id: 818939
cord_uid: 5uuhmftx

Viral infections have resulted in millions of victims in human history. Although great efforts have been made to find effective medication, there are still no drugs that truly cure viral infections. There are currently approximately 90 drugs approved for the treatment of human viral infections. As resistance toward available antiviral drugs has become a global threat to health, there is an intrinsic need to identify new scaffolds that are useful in discovering innovative, less toxic and highly active antiviral agents. 1,3,4-Thiadiazole derivatives have been extensively studied due to their pharmacological profile, physicochemical and pharmacokinetic properties. This review provides an overview of the various synthetic compounds containing the 2-amino-1,3,4-thiadiazole moiety that has been evaluated for antiviral activity against several viral strains and could be considered possible prototypes for the development of new antiviral drugs.

Viruses are the smallest among all self-replicating organisms and yet they are the etiological agents of many difficult to treat diseases in human populations [1] . There are broad types of human infections caused by viruses, such as respiratory infections (common cold, Influenza), digestive infections (viral gastroenteritis), central nervous system infections (viral meningitis, viral encephalitis), skin or mucosal infections (herpes, measles, mumps, smallpox and rubella), hepatic infections (hepatitis A, B, C, E), blood infections (acquired immunodeficiency syndrome) and hemorrhagic fever (yellow fever, Ebola hemorrhagic fever). Viruses are the most abundant and diverse biological entities on Earth and this is the reason for the high incidence of viral infections [2] . In addition, some viruses are etiological agents in the development of human tumors, particularly cervical cancer and hepatic cancer [3] .

The main method and most cost-effective strategy for preventing viral infections is through vaccination, which is meant to prevent outbreaks by increasing immunity [4] . Vaccines for the prevention of several common acute viral infections, such as polio, rubella, measles, mumps, Influenza, yellow fever, encephalitis, rabies, smallpox and hepatitis B were developed during the 20th century and are available on a large scale [1, 4] . Efforts to develop safe and effective vaccines against viruses that cause chronic infections, such as human immunodeficiency virus or hepatitis C virus did not give the expected results [1, 4, 5] .

For many viral infections, only symptomatic treatment is indicated, while it is expected the immune system to fight off the virus. However, there are high-virulence viruses that cause serious viral infections where antiviral treatment is essential for patient survival. Although great efforts have been made to find effective medication, there are still no drugs that truly cure viral infections. Moreover, CH(OH)CH 3 (4) ; CH 2 CH 2 SCH 3 (5) In vitro HIV inhibitory activity using human T-lymphocyte (MT-4) cells gave moderate or low half-maximal effective concentration (EC50) values in comparison to efavirenz (EC50 value of 0.003 μg/mL). The best results were obtained for derivatives 1 and 5 ( Figure 1 ) with moderate EC50 values. Thus, compound 1 showed EC50 > 14 μg/mL against HIV-1 (strain IIIB) and EC50 > 12.4 μg/mL against HIV-2 (strain ROD), while the compound 5 showed EC50 > 12.6 μg/mL against HIV-1 and EC50 > 12.5 μg/mL against HIV-2. Low values for cytotoxicity concentration 50% (compound concentration that reduces the viability of mock-infected MT-4 cells by 50%), namely the CC50 value of 14.0 ± 1.2 μg/mL for compound 1 and 13.3 ± 0.8 μg/mL for compound 5, respectively, resulted in low selectivity index SI ≤ 1 (SI = CC50/EC50). Other derivatives showed lower activity with EC50 within the range of 47.4-125 μg/mL. However, chemical modifications on this scaffold might lead to compounds with enhanced activity as NNRTIs [65] . [66] from amino acid analogs were screened for anti-HIV-1 (strain IIIB) and anti-HIV-2 (strain ROD) activity by the inhibition of the virus-induced cytopathic effect in human MT-4 cells based on 3-(4,5-dimethylthiazol-2-yl) -2,5-diphenyl tetrazolium bromide (MTT) assay. 2-(Naphthalen-2-yloxy)-N-((5-(phenylamino) -1,3,4-thiadiazol-2-yl)methyl)acetamide 6 showed in vitro inhibitory activity with EC50 values of 0.96 μg/mL (HIV-1 strain IIIB) and 2.92 μg/mL (HIV-2 strain ROD), respectively, but low selectivity (SI < 1). Structure-activity relationship (SAR) studies have suggested that the substitution of the acetamide moiety with a thiadiazole ring may lead to more active derivatives compared to other compounds bearing different heterocyclic rings. Even though anti-HIV activity and selectivity of derivative 6 are limited compared to efavirenz (EC50 value of 0.003 μg/mL and SI ≈ 13333), it may serve as the basis for future modification in the search for new potent non-nucleoside antiviral agents [66] . A new class of HIV-1 NNRTIs, N-aryl-2-arylthioacetamides, has been identified in the last years [67] [68] [69] [70] . Studies on the crystalline structure of the RT-NNRTI complex suggested that NNRTIs have a common mode of action and interact with a hydrophobic pocket. N-aryl- 2-arylthioacetamides In vitro HIV inhibitory activity using human T-lymphocyte (MT-4) cells gave moderate or low half-maximal effective concentration (EC 50 ) values in comparison to efavirenz (EC 50 value of 0.003 µg/mL). The best results were obtained for derivatives 1 and 5 ( Figure 1 ) with moderate EC 50 values. Thus, compound 1 showed EC 50 > 14 µg/mL against HIV-1 (strain IIIB) and EC 50 > 12.4 µg/mL against HIV-2 (strain ROD), while the compound 5 showed EC 50 > 12.6 µg/mL against HIV-1 and EC 50 > 12.5 µg/mL against HIV-2. Low values for cytotoxicity concentration 50% (compound concentration that reduces the viability of mock-infected MT-4 cells by 50%), namely the CC 50 value of 14.0 ± 1.2 µg/mL for compound 1 and 13.3 ± 0.8 µg/mL for compound 5, respectively, resulted in low selectivity index SI ≤ 1 (SI = CC 50 /EC 50 ). Other derivatives showed lower activity with EC 50 within the range of 47.4-125 µg/mL. However, chemical modifications on this scaffold might lead to compounds with enhanced activity as NNRTIs [65] .

Molecules 2020, 25 2 (1); CH 2 CH(CH 3 ) 2 (2); CH(CH 3 )CH 2 CH 3 (3) CH(OH)CH 3 (4) ; CH 2 CH 2 SCH 3 (5) In vitro HIV inhibitory activity using human T-lymphocyte (MT-4) cells gave moderate or low half-maximal effective concentration (EC50) values in comparison to efavirenz (EC50 value of 0.003 μg/mL). The best results were obtained for derivatives 1 and 5 ( Figure 1 ) with moderate EC50 values. Thus, compound 1 showed EC50 > 14 μg/mL against HIV-1 (strain IIIB) and EC50 > 12.4 μg/mL against HIV-2 (strain ROD), while the compound 5 showed EC50 > 12.6 μg/mL against HIV-1 and EC50 > 12.5 μg/mL against HIV-2. Low values for cytotoxicity concentration 50% (compound concentration that reduces the viability of mock-infected MT-4 cells by 50%), namely the CC50 value of 14.0 ± 1.2 μg/mL for compound 1 and 13.3 ± 0.8 μg/mL for compound 5, respectively, resulted in low selectivity index SI ≤ 1 (SI = CC50/EC50). Other derivatives showed lower activity with EC50 within the range of 47.4-125 μg/mL. However, chemical modifications on this scaffold might lead to compounds with enhanced activity as NNRTIs [65] . [66] from amino acid analogs were screened for anti-HIV-1 (strain IIIB) and anti-HIV-2 (strain ROD) activity by the inhibition of the virus-induced cytopathic effect in human MT-4 cells based on 3-(4,5-dimethylthiazol-2-yl) -2,5-diphenyl tetrazolium bromide (MTT) assay. 2-(Naphthalen-2-yloxy)-N-((5-(phenylamino) -1,3,4-thiadiazol-2-yl)methyl)acetamide 6 showed in vitro inhibitory activity with EC50 values of 0.96 μg/mL (HIV-1 strain IIIB) and 2.92 μg/mL (HIV-2 strain ROD), respectively, but low selectivity (SI < 1). Structure-activity relationship (SAR) studies have suggested that the substitution of the acetamide moiety with a thiadiazole ring may lead to more active derivatives compared to other compounds bearing different heterocyclic rings. Even though anti-HIV activity and selectivity of derivative 6 are limited compared to efavirenz (EC50 value of 0.003 μg/mL and SI ≈ 13333), it may serve as the basis for future modification in the search for new potent non-nucleoside antiviral agents [66] . A new class of HIV-1 NNRTIs, N-aryl-2-arylthioacetamides, has been identified in the last years [67] [68] [69] [70] . Studies on the crystalline structure of the RT-NNRTI complex suggested that NNRTIs have a common mode of action and interact with a hydrophobic pocket. N-aryl-2-arylthioacetamides [66] from amino acid analogs were screened for anti-HIV-1 (strain IIIB) and anti-HIV-2 (strain ROD) activity by the inhibition of the virus-induced cytopathic effect in human MT-4 cells based on 3-(4,5-dimethylthiazol-2-yl) -2,5-diphenyl tetrazolium bromide (MTT) assay. 2-(Naphthalen-2-yloxy)-N-((5-(phenylamino) -1,3,4-thiadiazol-2-yl)methyl)acetamide 6 showed in vitro inhibitory activity with EC 50 values of 0.96 µg/mL (HIV-1 strain IIIB) and 2.92 µg/mL (HIV-2 strain ROD), respectively, but low selectivity (SI < 1). Structure-activity relationship (SAR) studies have suggested that the substitution of the acetamide moiety with a thiadiazole ring may lead to more active derivatives compared to other compounds bearing different heterocyclic rings. Even though anti-HIV activity and selectivity of derivative 6 are limited compared to efavirenz (EC 50 value of 0.003 µg/mL and SI ≈ 13333), it may serve as the basis for future modification in the search for new potent non-nucleoside antiviral agents [66] . (3) CH(OH)CH 3 (4); CH 2 CH 2 SCH 3 (5) In vitro HIV inhibitory activity using human T-lymphocyte (MT-4) cells gave moderate or low half-maximal effective concentration (EC50) values in comparison to efavirenz (EC50 value of 0.003 μg/mL). The best results were obtained for derivatives 1 and 5 ( Figure 1 ) with moderate EC50 values. Thus, compound 1 showed EC50 > 14 μg/mL against HIV-1 (strain IIIB) and EC50 > 12.4 μg/mL against HIV-2 (strain ROD), while the compound 5 showed EC50 > 12.6 μg/mL against HIV-1 and EC50 > 12.5 μg/mL against HIV-2. Low values for cytotoxicity concentration 50% (compound concentration that reduces the viability of mock-infected MT-4 cells by 50%), namely the CC50 value of 14.0 ± 1.2 μg/mL for compound 1 and 13.3 ± 0.8 μg/mL for compound 5, respectively, resulted in low selectivity index SI ≤ 1 (SI = CC50/EC50). Other derivatives showed lower activity with EC50 within the range of 47.4-125 μg/mL. However, chemical modifications on this scaffold might lead to compounds with enhanced activity as NNRTIs [65] .

Substitution with bulky groups decreased antiviral activity groups beneficial for antiviral activity butyl groups (2, 3) CH(OH)CH 3 (4); Some 1,3,4-thiadiazole derivatives obtained by Hamad et al. [66] from amino acid analogs were screened for anti-HIV-1 (strain IIIB) and anti-HIV-2 (strain ROD) activity by the inhibition of the virus-induced cytopathic effect in human MT-4 cells based on 3-(4,5-dimethylthiazol-2-yl) -2,5-diphenyl tetrazolium bromide (MTT) assay. 2-(Naphthalen-2-yloxy)-N-((5-(phenylamino) -1,3,4-thiadiazol-2-yl)methyl)acetamide 6 showed in vitro inhibitory activity with EC50 values of 0.96 μg/mL (HIV-1 strain IIIB) and 2.92 μg/mL (HIV-2 strain ROD), respectively, but low selectivity (SI < 1). Structure-activity relationship (SAR) studies have suggested that the substitution of the acetamide moiety with a thiadiazole ring may lead to more active derivatives compared to other compounds bearing different heterocyclic rings. Even though anti-HIV activity and selectivity of derivative 6 are limited compared to efavirenz (EC50 value of 0.003 μg/mL and SI ≈ 13333), it may serve as the basis for future modification in the search for new potent non-nucleoside antiviral agents [66] . A new class of HIV-1 NNRTIs, N-aryl-2-arylthioacetamides, has been identified in the last years [67] [68] [69] [70] . Studies on the crystalline structure of the RT-NNRTI complex suggested that NNRTIs have a common mode of action and interact with a hydrophobic pocket. N-aryl-2-arylthioacetamides adopted a butterfly-like conformation in which the arylthio moiety and the phenyl ring mimic the butterfly wings. SAR studies showed that the arylthio moiety strongly influenced the antiviral activity, leading to different results depending on the steric/electronic properties of the groups [47] . Based on these findings, Xiaohe et al. synthesized 2-(5-amino-1,3,4-thiadiazol-2-ylthio)-N-(aryl) acetamide derivatives 7-10 as new NNRTIs [47] .

Molecules 2020, 25, 942 5 of 22 adopted a butterfly-like conformation in which the arylthio moiety and the phenyl ring mimic the butterfly wings. SAR studies showed that the arylthio moiety strongly influenced the antiviral activity, leading to different results depending on the steric/electronic properties of the groups [47] . Based on these findings, Xiaohe et al. synthesized 2-(5-amino-1,3,4-thiadiazol-2-ylthio)-N-(aryl) acetamide derivatives 7-10 as new NNRTIs [47] .

Although they exhibited less anti-HIV-1 activity compared to standard drug zidovudine (half-maximal inhibitory concentration IC50 = 0.016 μM), these compounds showed significant anti-HIV-1 activity at micromolar concentrations (IC50 within the range of 7.50-20.83 μM) ( Table 1) . It has been observed that the 2-amino-1,3,4-thiadiazole moiety may be a good group for anti-HIV-1 activity by providing promising antiviral agents. Moreover, the electronic properties of the N-aryl group influenced antiviral potency. The introduction of electron-withdrawing groups, such as fluorine or trifluoromethyl on phenyl ring (derivatives 8 and 9), enhanced antiviral activity compared to the unsubstituted phenyl derivative 7. SAR studies suggested that the steric/electronic properties of the N-phenyl substituents influenced the antiretroviral activity more than their positions. In addition, the nature of the N-aryl ring influenced the antiviral potency as can be observed for derivative 10 with a pyrimidyl ring which was the most active compound ( Figure 2 ) [47] . (7) substitution with F atoms (8, 9) X = N heterocyclic ring increases activity introduction of CH 3 Although they exhibited less anti-HIV-1 activity compared to standard drug zidovudine (half-maximal inhibitory concentration IC 50 = 0.016 µM), these compounds showed significant anti-HIV-1 activity at micromolar concentrations (IC 50 within the range of 7.50-20.83 µM) ( Table 1) . It has been observed that the 2-amino-1,3,4-thiadiazole moiety may be a good group for anti-HIV-1 activity by providing promising antiviral agents. Moreover, the electronic properties of the N-aryl group influenced antiviral potency. The introduction of electron-withdrawing groups, such as fluorine or trifluoromethyl on phenyl ring (derivatives 8 and 9), enhanced antiviral activity compared to the unsubstituted phenyl derivative 7. SAR studies suggested that the steric/electronic properties of the N-phenyl substituents influenced the antiretroviral activity more than their positions. In addition, the nature of the N-aryl ring influenced the antiviral potency as can be observed for derivative 10 with a pyrimidyl ring which was the most active compound ( Figure 2 ) [47] . adopted a butterfly-like conformation in which the arylthio moiety and the phenyl ring mimic the butterfly wings. SAR studies showed that the arylthio moiety strongly influenced the antiviral activity, leading to different results depending on the steric/electronic properties of the groups [47] . Based on these findings, Xiaohe et al. synthesized 2-(5-amino-1,3,4-thiadiazol-2-ylthio)-N-(aryl) acetamide derivatives 7-10 as new NNRTIs [47] .

Although they exhibited less anti-HIV-1 activity compared to standard drug zidovudine (half-maximal inhibitory concentration IC50 = 0.016 μM), these compounds showed significant anti-HIV-1 activity at micromolar concentrations (IC50 within the range of 7.50-20.83 μM) ( Table 1) . It has been observed that the 2-amino-1,3,4-thiadiazole moiety may be a good group for anti-HIV-1 activity by providing promising antiviral agents. Moreover, the electronic properties of the N-aryl group influenced antiviral potency. The introduction of electron-withdrawing groups, such as fluorine or trifluoromethyl on phenyl ring (derivatives 8 and 9), enhanced antiviral activity compared to the unsubstituted phenyl derivative 7. SAR studies suggested that the steric/electronic properties of the N-phenyl substituents influenced the antiretroviral activity more than their positions. In addition, the nature of the N-aryl ring influenced the antiviral potency as can be observed for derivative 10 with a pyrimidyl ring which was the most active compound ( Figure 2 ) [47] . (7) substitution with F atoms (8, 9) Molecular modeling studies for the pyrimidyl derivative 10 showed the formation of two potential intermolecular hydrogen bonds involving a nitrogen atom and the amino group of the thiadiazole ring and aminoacids from NNBS of RT. In addition, the electron-deficient pyrimidine ring of the ligand establishes π-π interactions with the electron-rich benzene rings of RT. Despite the docking simulation results, the inhibitory activity of compound 10 against HIV-1 (strain IIIB) replication in MT-4 cell culture was lower than that of zidovudine. However, given the butterfly-like orientation as a necessary structural condition for antiretroviral activity, these results reveal the promising inhibitory potential of this scaffold [47] .

The series of 5-(pyridin-2-ylmethyl)-1,3,4-thiadiazol-2-amine derivatives 11-16 were synthesized by intramolecular cyclization of the corresponding hydrazinecarbothioamides under acidic conditions and the activity against HIV-1 was tested on MT-4 cells by MTT assay using efavirenz as a standard drug [64] . Molecular modeling studies for the pyrimidyl derivative 10 showed the formation of two potential intermolecular hydrogen bonds involving a nitrogen atom and the amino group of the thiadiazole ring and aminoacids from NNBS of RT. In addition, the electron-deficient pyrimidine ring of the ligand establishes π-π interactions with the electron-rich benzene rings of RT. Despite the docking simulation results, the inhibitory activity of compound 10 against HIV-1 (strain IIIB) replication in MT-4 cell culture was lower than that of zidovudine. However, given the butterfly-like orientation as a necessary structural condition for antiretroviral activity, these results reveal the promising inhibitory potential of this scaffold [47] .

The series of 5-(pyridin-2-ylmethyl)-1,3,4-thiadiazol-2-amine derivatives 11-16 were synthesized by intramolecular cyclization of the corresponding hydrazinecarbothioamides under acidic conditions and the activity against HIV-1 was tested on MT-4 cells by MTT assay using efavirenz as a standard drug [64] . 

Ar Except for derivative 11 which showed low activity (EC50 values of 47 μM), the activity of the other compounds was even lower (EC50 values > 70 μM) proving that substitution with halogens or halogenoalkyl groups at C3 and/or C4 of phenyl ring led to a decrease or loss of activity ( Figure 3 ). Although pyridine derivatives did not exhibit selective anti-HIV-1 activity, the fact that compound 11 showed some antiviral activity may encourage further research on this structure. Subsequent chemical modifications by substitutions on aromatic rings with different groups may lead to compounds with improved activity [64] . The invasion of the central nervous system (CNS) by the HIV-1 virus frequently causes brain inflammation and progressive neurological diseases, which are commonly referred to as HIV associated neurocognitive disorders (HAND) [71] . HAND affects 7%-15% of AIDS patients and is characterized by neuronal dysfunction including synaptic damage, neuronal degeneration and cell dropout [72] . Cells involved in HAND pathogenesis are macrophages and microglia, which are the main targets of HIV-1 infection in the brain. When infected with HIV-1, macrophages and microglia increase the production and release of several soluble neurotoxic factors, such as glutamate, inducing neuronal damage [71] .

Glutamine is the most abundant amino acid in the human body and is involved in more metabolic processes than any other amino acid. Glutamine is produced from glutamate and ammonia by the enzyme glutamine synthetase [73, 74] . The conversion of glutamine to glutamate is catalyzed by the mitochondrial enzyme, glutaminase [72, 75] . The glutamine/glutamate cycle in the human body plays several important metabolic functions. Thus, glutamine and glutamate are Except for derivative 11 which showed low activity (EC 50 values of 47 µM), the activity of the other compounds was even lower (EC 50 values > 70 µM) proving that substitution with halogens or halogenoalkyl groups at C3 and/or C4 of phenyl ring led to a decrease or loss of activity ( Figure 3 ). Although pyridine derivatives did not exhibit selective anti-HIV-1 activity, the fact that compound 11 showed some antiviral activity may encourage further research on this structure. Subsequent chemical modifications by substitutions on aromatic rings with different groups may lead to compounds with improved activity [64] . Molecular modeling studies for the pyrimidyl derivative 10 showed the formation of two potential intermolecular hydrogen bonds involving a nitrogen atom and the amino group of the thiadiazole ring and aminoacids from NNBS of RT. In addition, the electron-deficient pyrimidine ring of the ligand establishes π-π interactions with the electron-rich benzene rings of RT. Despite the docking simulation results, the inhibitory activity of compound 10 against HIV-1 (strain IIIB) replication in MT-4 cell culture was lower than that of zidovudine. However, given the butterfly-like orientation as a necessary structural condition for antiretroviral activity, these results reveal the promising inhibitory potential of this scaffold [47] .

The series of 5-(pyridin-2-ylmethyl)-1,3,4-thiadiazol-2-amine derivatives 11-16 were synthesized by intramolecular cyclization of the corresponding hydrazinecarbothioamides under acidic conditions and the activity against HIV-1 was tested on MT-4 cells by MTT assay using efavirenz as a standard drug [64] . 

Ar Except for derivative 11 which showed low activity (EC50 values of 47 μM), the activity of the other compounds was even lower (EC50 values > 70 μM) proving that substitution with halogens or halogenoalkyl groups at C3 and/or C4 of phenyl ring led to a decrease or loss of activity ( Figure 3 ). Although pyridine derivatives did not exhibit selective anti-HIV-1 activity, the fact that compound 11 showed some antiviral activity may encourage further research on this structure. Subsequent chemical modifications by substitutions on aromatic rings with different groups may lead to compounds with improved activity [64] . The invasion of the central nervous system (CNS) by the HIV-1 virus frequently causes brain inflammation and progressive neurological diseases, which are commonly referred to as HIV associated neurocognitive disorders (HAND) [71] . HAND affects 7%-15% of AIDS patients and is characterized by neuronal dysfunction including synaptic damage, neuronal degeneration and cell dropout [72] . Cells involved in HAND pathogenesis are macrophages and microglia, which are the main targets of HIV-1 infection in the brain. When infected with HIV-1, macrophages and microglia increase the production and release of several soluble neurotoxic factors, such as glutamate, inducing neuronal damage [71] .

Glutamine is the most abundant amino acid in the human body and is involved in more metabolic processes than any other amino acid. Glutamine is produced from glutamate and ammonia by the enzyme glutamine synthetase [73, 74] . The conversion of glutamine to glutamate is catalyzed by the mitochondrial enzyme, glutaminase [72, 75] . The glutamine/glutamate cycle in the human body plays several important metabolic functions. Thus, glutamine and glutamate are The invasion of the central nervous system (CNS) by the HIV-1 virus frequently causes brain inflammation and progressive neurological diseases, which are commonly referred to as HIV associated neurocognitive disorders (HAND) [71] . HAND affects 7%-15% of AIDS patients and is characterized by neuronal dysfunction including synaptic damage, neuronal degeneration and cell dropout [72] . Cells involved in HAND pathogenesis are macrophages and microglia, which are the main targets of HIV-1 infection in the brain. When infected with HIV-1, macrophages and microglia increase the production and release of several soluble neurotoxic factors, such as glutamate, inducing neuronal damage [71] .

Glutamine is the most abundant amino acid in the human body and is involved in more metabolic processes than any other amino acid. Glutamine is produced from glutamate and ammonia by the enzyme glutamine synthetase [73, 74] . The conversion of glutamine to glutamate is catalyzed by the mitochondrial enzyme, glutaminase [72, 75] . The glutamine/glutamate cycle in the human body plays several important metabolic functions. Thus, glutamine and glutamate are precursors to the biosynthesis of proteins, neurotransmitters, nucleotides, nucleic acids and other important biological molecules. The glutamine/glutamate cycle is the substrate for the synthesis of urea in the liver, genesis of ammonia in the kidneys and for hepatic and renal gluconeogenesis. The glutamine/glutamate exchange regulates the acid-base balance in kidneys, acts as an oxidative fuel for the intestines and cells of the immune system and provides the transport of nitrogen between organs [74] [75] [76] . The existence of a glutamine/glutamate cycle in CNS was confirmed in the last years [76, 77] . Phosphate-activated mitochondrial glutaminase is the predominant enzyme that uses glutamine in the brain. Glutamine is present in the extracellular fluid of the brain at high concentrations and provides an abundant substrate for glutaminase [72, 75] . Therefore, it has been hypothesized that mitochondrial glutaminase activation is responsible for the high levels of glutamate in the brains of HIV-1 infected patients [72] . While glutamate mediates different physiologic processes, elevated extracellular concentrations of glutamate can induce neuronal damage (e.g., dementia, brain atrophy) [71, 72] .

Some glutaminase inhibitors (e.g., 6-diazo-5-oxo-L-norleucine, etc.) were studied in vitro for their ability to prevent the generation of glutamate by HIV-1 infected macrophages. The results support the hypothesis that glutaminase mediates glutamate generation in HIV-infected human macrophages. When glutaminase was inhibited by various inhibitors, HIV-induced glutamate production decreased and the neuronal damage was diminished [71, 72, 78] . Furthermore, for some glutaminase inhibitors, a non-competitive mechanism of inhibition has been described [78] . These findings support glutaminase as a potential component of the HAND process and can provide a new therapeutic target for the treatment of neurocognitive disorders associated with HIV infection [71, 72, 78] . In connection with these results, a large number of glutaminase inhibitors having a bis-thiadiazole (17) and a pyridazine-thiadiazole (18) skeleton ( Figure 4) , respectively, were synthesized as a method of treating or preventing multiple viral infections, including infections with retroviruses [75] . precursors to the biosynthesis of proteins, neurotransmitters, nucleotides, nucleic acids and other important biological molecules. The glutamine/glutamate cycle is the substrate for the synthesis of urea in the liver, genesis of ammonia in the kidneys and for hepatic and renal gluconeogenesis. The glutamine/glutamate exchange regulates the acid-base balance in kidneys, acts as an oxidative fuel for the intestines and cells of the immune system and provides the transport of nitrogen between organs [74] [75] [76] . The existence of a glutamine/glutamate cycle in CNS was confirmed in the last years [76, 77] . Phosphate-activated mitochondrial glutaminase is the predominant enzyme that uses glutamine in the brain. Glutamine is present in the extracellular fluid of the brain at high concentrations and provides an abundant substrate for glutaminase [72, 75] . Therefore, it has been hypothesized that mitochondrial glutaminase activation is responsible for the high levels of glutamate in the brains of HIV-1 infected patients [72] . While glutamate mediates different physiologic processes, elevated extracellular concentrations of glutamate can induce neuronal damage (e.g., dementia, brain atrophy) [71, 72] . Some glutaminase inhibitors (e.g., 6-diazo-5-oxo-L-norleucine, etc.) were studied in vitro for their ability to prevent the generation of glutamate by HIV-1 infected macrophages. The results support the hypothesis that glutaminase mediates glutamate generation in HIV-infected human macrophages. When glutaminase was inhibited by various inhibitors, HIV-induced glutamate production decreased and the neuronal damage was diminished [71, 72, 78] . Furthermore, for some glutaminase inhibitors, a non-competitive mechanism of inhibition has been described [78] . These findings support glutaminase as a potential component of the HAND process and can provide a new therapeutic target for the treatment of neurocognitive disorders associated with HIV infection [71, 72, 78] . In connection with these results, a large number of glutaminase inhibitors having a bis-thiadiazole (17) and a pyridazine-thiadiazole (18) skeleton ( Figure 4) , respectively, were synthesized as a method of treating or preventing multiple viral infections, including infections with retroviruses [75] . Multiple experiments were performed in order to study the biological profile of the compounds. Some of the synthesized derivatives are prodrugs, which under physiologic conditions (in vivo), are converted into the therapeutically active parent compound. Studies have also been conducted to obtain pharmaceutical preparations suitable for use in human patients comprising any of the synthesized derivatives and one or more pharmaceutically acceptable excipients. In addition, the authors assume that the derivatives may be used alone or in combination with known antiviral drugs. Studies on kidney-type glutaminase inhibition showed good results for many derivatives such as compound 19 with an IC50 value of 0.24 μM and its deuterium derivative 20 with an IC50 value of 0.54 μM [75] . Multiple experiments were performed in order to study the biological profile of the compounds. Some of the synthesized derivatives are prodrugs, which under physiologic conditions (in vivo), are converted into the therapeutically active parent compound. Studies have also been conducted to obtain pharmaceutical preparations suitable for use in human patients comprising any of the synthesized derivatives and one or more pharmaceutically acceptable excipients. In addition, the authors assume that the derivatives may be used alone or in combination with known antiviral drugs. Studies on 

Human cytomegalovirus (HCMV, Herpesviridae family) is a ubiquitous deoxyribonucleic acid virus that infects people of all ages [79, 80] . HCMV infection can be acquired through horizontal and vertical transmission. HCMV spreads from infected people through direct contact with body fluids that carry the virus, such as urine, saliva, cervicovaginal secretions, sperm and breast milk. Vertical transmission through organ transplantation, from mother to child or transmission via blood transfusion, is also possible [79, 80] . Blood tests indicate that 60%-90% of the adult population experienced HCMV infection at some time during their life [81] . Although most of these infections are asymptomatic, certain patient groups such as babies that are infected before birth and children or adults with weakened immune systems due to diseases or medications (e.g., HIV-infected patients, organ transplant recipients) can develop severe illnesses that require medical treatment [79] . HCMV is able to remain latent in several cells of the human body for a long time and can be reactivated if the person develops immune system suppression [79, 82] .

The first-line drugs recommended for the treatment of HCMV infection are intravenous ganciclovir or orally administered valganciclovir [83] . Although tolerability of ganciclovir and valganciclovir is acceptable, hematological or neurological side effects can occur. Neutropenia, thrombocytopenia and anemia are the main toxic effects that limit therapy with these drugs. Serum creatinine levels may increase during ganciclovir therapy, which requires monitoring of renal function [84] . Encephalopathy is the neurotoxic effect of ganciclovir and valganciclovir [85] . Foscarnet is also a very effective anti-HCMV drug, and cidofovir is a broad-spectrum antiviral with good activity against HCMV. Both drugs cause a high level of nephrotoxicity that limits treatment [83] .

Novel 2-amino-1,3,4-thiadiazole derivatives with antiviral activity against HCMV have been patented [86] . A large number of 472 synthesized compounds were tested in an HCMV polymerase assay at a concentration of 25 μM. The degree of enzyme inhibition ranged from 20% to 100%. Among the most active compounds, four derivatives exhibited a 100% inhibition rate, 29 derivatives showed an inhibition rate of 90.1%-99.9% and 16 derivatives showed an inhibition rate of 80.3%-89.9%. Three structural series stand out among the most active 1,3,4-thiadiazole derivatives: 1,3-dioxo-1,3-dihydro-2-benzofuran-5-carboxamide derivatives such as 21-30, 9-octadecenamide derivatives such as 31-38 and 2-ethoxy-1-naphthamide derivatives such as 39-42 (Tables 2, 3 

Most of the derivatives belong to the 1,3-dioxo-1,3-dihydro-2-benzofuran-5-carboxamide series. At the same time, the most active compounds belong to this series, so it can be concluded that the 1,3-dioxo-1,3-dihydro-2-benzofuran-5-carboxamide moiety is a good scaffold for anti-HCMV activity [86] . 

Human cytomegalovirus (HCMV, Herpesviridae family) is a ubiquitous deoxyribonucleic acid virus that infects people of all ages [79, 80] . HCMV infection can be acquired through horizontal and vertical transmission. HCMV spreads from infected people through direct contact with body fluids that carry the virus, such as urine, saliva, cervicovaginal secretions, sperm and breast milk. Vertical transmission through organ transplantation, from mother to child or transmission via blood transfusion, is also possible [79, 80] . Blood tests indicate that 60%-90% of the adult population experienced HCMV infection at some time during their life [81] . Although most of these infections are asymptomatic, certain patient groups such as babies that are infected before birth and children or adults with weakened immune systems due to diseases or medications (e.g., HIV-infected patients, organ transplant recipients) can develop severe illnesses that require medical treatment [79] . HCMV is able to remain latent in several cells of the human body for a long time and can be reactivated if the person develops immune system suppression [79, 82] .

The first-line drugs recommended for the treatment of HCMV infection are intravenous ganciclovir or orally administered valganciclovir [83] . Although tolerability of ganciclovir and valganciclovir is acceptable, hematological or neurological side effects can occur. Neutropenia, thrombocytopenia and anemia are the main toxic effects that limit therapy with these drugs. Serum creatinine levels may increase during ganciclovir therapy, which requires monitoring of renal function [84] . Encephalopathy is the neurotoxic effect of ganciclovir and valganciclovir [85] . Foscarnet is also a very effective anti-HCMV drug, and cidofovir is a broad-spectrum antiviral with good activity against HCMV. Both drugs cause a high level of nephrotoxicity that limits treatment [83] .

Novel 2-amino-1,3,4-thiadiazole derivatives with antiviral activity against HCMV have been patented [86] . A large number of 472 synthesized compounds were tested in an HCMV polymerase assay at a concentration of 25 µM. The degree of enzyme inhibition ranged from 20% to 100%. Among the most active compounds, four derivatives exhibited a 100% inhibition rate, 29 derivatives showed an inhibition rate of 90.1%-99.9% and 16 derivatives showed an inhibition rate of 80.3%-89.9%. Three structural series stand out among the most active 1,3,4-thiadiazole derivatives: 1,3-dioxo-1,3-dihydro-2-benzofuran-5-carboxamide derivatives such as 21-30, 9-octadecenamide derivatives such as 31-38 and 2-ethoxy-1-naphthamide derivatives such as 39-42 (Tables 2-4 ). Most of the derivatives belong to the 1,3-dioxo-1,3-dihydro-2-benzofuran-5-carboxamide series. At the same time, the most active compounds belong to this series, so it can be concluded that the 1,3-dioxo-1,3-dihydro-2-benzofuran-5-carboxamide moiety is a good scaffold for anti-HCMV activity [86] . 

Human cytomegalovirus (HCMV, Herpesviridae family) is a ubiquitous deoxyribonucleic acid virus that infects people of all ages [79, 80] . HCMV infection can be acquired through horizontal and vertical transmission. HCMV spreads from infected people through direct contact with body fluids that carry the virus, such as urine, saliva, cervicovaginal secretions, sperm and breast milk. Vertical transmission through organ transplantation, from mother to child or transmission via blood transfusion, is also possible [79, 80] . Blood tests indicate that 60%-90% of the adult population experienced HCMV infection at some time during their life [81] . Although most of these infections are asymptomatic, certain patient groups such as babies that are infected before birth and children or adults with weakened immune systems due to diseases or medications (e.g., HIV-infected patients, organ transplant recipients) can develop severe illnesses that require medical treatment [79] . HCMV is able to remain latent in several cells of the human body for a long time and can be reactivated if the person develops immune system suppression [79, 82] .

The first-line drugs recommended for the treatment of HCMV infection are intravenous ganciclovir or orally administered valganciclovir [83] . Although tolerability of ganciclovir and valganciclovir is acceptable, hematological or neurological side effects can occur. Neutropenia, thrombocytopenia and anemia are the main toxic effects that limit therapy with these drugs. Serum creatinine levels may increase during ganciclovir therapy, which requires monitoring of renal function [84] . Encephalopathy is the neurotoxic effect of ganciclovir and valganciclovir [85] . Foscarnet is also a very effective anti-HCMV drug, and cidofovir is a broad-spectrum antiviral with good activity against HCMV. Both drugs cause a high level of nephrotoxicity that limits treatment [83] .

Novel 2-amino-1,3,4-thiadiazole derivatives with antiviral activity against HCMV have been patented [86] . A large number of 472 synthesized compounds were tested in an HCMV polymerase assay at a concentration of 25 μM. The degree of enzyme inhibition ranged from 20% to 100%. Among the most active compounds, four derivatives exhibited a 100% inhibition rate, 29 derivatives showed an inhibition rate of 90.1%-99.9% and 16 derivatives showed an inhibition rate of 80.3%-89.9%. Three structural series stand out among the most active 1,3,4-thiadiazole derivatives: 1,3-dioxo-1,3-dihydro-2-benzofuran-5-carboxamide derivatives such as 21-30, 9-octadecenamide derivatives such as 31-38 and 2-ethoxy-1-naphthamide derivatives such as 39-42 (Tables 2, 3 

Most of the derivatives belong to the 1,3-dioxo-1,3-dihydro-2-benzofuran-5-carboxamide series. At the same time, the most active compounds belong to this series, so it can be concluded that the 1,3-dioxo-1,3-dihydro-2-benzofuran-5-carboxamide moiety is a good scaffold for anti-HCMV activity [86] . 

Molecules 2020, 25, 942 9 of 22 Other compounds also showed good inhibitory activity. These derivatives contain a five-to six-membered saturated heterocyclic moiety, such as imidazolidinyl, tetrahydrofuryl, piperidinyl, morpholinyl, thiomorpholinyl or 5-to 10-membered aromatic or unsaturated heterocyclic moiety such as furyl, pyrrolyl, pyridyl, benzothiazolyl, etc. (e.g., derivatives 43,44) [86] .

Molecules 2020, 25, 942 10 of 22

Other compounds also showed good inhibitory activity. These derivatives contain a five-to six-membered saturated heterocyclic moiety, such as imidazolidinyl, tetrahydrofuryl, piperidinyl, morpholinyl, thiomorpholinyl or 5-to 10-membered aromatic or unsaturated heterocyclic moiety such as furyl, pyrrolyl, pyridyl, benzothiazolyl, etc. (e.g., derivatives 43,44) [86] . 

While the synthesized derivatives have shown inhibitory activity against HCMV polymerase, their antiviral activity cannot be limited to a specific mechanism of action. These compounds may be active against cytomegalovirus by HCMV polymerase inhibition or by other mechanisms of action. In addition, during the experiments, many of these compounds also showed activity against other herpes viruses, such as varicella-zoster virus (VZV), Epstein-Barr virus (EBV), herpes simplex virus (HSV), and human herpesvirus type 8 (HHV-8). Pharmaceutical compositions containing such compounds or their pharmaceutically acceptable salts useful as antiviral agents have also been studied. Studies have been conducted for the administration of pharmaceutical preparations by parenteral, topical, oral or rectal route, depending on the purpose of their use to treat internal or external viral infections [86] .

Acute respiratory infections are a major global health problem responsible for about 3.9 million deaths worldwide each year [87, 88] . These infections are of the top five causes of mortality worldwide and the leading cause of mortality among children under five years of age in many developing countries [87, 89] . Acute respiratory infections are most often caused by viruses. Over 200 viral serotypes are associated with human respiratory diseases [90] including Influenza A and Influenza B virus, respiratory syncytial virus (RSV), parainfluenza virus (PIV), human adenovirus (HAdV), human coronavirus (HCoV), human rhinovirus (HRV), human metapneumovirus (HMPV) and human bocavirus (HBoV). In addition, two human polyomaviruses (HPyV), KIPyV and WUPyV, have been detected in patients with respiratory infections [91] . These infections affect all age groups, but nearly all severe episodes occur in children under five years, the elderly and immunocompromised individuals (e.g., HIV-infected patients) [87, 89] . In adults, viral respiratory infections are the cause of 30%-50% of pneumonia cases, 80% of asthma complications and 20%-60% of chronic obstructive pulmonary disease exacerbations [87] . Consequently, common viral respiratory infections cause a greater economic burden than many other clinical conditions in terms of medical expenses and productivity losses [87, 92] . The World Health Organization has supported the monitoring of acute respiratory diseases worldwide since 1977 [91] .

The Influenza virus belongs to the Orthomyxoviridae family and causes respiratory infections in about 20% of the global population every year. The 1918 flu pandemic was caused by Influenza A subtype H1N1 and killed 50 million people around the world [93] . The Asian Influenza caused by Influenza A subtype H2N2 occurred in 1957 and the Hong Kong Influenza caused by Influenza A subtype H3N2 took place in 1968 and made far fewer victims than the 1918 Spanish flu. About 70 people died in Asia in 2004-2005 due to the H5N1 strain of avian flu [93] . The 2009 flu pandemic (swine flu) was the second pandemic involving a strain of Influenza A virus. It was classified as Influenza A H1N1 2009 and the genetic material originated from three different species: human, avian and swine [7, 94] . The chemotherapy or prophylaxis of Influenza infections comprises agents blocking the Influenza A virus M2 proton-selective ion channel (amantadine, rimantadine) and neuraminidase inhibitors (zanamivir, oseltamivir, laninamivir, peramivir) [1, 93] . Both classes can While the synthesized derivatives have shown inhibitory activity against HCMV polymerase, their antiviral activity cannot be limited to a specific mechanism of action. These compounds may be active against cytomegalovirus by HCMV polymerase inhibition or by other mechanisms of action. In addition, during the experiments, many of these compounds also showed activity against other herpes viruses, such as varicella-zoster virus (VZV), Epstein-Barr virus (EBV), herpes simplex virus (HSV), and human herpesvirus type 8 (HHV-8). Pharmaceutical compositions containing such compounds or their pharmaceutically acceptable salts useful as antiviral agents have also been studied. Studies have been conducted for the administration of pharmaceutical preparations by parenteral, topical, oral or rectal route, depending on the purpose of their use to treat internal or external viral infections [86] .

Acute respiratory infections are a major global health problem responsible for about 3.9 million deaths worldwide each year [87, 88] . These infections are of the top five causes of mortality worldwide and the leading cause of mortality among children under five years of age in many developing countries [87, 89] . Acute respiratory infections are most often caused by viruses. Over 200 viral serotypes are associated with human respiratory diseases [90] including Influenza A and Influenza B virus, respiratory syncytial virus (RSV), parainfluenza virus (PIV), human adenovirus (HAdV), human coronavirus (HCoV), human rhinovirus (HRV), human metapneumovirus (HMPV) and human bocavirus (HBoV). In addition, two human polyomaviruses (HPyV), KIPyV and WUPyV, have been detected in patients with respiratory infections [91] . These infections affect all age groups, but nearly all severe episodes occur in children under five years, the elderly and immunocompromised individuals (e.g., HIV-infected patients) [87, 89] . In adults, viral respiratory infections are the cause of 30%-50% of pneumonia cases, 80% of asthma complications and 20%-60% of chronic obstructive pulmonary disease exacerbations [87] . Consequently, common viral respiratory infections cause a greater economic burden than many other clinical conditions in terms of medical expenses and productivity losses [87, 92] . The World Health Organization has supported the monitoring of acute respiratory diseases worldwide since 1977 [91] .

The Influenza virus belongs to the Orthomyxoviridae family and causes respiratory infections in about 20% of the global population every year. The 1918 flu pandemic was caused by Influenza A subtype H1N1 and killed 50 million people around the world [93] . The Asian Influenza caused by Influenza A subtype H2N2 occurred in 1957 and the Hong Kong Influenza caused by Influenza A subtype H3N2 took place in 1968 and made far fewer victims than the 1918 Spanish flu. About 70 people died in Asia in 2004-2005 due to the H5N1 strain of avian flu [93] . The 2009 flu pandemic (swine flu) was the second pandemic involving a strain of Influenza A virus. It was classified as Influenza A H1N1 2009 and the genetic material originated from three different species: human, avian and swine [7, 94] .

The chemotherapy or prophylaxis of Influenza infections comprises agents blocking the Influenza A virus M2 proton-selective ion channel (amantadine, rimantadine) and neuraminidase inhibitors (zanamivir, oseltamivir, laninamivir, peramivir) [1, 93] . Both classes can induce virus resistance and therefore there is an urgent need to develop new antiviral agents with novel mechanisms of action. An alternative concept has recently emerged and it is based on the idea of designing new molecules targeting host cell factors that are hijacked by the virus during its replication. Host-targeting antivirals are an alternative strategy for addressing host structures involved in the virus life cycle. This type of inhibitors could exhibit a significantly greater barrier for selecting drug-resistant viruses and, in addition, display broad-spectrum antiviral activity when interacting with a cellular target common to several viruses. The host factor-directed antiviral therapy is recently studied. This is increasingly recognized as a relevant approach to combat viral resistance and provides broad-spectrum antiviral agents [95, 96] .

Many studies are currently being developed to find new Influenza inhibitors. Tatar et al. induce virus resistance and therefore there is an urgent need to develop new antiviral agents with novel mechanisms of action. An alternative concept has recently emerged and it is based on the idea of designing new molecules targeting host cell factors that are hijacked by the virus during its replication. Host-targeting antivirals are an alternative strategy for addressing host structures involved in the virus life cycle. This type of inhibitors could exhibit a significantly greater barrier for selecting drug-resistant viruses and, in addition, display broad-spectrum antiviral activity when interacting with a cellular target common to several viruses. The host factor-directed antiviral therapy is recently studied. This is increasingly recognized as a relevant approach to combat viral resistance and provides broad-spectrum antiviral agents [95, 96] . Many studies are currently being developed to find new Influenza inhibitors. Tatar et al. synthesized 2-phenylamino-1,3,4-thiadiazole derivatives 45-48 [49] . The antiviral activity against some respiratory viruses such as Influenza A H1N1, Influenza A H3N2, Influenza B, Parainfluenza-3, RSV, Reovirus-1and Feline Coronavirus was investigated and the results are summarized in Table 5 . No activity was observed at the highest concentration tested or at subtoxic concentration against Influenza B and RSV [49] . With an EC50 value of 31.4 μM, the derivative 45 was the most potent among the tested compounds and moderate active compared to standard drug oseltamivir, but a promising scaffold for future developments. Derivatives 47 and 48 exhibited activity against Parainfluenza-3 and Reovirus-1 and probably the thiourea moiety favors antiviral activity on these strains ( Figure 5 ) [49] .

The antiviral activity against some respiratory viruses such as Influenza A H1N1, Influenza A H3N2, Influenza B, Parainfluenza-3, RSV, Reovirus-1and Feline Coronavirus was investigated and the results are summarized in Table 5 . No activity was observed at the highest concentration tested or at subtoxic concentration against Influenza B and RSV [49] . The in vitro antiviral assay showed N-{3-(methylthio)-1-[5-(phenylamino)-1,3,4-thiadiazol-2-yl]propyl} benzamide 45 as an Influenza A H 3 N 2 virus subtype inhibitor. With an EC 50 value of 31.4 µM, the derivative 45 was the most potent among the tested compounds and moderate active compared to standard drug oseltamivir, but a promising scaffold for future developments. Derivatives 47 and 48 exhibited activity against Parainfluenza-3 and Reovirus-1 and probably the thiourea moiety favors antiviral activity on these strains ( Figure 5 ) [49] . 

Viral hepatitis is a liver inflammation responsible for about 171,000 deaths every year in the European Region. Patients may have an acute form as a recent infection, with relatively rapid onset or a chronic form. There are five main hepatitis viruses (HAV, HBV, HCV, HDV and HEV) with different ways of transmission and different impact on human health [97] . While HAV or HEV infection is usually mild, with most people recovering quickly and completely, infection with HBV, HCV or HDV often leads to chronic infections and progressive liver damage with the development of cirrhosis and liver cancer [97] . There are about 15 million people living with chronic HBV infection and about 14 million with HCV infection in the European Region [97] . Safe and effective vaccines for the prevention of HBV infection have been available since the 1990s. These vaccines also provide protection from HDV infection. Unfortunately, the HCV vaccine has not yet been developed [97, 98] . Many patients infected with HBV are adults born before the hepatitis B vaccine became available in the 1990s. In these cases, drug treatment is the only option [98] . Several nucleoside and non-nucleoside derivatives with anti-HBV (e.g., adefovir, entecavir, lamivudine, telbivudine, tenofovir) or anti-HCV activity (e.g., boceprevir, grazoprevir, elbasvir, ledipasvir, sofosbuvir, telaprevir) are in use [3, 99] and chronic infections with HBV and HCV can be currently controlled or even cured. Due to the costs of antiviral drugs for chronic hepatitis, access to treatment is a major obstacle in many countries and finding new, less expensive antiviral drugs is a necessity [97] .

1,2-Dihydro-4,6-dimethyl-2-oxo-1-[(5-(phenylamino)-1,3,4-thiadiazol-2-yl)methyl]pyridine-3-ca rbonitrile 49 was prepared from the corresponding phehylthiosemicarbazide by cyclization in sulfuric acid [6] . The derivative 49 was tested for antiviral activity against the hepatitis B virus (HBV) using HepG2.2.2.15 cell line, a human hepatoblastoma cell line that produces HBV viral particles. Cytotoxicity was also tested by the cell viability method (MTT assay). Preliminary screening indicated high inhibitory activity against HBV with an IC50 value of 0.3 μM, low cytotoxicity (CC50 value of 333.3 μM) and a selectivity index SI of 1111 compared to the standard drug lamivudine (IC50 value of 0.1μM). From these results, it can be concluded that pyridine-2-one may be a good substituent on the 1,3,4-thiadiazole ring, and these two moieties together make a promising scaffold in promoting anti-HBV activity [6] . 

Viral hepatitis is a liver inflammation responsible for about 171,000 deaths every year in the European Region. Patients may have an acute form as a recent infection, with relatively rapid onset or a chronic form. There are five main hepatitis viruses (HAV, HBV, HCV, HDV and HEV) with different ways of transmission and different impact on human health [97] . While HAV or HEV infection is usually mild, with most people recovering quickly and completely, infection with HBV, HCV or HDV often leads to chronic infections and progressive liver damage with the development of cirrhosis and liver cancer [97] . There are about 15 million people living with chronic HBV infection and about 14 million with HCV infection in the European Region [97] . Safe and effective vaccines for the prevention of HBV infection have been available since the 1990s. These vaccines also provide protection from HDV infection. Unfortunately, the HCV vaccine has not yet been developed [97, 98] . Many patients infected with HBV are adults born before the hepatitis B vaccine became available in the 1990s. In these cases, drug treatment is the only option [98] . Several nucleoside and non-nucleoside derivatives with anti-HBV (e.g., adefovir, entecavir, lamivudine, telbivudine, tenofovir) or anti-HCV activity (e.g., boceprevir, grazoprevir, elbasvir, ledipasvir, sofosbuvir, telaprevir) are in use [3, 99] and chronic infections with HBV and HCV can be currently controlled or even cured. Due to the costs of antiviral drugs for chronic hepatitis, access to treatment is a major obstacle in many countries and finding new, less expensive antiviral drugs is a necessity [97] .

1,2-Dihydro-4,6-dimethyl-2-oxo-1-[(5-(phenylamino)-1,3,4-thiadiazol-2-yl)methyl]pyridine-3carbonitrile 49 was prepared from the corresponding phehylthiosemicarbazide by cyclization in sulfuric acid [6] . The derivative 49 was tested for antiviral activity against the hepatitis B virus (HBV) using HepG2.2.2.15 cell line, a human hepatoblastoma cell line that produces HBV viral particles. Cytotoxicity was also tested by the cell viability method (MTT assay). Preliminary screening indicated high inhibitory activity against HBV with an IC 50 value of 0.3 µM, low cytotoxicity (CC 50 value of 333.3 µM) and a selectivity index SI of 1111 compared to the standard drug lamivudine (IC 50 value of 0.1µM). From these results, it can be concluded that pyridine-2-one may be a good substituent on the 1,3,4-thiadiazole ring, and these two moieties together make a promising scaffold in promoting anti-HBV activity [6] . 

Viral hepatitis is a liver inflammation responsible for about 171,000 deaths every year in the European Region. Patients may have an acute form as a recent infection, with relatively rapid onset or a chronic form. There are five main hepatitis viruses (HAV, HBV, HCV, HDV and HEV) with different ways of transmission and different impact on human health [97] . While HAV or HEV infection is usually mild, with most people recovering quickly and completely, infection with HBV, HCV or HDV often leads to chronic infections and progressive liver damage with the development of cirrhosis and liver cancer [97] . There are about 15 million people living with chronic HBV infection and about 14 million with HCV infection in the European Region [97] . Safe and effective vaccines for the prevention of HBV infection have been available since the 1990s. These vaccines also provide protection from HDV infection. Unfortunately, the HCV vaccine has not yet been developed [97, 98] . Many patients infected with HBV are adults born before the hepatitis B vaccine became available in the 1990s. In these cases, drug treatment is the only option [98] . Several nucleoside and non-nucleoside derivatives with anti-HBV (e.g., adefovir, entecavir, lamivudine, telbivudine, tenofovir) or anti-HCV activity (e.g., boceprevir, grazoprevir, elbasvir, ledipasvir, sofosbuvir, telaprevir) are in use [3, 99] and chronic infections with HBV and HCV can be currently controlled or even cured. Due to the costs of antiviral drugs for chronic hepatitis, access to treatment is a major obstacle in many countries and finding new, less expensive antiviral drugs is a necessity [97] .

1,2-Dihydro-4,6-dimethyl-2-oxo-1-[(5-(phenylamino)-1,3,4-thiadiazol-2-yl)methyl]pyridine-3-ca rbonitrile 49 was prepared from the corresponding phehylthiosemicarbazide by cyclization in sulfuric acid [6] . The derivative 49 was tested for antiviral activity against the hepatitis B virus (HBV) using HepG2.2.2.15 cell line, a human hepatoblastoma cell line that produces HBV viral particles. Cytotoxicity was also tested by the cell viability method (MTT assay). Preliminary screening indicated high inhibitory activity against HBV with an IC50 value of 0.3 μM, low cytotoxicity (CC50 value of 333.3 μM) and a selectivity index SI of 1111 compared to the standard drug lamivudine (IC50 value of 0.1μM). From these results, it can be concluded that pyridine-2-one may be a good substituent on the 1,3,4-thiadiazole ring, and these two moieties together make a promising scaffold in promoting anti-HBV activity [6] . 

Sindbis fever, a less common human viral disease, is caused by a mosquito-borne virus called Sindbis virus (Togaviridae family). Despite the wide distribution of Sindbis virus, symptomatic infections in humans have been reported in only a few limited geographical areas such as northern Europe (Finland, Sweden and Russia), South Africa, Australia and China [100] . 1,3,4-Thiadiazole derivatives 50-55 were tested for antiviral activity against several viruses [101] .

Molecules 2020, 25, 942 13 of 22

Sindbis fever, a less common human viral disease, is caused by a mosquito-borne virus called Sindbis virus (Togaviridae family). Despite the wide distribution of Sindbis virus, symptomatic infections in humans have been reported in only a few limited geographical areas such as northern Europe (Finland, Sweden and Russia), South Africa, Australia and China [100] . 1,3,4-Thiadiazole derivatives 50-55 were tested for antiviral activity against several viruses [101] . 

Sindbis fever, a less common human viral disease, is caused by a mosquito-borne virus called Sindbis virus (Togaviridae family). Despite the wide distribution of Sindbis virus, symptomatic infections in humans have been reported in only a few limited geographical areas such as northern Europe (Finland, Sweden and Russia), South Africa, Australia and China [100] . 1,3,4-Thiadiazole derivatives 50-55 were tested for antiviral activity against several viruses [101] . 2-Amino-5-(2-sulphamoylphenyl)-1,3,4-thiadiazole 56 reduced the replication of some DNA viruses such as adenovirus Ad17 and herpes simplex HSV-1 and RNA viruses such as Poliovirus 1, Echovirus 2 and Coxsackie virus B4 at concentrations ranging from 20 to 100 μg/mL [102, 103] . In vitro experiments were performed using samples of 10 6 human aneuploid HEp-2 cells that were infected with 10 infectious units per cell. Derivative 56 was highly active against all viral strains, significantly reducing viral replication at a concentration of 50 μg/mL. The best inhibition was recorded against Echovirus 2 virions that were completely inhibited at a concentration of 20 μg/mL (Table 7) . Regarding the mechanism of action, the authors assume that compound 56 may act on the viral structural proteins preventing the assembly of virus particles [102] .

Derivatives of compound 56 were prepared. Methyl derivative 57 and allyl derivative 58 reduced the replication of RNA viruses (Poliovirus 1 and Coxsackie virus B4) at concentrations of 50 and 100 μg/mL, while ethyl derivative 59 was completely inactive against all viral strains (Table 7) . These results suggest the importance of the side chain for antiviral activity (Figure 8 ) [102] . 2-Amino-5-(2-sulphamoylphenyl)-1,3,4-thiadiazole 56 reduced the replication of some DNA viruses such as adenovirus Ad17 and herpes simplex HSV-1 and RNA viruses such as Poliovirus 1, Echovirus 2 and Coxsackie virus B4 at concentrations ranging from 20 to 100 µg/mL [102, 103] . In vitro experiments were performed using samples of 10 6 human aneuploid HEp-2 cells that were infected with 10 infectious units per cell. Derivative 56 was highly active against all viral strains, significantly reducing viral replication at a concentration of 50 µg/mL. The best inhibition was recorded against Echovirus 2 virions that were completely inhibited at a concentration of 20 µg/mL (Table 7) . Regarding the mechanism of action, the authors assume that compound 56 may act on the viral structural proteins preventing the assembly of virus particles [102] .

Derivatives of compound 56 were prepared. Methyl derivative 57 and allyl derivative 58 reduced the replication of RNA viruses (Poliovirus 1 and Coxsackie virus B4) at concentrations of 50 and 100 µg/mL, while ethyl derivative 59 was completely inactive against all viral strains (Table 7) . These results suggest the importance of the side chain for antiviral activity (Figure 8 ) [102] . 2-Amino-5-(2-sulphamoylphenyl)-1,3,4-thiadiazole 56 reduced the replication of some DNA viruses such as adenovirus Ad17 and herpes simplex HSV-1 and RNA viruses such as Poliovirus 1, Echovirus 2 and Coxsackie virus B4 at concentrations ranging from 20 to 100 μg/mL [102, 103] . In vitro experiments were performed using samples of 10 6 human aneuploid HEp-2 cells that were infected with 10 infectious units per cell. Derivative 56 was highly active against all viral strains, significantly reducing viral replication at a concentration of 50 μg/mL. The best inhibition was recorded against Echovirus 2 virions that were completely inhibited at a concentration of 20 μg/mL (Table 7) . Regarding the mechanism of action, the authors assume that compound 56 may act on the viral structural proteins preventing the assembly of virus particles [102] .

Derivatives of compound 56 were prepared. Methyl derivative 57 and allyl derivative 58 reduced the replication of RNA viruses (Poliovirus 1 and Coxsackie virus B4) at concentrations of 50 and 100 μg/mL, while ethyl derivative 59 was completely inactive against all viral strains (Table 7) . These results suggest the importance of the side chain for antiviral activity (Figure 8 ) [102] . (58) loss of activity against DNA viruses beneficial for activity against RNA viruses Cui et al. synthesized several pyrrolyl-1,3,4-thiadiazoles with general formula 60 ( Figure 9 ). The compounds showed antiviral activity against some viruses of the Flaviviridae family such as West Nile virus and dengue virus [25, 104] . The use of non-nucleoside derivatives as antiviral chemotherapeutic agents has stimulated extensive research into the synthesis of compounds of this class. However, many antiviral drugs are nucleoside analogs that act by suppressing the synthesis of viral DNA or RNA which leads to inhibition of virus replication or cell division. Research has been carried out to find new nucleoside Figure 9 ). The compounds showed antiviral activity against some viruses of the Flaviviridae family such as West Nile virus and dengue virus [25, 104] . (57) or CH 2 CH=CH 2 (58) loss of activity against DNA viruses beneficial for activity against RNA viruses Cui et al. synthesized several pyrrolyl-1,3,4-thiadiazoles with general formula 60 ( Figure 9 ). The compounds showed antiviral activity against some viruses of the Flaviviridae family such as West Nile virus and dengue virus [25, 104] . The use of non-nucleoside derivatives as antiviral chemotherapeutic agents has stimulated extensive research into the synthesis of compounds of this class. However, many antiviral drugs are nucleoside analogs that act by suppressing the synthesis of viral DNA or RNA which leads to inhibition of virus replication or cell division. Research has been carried out to find new nucleoside The use of non-nucleoside derivatives as antiviral chemotherapeutic agents has stimulated extensive research into the synthesis of compounds of this class. However, many antiviral drugs are nucleoside analogs that act by suppressing the synthesis of viral DNA or RNA which leads to inhibition of virus replication or cell division. Research has been carried out to find new nucleoside antiviral agents in which the natural nucleobases have been replaced by heterocyclic rings, as can be seen in derivatives 61-64 [105] . antiviral agents in which the natural nucleobases have been replaced by heterocyclic rings, as can be seen in derivatives 61-64 [105] . 

The antiviral activity was evaluated in vitro against viral strains parasitizing Chenopodium amaranticolor. The ability of derivatives 61-64 to control the viral infection of Chenopodium amaranticolor leaves was studied at two concentrations: 1000 ppm and 100 ppm. Generally, the compounds showed good rates of viral infection control at 1000 ppm. The best results were observed for the derivatives bearing the D-xylobutyl group (compound 62-82% control and derivative 64-76% control). The substituent on the aryl ring did not significantly influence biological activity, although the compounds 61 and 62 having a methoxy group were slightly more active than derivatives 63 and 64 bearing a methyl group (Table 8, Figure 10 ). The study may be useful in obtaining new pesticides for agriculture [105] . 

The research focused on 1,3,4-thiadiazole derivatives indicates a broad spectrum of pharmacological activities associated with good physicochemical and pharmacokinetic properties. This article presents a literature review of 2-amino-1,3,4-thiadiazole derivatives that have been evaluated for antiviral activity against several viral strains. In addition to the 2-amino-1,3,4-thiadiazole moiety, antiviral activity is also dependent on the nature of the substituents, and structure-activity studies have shown the most efficient substituents for antiviral activity in each class. Based on the literature data, the 2-amino-1,3,4-thiadiazole scaffold may be considered a possible pharmacophore group that can be incorporated into the structure of known compounds to enhance antiviral activity and contributes to the search and development of new medicines as an alternative to the treatment of viral infections.

The antiviral activity was evaluated in vitro against viral strains parasitizing Chenopodium amaranticolor. The ability of derivatives 61-64 to control the viral infection of Chenopodium amaranticolor leaves was studied at two concentrations: 1000 ppm and 100 ppm. Generally, the compounds showed good rates of viral infection control at 1000 ppm. The best results were observed for the derivatives bearing the D-xylobutyl group (compound 62-82% control and derivative 64-76% control). The substituent on the aryl ring did not significantly influence biological activity, although the compounds 61 and 62 having a methoxy group were slightly more active than derivatives 63 and 64 bearing a methyl group (Table 8, Figure 10 ). The study may be useful in obtaining new pesticides for agriculture [105] . antiviral agents in which the natural nucleobases have been replaced by heterocyclic rings, as can be seen in derivatives 61-64 [105] . 

The antiviral activity was evaluated in vitro against viral strains parasitizing Chenopodium amaranticolor. The ability of derivatives 61-64 to control the viral infection of Chenopodium amaranticolor leaves was studied at two concentrations: 1000 ppm and 100 ppm. Generally, the compounds showed good rates of viral infection control at 1000 ppm. The best results were observed for the derivatives bearing the D-xylobutyl group (compound 62-82% control and derivative 64-76% control). The substituent on the aryl ring did not significantly influence biological activity, although the compounds 61 and 62 having a methoxy group were slightly more active than derivatives 63 and 64 bearing a methyl group (Table 8, Figure 10 ). The study may be useful in obtaining new pesticides for agriculture [105] . 

The research focused on 1,3,4-thiadiazole derivatives indicates a broad spectrum of pharmacological activities associated with good physicochemical and pharmacokinetic properties. This article presents a literature review of 2-amino-1,3,4-thiadiazole derivatives that have been evaluated for antiviral activity against several viral strains. In addition to the 2-amino-1,3,4-thiadiazole moiety, antiviral activity is also dependent on the nature of the substituents, and structure-activity studies have shown the most efficient substituents for antiviral activity in each class. Based on the literature data, the 2-amino-1,3,4-thiadiazole scaffold may be considered a possible pharmacophore group that can be incorporated into the structure of known compounds to enhance antiviral activity and contributes to the search and development of new medicines as an alternative to the treatment of viral infections. 

The research focused on 1,3,4-thiadiazole derivatives indicates a broad spectrum of pharmacological activities associated with good physicochemical and pharmacokinetic properties. This article presents a literature review of 2-amino-1,3,4-thiadiazole derivatives that have been evaluated for antiviral activity against several viral strains. In addition to the 2-amino-1,3,4-thiadiazole moiety, antiviral activity is also dependent on the nature of the substituents, and structure-activity studies have shown the most efficient substituents for antiviral activity in each class. Based on the literature data, the 2-amino-1,3,4-thiadiazole scaffold may be considered a possible pharmacophore group that can be incorporated into the structure of known compounds to enhance antiviral activity and contributes to the search and development of new medicines as an alternative to the treatment of viral infections.

Funding: This research received no external funding.

The author declares no conflicts of interest.

In Wilson and Gisvold's Textbook of Organic Medicinal and Pharmaceutical Chemistry

Viral information

Antiviral agents and protease inhibitors

Progress on new vaccine strategies against chronic viral infections

Human papillomavirus vaccines: WHO position paper

Anti-Hepatitis B virus activity of new 1,2,4-triazol-2-yl-and1,3,4-oxadiazol-2-yl-2-pyridinone derivatives

Fight against H1N1 Influenza A virus: recent insights towards the development of druggable compounds

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Medicinal significance of benzothiazole scaffold: An insight view

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Rapid detection of common HIV-1 drug resistance mutations by use of high-resolution melting analysis and unlabeled probes

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3-Thiadiazole thioacetanilides as a novel class of potent HIV-1 non-nucleoside reverse transcriptase inhibitors

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Glutaminase dysregulation in HIV-1-infected human microglia mediates neurotoxicity: relevant to HIV-1 associated neurocognitive disorders

Mitochondrial glutaminase enhances extracellular glutamate production in HIV-1-infected macrophages: Linkage to HIV-1 associated dementia

Role of glutamine in human carbohydrate metabolism in kidney and other tissues

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In vivo NMR studies of glutamate-GABA-glutamine cycling in rodent and human cortex: the central role of glutamine

Glutamate production by HIV-1 infected human macrophage is blocked by the inhibition of glutaminase

Serological evidence and sociodemographic risk factors of recent cytomegalovirus infection in pregnant women attending a tertiary hospital in Maiduguri, Nigeria

Acquisition of cytomegalovirus infection: An update

Viral infections. In The Merck Manual of Medical Information: Second Home Edition

Cytomegalovirus (CMV) and Congenital CMV Infection

Cytomegalovirus treatment

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A case of severe ganciclovir-induced encephalopathy

1,3,4-Thiadiazoles useful for the treatment of CMV infections

Battle against Respiratory Viruses (BRaVe) initiative. Available online

Research needs for the battle against respiratory viruses (BRAve)

The burden of acute respiratory infections in crisis-affected populations: A systematic review

Viral etiology of acute respiratory infections among children in Porto Alegre, RS

Frequency of viral etiology in symptomatic adult upper respiratory tract infections

The economic burden of non-influenza-related viral respiratory tract infections in the United States

Neuraminidase inhibitors for influenza: oseltamivir phosphate (Tamiflu) and zanamivir (Relenza)

Understanding the Influenza A H1N1 2009 pandemic

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Fact sheets on sustainable development goals: health target, Viral hepatitis

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Structure-activity relationships of new antiviral compounds

New antiviral compounds

Compounds for use as anti-viral agents

Synthesis of antiviral acyclic C-nucleosides incorporating thiazolo-1,3,4-oxa(thia)diazole or thiazolo-1,2,4-triazole structure as a nucleobase

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