key: cord-0728549-p6y4t7k5
authors: Li, Dingzhong; Hu, Jianbing; Li, Dian; Yang, Weijun; Yin, Shuang-Feng; Qiu, Renhua
title: Reviews on Biological Activity, Clinical Trial and Synthesis Progress of Small Molecules for the Treatment of COVID-19
date: 2021-01-11
journal: Top Curr Chem (Cham)
DOI: 10.1007/s41061-020-00318-2
sha: 450ebbbe48dbde28dc2b8f232bbab878dfce7701
doc_id: 728549
cord_uid: p6y4t7k5

COVID-19 has broken out rapidly in nearly all countries worldwide, and has blossomed into a pandemic. Since the beginning of the spread of COVID-19, many scientists have been cooperating to study a vast array of old drugs and new clinical trial drugs to discover potent drugs with anti-COVID-19 activity, including antiviral drugs, antimalarial drugs, immunosuppressants, Chinese medicines, M(pro) inhibitors, JAK inhibitors, etc. The most commonly used drugs are antiviral compounds, antimalarial drugs and JAK inhibitors. In this review, we summarize mainly the antimalarial drugs chloroquine and hydroxychloroquine, the antiviral drugs Favipiravir and Remdesivir, and JAK inhibitor Ruxolitinib, discussing their biological activities, clinical trials and synthesis progress.

Coronavirus disease 2019 (COVID-19) has broken out rapidly in nearly all countries worldwide, and has blossomed into a pandemic. COVID-19 infections normally manifest with symptoms of high temperature, cough, myalgia, weakness, polypnea and other symptoms [1] . In grievous cases, it can also cause acute respiratory distress syndrome (ARDS), and result in fluids around in the lungs, eliciting infectious shock. Since the beginning of the COVID-19 spread, scientists have investigated cooperatively, examining abundant old drugs and new clinical treatments, such as Chinese medicines [2] , vaccine development [3, 4] , convalescent plasma [5] [6] [7] , interferon-based therapies [8] , monoclonal antibodies [9] , cell-based therapies [10] , immunopathology therapies [11] and small molecule drugs, aiming to discover drugs with potent anti-COVID-19 activity. However, the pathway to develop a new drug or vaccine usually takes more than 1 year or even 3-5 years. Monoclonal antibodies, cell-based therapies, interferon-based therapies, and immunopathology therapies are unacceptable for their high cost. Considering cost and time constraints, small molecule drugs, including existing drugs, e.g., those used to treat influenza, HBV, HCV, HIV, antimalarial and anti-filovirus drugs, have evoked great interest among researchers as they might allow more rapid development [12] .

As traditional small molecule drugs used for treating malaria and certain autoimmune diseases, chloroquine (CLQ) and hydroxychloroquine (CLQ-OH) ( Fig. 1) were demonstrated recently to exhibit certain activity against COVID-19 both in vitro and in vivo. Preliminary clinical results showed that CLQ has potential for use in the treatment of COVID-19 patients [13] . Compared with CLQ, CLQ-OH is more effective and has better safety properties in vitro [14] . Recently, the Gautret group [15] conducted a clinical trial using CLQ-OH in combination with Azithromycin to treat patients with COVID-19; the results showed that this was effective. But, afterwards, it was reported that use of these two antimalarial drugs may be fatal in some cases [16] .

Shah et al. [17] reviewed a total of 61 antiviral drugs to screen efficient drugs against COVID-19 as shown in Tables 1, 2, 3, 4, 5, 6 and Figs. 2, 3, 4, 5, 6, 7. Some biological activities against COVID-19 are also listed based on literature reports [18] [19] [20] [21] [22] [23] [24] [25] [26] [27] [28] [29] [30] [31] [32] [33] [34] [35] [36] [37] .

Yan and Muller [37] provided a detailed analysis and described the use of the parent nucleoside of remdesivir, GS-441524 ( Fig. 8) , over remdesivir for the treatment of COVID-19, and appealed to Gilead Science to ditch GS-441524.

Riva et al. [38] identified 100 known drugs that can inhibit COVID-19 replication in mammalian cells, and found 21 compounds exhibiting effective dose response relationships with antiviral activity and confirmed their dose/activity relationships. Then, they found 13 compounds harboring EC 50 values < 500 nM in at least one cell line (Table 7) ; for structures of these compounds see Fig. 9 .

In addition to antimalarial and antiviral drugs, M pro has also attracted the interest of researchers as a drug target for COVID-19 as it can mediate virus duplication and transcription. Jin and co-workers [39] reported the mechanism of M pro inhibitor N 3 via computer-aided drug design, and confirmed the crystal structure of COVID-19 M pro and N 3 . Their results showed that N 3 had the strongest antiviral COVID-19 effects at a concentration of 10 μM, the inhibition against COVID-19 EC 50 value was 16.77 μM. They also discovered the crystal structure of the M pro -Carmofur complex, confirming that Carmofur covalently links to the Cys145 residue via the carbonyl group, while the fatty acid group married with the hydrophobic S2 subsite of M pro [40] . Su and co-workers [41] investigated the inhibition of COVID-19 M pro by natural products derived from Chinese traditional medicines. They found that baicalin and baicalein showed non-covalent, non-peptidomimetic inhibition of COVID-19 M pro , and had strong antiviral activities both in vitro and in a cell-based system. The in vitro study results and favorable safety data from clinical trials showed that baicalein has great potential to become a candidate for a much needed anti-coronaviral drug. Dai and coworkers [42] designed two M pro inhibitors 11a and 11b, which showed perfect anti-COVID-19 activity. The structure-function relationship showed that the aldehyde group of the two compounds can covalently link to the M pro Cys145 residue. Zhang and co-workers [43] reported the complex structure of COVID-19 M pro and 11r, found that 11r showed excellent inhibitory activity and potent anti-COVID-19 activity. 11r could be used as a lead compound to develop potent inhibitors of COVID-19 M pro (Fig. 10 ). Vitner et al. [44] examined a Glucosyl Ceramide synthase (GCS) inhibitor GENZ-123346 (analogue of Cerdelga) and GENZ-66761 (structure unknown) for their antiviral effects on COVID-19. Both drugs can inhibit COVID-19 virus, and could be assessed further in preclinical and clinical trials (Fig. 11) .

Cytokine storm is a driver of pathology and mortality in viral infections. In COVID-19-infected patients, cytokine storm increases the risk of death and other severe symptoms [45] . Plenty of COVID-19 patients with cytokine storm syndrome encounter a sharp respiratory function obstacle [46] . Secondary hemophagocytic lymphohistiocytosis (sHLH) is a hyper inflammatory syndrome characterized by noteworthy augmentation of cytokines, with multi-organ failure and high mortality rate [47] . COVID-19 patients with cytokine storm syndrome exhibit increased levels of several interleukins: IL-2, IL-6, IL-7, granulocyte colony-stimulating factor (G-CSF), interferon-gamma (IFN-γ) and tumor necrosis factor alpha (TNF-α). The study showed that COVID-19 patients who died have higher plasma levels of ferritin and IL-6 [48] . Four United States Food and Drug Administration (FDA)-approved Janus kinase (JAK) inhibitors have proved useful for the treatment of COVID-19 [49] : Jakafi/Ruxolitinib; Xeljanz/Tofacitinib; Olumiant/Baricitinib; and Rinvoq/Upadacitinib (Fig. 12 ). Among these four JAK inhibitors, Ruxolitinib can significantly reduce the IL-6 and TNF-α level in spleen [50] . Of all the above-mentioned drugs that have potential activity in inhibiting COVID-19, CLQ, CLQ-OH, Favipiravir, Remdesivir and Ruxolitinib attracted our interest due to extensive research on these drugs worldwide. 

Coronavirus is a positive sense, single-chain RNA virus [51] . Coronaviruses are classified as α-, β-, γ-, and δ-coronavirus. Only α-coronavirus and β-coronavirus can infect humans [52] . γ-Coronavirus and δ-coronavirus can affect humans indirectly through animals [53] . The coronavirus (severe acute respiratory syndrome coronavirus (SARS-CoV)-2) causing COVID-19 is a β-coronavirus and shares about 80% RNA sequence consistency with SARS-CoV [54] . The SARS-CoV-2 genome encodes four main non-structural proteins: helicase, M pro , RNA-dependent papainlike protease, and RNA polymerase [55] , which are absolutely necessary for the survival of SARS-CoV-2. Initial analyses found that the four main SARS-CoV-2 enzymes mentioned above are highly conserved [56] , and the spike glycoprotein is indispensable for SARS-CoV-2 invading the host cell [57] . Similar to SARS-CoV, SARS-CoV-2 encodes a large spike protein with two domains (S1 and S2); SARS-CoV-2 virus binds and enters a host cell via this spike protein [58, 59] (Fig. 13) . New research has shown that SARS-CoV-2 engages a receptor binding domain (RBD), binding to angiotensin-converting enzyme 2 (ACE2) to invade its human host cell [60] (Fig. 14) .

Nevertheless, non-conserved mutations are highly accumulated in regions S1 and S2 which interact directly with ACE2. Mercurio et al. [61] performed a comparative in silico modeling analysis, and gained new insights into the spike protein of SARS-CoV-2. SARS-CoV-2 spike protein can interact with the ACE2 receptor on human cells at the RBD. This analysis can supply an ideal pipeline to identify characterized antibodies that might target the SARS-CoV-2 spike protein RBD to prevent interacting with human ACE2. Laurini et al. [62] reported an atomistic-based, reliable in silico structure of the viral transmembrane spike (Fig. 15) , showing that residues D38, K31, E37, K353, Y41 on ACE2 and Q498, T500, R403 on the SARS-CoV-2 S-protein RBD are true hot spots to shaping and determining the stability of the relevant protein-protein interface. These results could be used in the structurebased design and development of neutralizing antibodies, vaccines, and protein-protein inhibitors against COVID-19.

Monteil et al. [63] afforded a molecular explanation for the severe lung failure and death due to COVID-19, and proved that APN01 (human recombinant soluble ACE2, also named hrsACE2) can inhibit SARS-CoV-2 infections, which can be used for treatment of COVID-19 patients.

CLQ is an old antimalarial drug used to treat malaria, amebiasis, rheumatoid, arthritis and lupus erythematosus syndrome. It inhibits the heme polymerase in malarial trophozoites via preventing heme conversion to hemozoin [64] . CLQ has strong antiviral effects on SARS-Cov infection [65] and Ebola in vitro [66] , and is also able to inhibit influenza A virus replication in vitro [67] . Moreover, CLQ also has been shown to have some level of anti-HIV [68] and anti-H5N1 [69] activity.

CLQ can increase the pH value of host cell vacuoles. In lysosomes of the host cell, CLQ can change the catalytic activity of acidic hydrolases, affecting protein degradation, endosomal macromolecule composition, and post-translational modifications in Golgi [70] . In macrophages and antigen-presenting cells, an antirheumatic response is present that interrupts the immunological process [71] . Recent literature reports [72] [73] [74] assist our understanding of the three probable mechanisms of CLQ activity (Fig. 16 ). Gao et al. [13] found an EC 50 value of 1.13 μM and a CC 50 value greater than 100 mM for CLQ anti-COVID-19. Wang et al. [33] evaluated the efficiency of CLQ and six other drugs against SARS-CoV-2 in vitro, obtaining an EC 50 value for CLQ of 1.13 μM and EC90 value of 6.90 μM in Vero E6 cells. 

Since the outbreak of COVID-19, CLQ has been used extensively to treat COVID-19 patients. Sun et al. [75] reported using CLQ phosphate at a dose of 500 mg to treat COVID-19 with a duration not exceeding 10 days in elderly patients; these authors summarized the main adverse reactions of CLQ in elderly patients: cardiac Image reproduced from Ref. [74] with permission from Elsevier arrest, effects on skeletal musculoskeletal system, nerve irritability, medicated psychosis, granulocytopenia, aplastic anemia, thrombocytopenia, irreversible visual impairment, and others. Verscheijden et al. [76] established the best-evidence pediatric CLQ (free base) doses: 35 mg/kg, children 0-1 month, 47 mg/kg; children 1-6 months, 55 mg/kg; children 6 months to 12 years; and adolescents 44 mg/kg. Gao et al. [13] revealed that CLQ used in an intervention group had potent efficacy compared with a control group. Borba et al. [77] performed a parallel phase IIb clinical trial study to evaluate the safety and efficacy of high (0.6 g) and low (0.45 g) dose CLQ. Double-blinded and randomized participants were treated in intervention and control groups; the results suggested that the high dose of CLQ is hazardous to COVID-19 patients. Huang et al. [78] undertook a multicenter prospective observational study. Patients received a CLQ dose of 500 mg once or twice daily; patients treated with non-CLQ therapy were used as historical controls. In total, 197 patients used CLQ treatment, and 176 patients were treated as the historical control group. The duration of fever was clearly shortened. No serious adverse events were found in patients treated with CLQ. Patients treated with half dose CLQ experienced a lower rate of adverse events than with full dose. This study provides evidence for the safety and efficacy of CLQ in treatment of COVID-19 patients. Smit et al. [79] introduced pharmacokinetic and safety properties of CLQ for treatment of COVID-19, revealing that, for the use of CLQ to treatment of COVID-19 infection, early achievement of high 'target' concentrations is necessary, but, due to the high loading dose of CLQ and slow elimination, it can cause severe life-threatening toxicity and increased risk of mortality. Sinkeler [80] conducted a retrospective and observational study in a total of 397 patients aged over 18 years, found the CLQ gradually increased the QTc interval during treatment, which may result in ventricular tachycardia in patients. Sinkeler [80] suggested to measure the QTc interval before adjusting the dose of CLQ or withdrawing this potentially beneficial medication. While the pathogenesis of COVID-19 is still unknown, and because it does not show any anti SARS-Cov effect in an in vivo model, CLQ could be useless in treatment of COVID-19 patients and might even be harmful [81] ; hence, before the pathogenesis of COVID-19 is known and the effect of CLQ is evaluated in clinical trials, it should be used cautiously.

Surrey and Hammer [82] reported the first synthesis of CLQ (Scheme 1).

Ethyl ethoxalylacetate reacting with m-chloroaniline (I) in the presence of HOAc under mild condition obtained II, then ring-closure at high temperature in a short time yields III and its isomer IIIa; III and IIIa were refluxed in strong base solution to obtain a mixture of IV and IVa, with a final coupling of IV and V at high temperature obtaining CLQ. This synthetic route was unacceptable due to steps (ii) and (iii) producing nearly half of an isomer byproduct and steps (ii) and (iv) proceeding at high temperature.

Jonnson and Buell [83] reported a second generation synthesis of CLQ (Scheme 2).

Methyl acrylate and m-chloroaniline (I) were refluxed in HOAc to obtain II, then II was protected by TsCl and ring-closure obtained IV. Finally, IV and V were Scheme 2 Compound II should be added an C-Cl at meta position refluxed in the presence of phenol to obtain CLQ. The total yield of this procedure is about 24.7%, which is higher than the first generation process, but, in step d, the reaction temperature is as high as more than 150 °C, at which temperature byproducts are easily produced, and the solvent phenol is harder to recover.

Margolis et al. [84] reported a third generation synthesis of CLQ (Scheme 3). I and II were refluxed without solvent and ring-closure obtained IV, then chlorination in the presence of POCl 3 obtained V. Finally, V and VI coupling via Suzuki coupling obtained CLQ. The totally yield of this procedure is approximately 58% in mild conditions, which is suitable for large-scale production.

CLQ-OH is similar to CLQ, and. as an old antimalarial drug, also has potential effects on COVID-19 and lower toxicity than CLQ [85] . Moreover, it showed better anti-SARS-CoV-2 efficiency compared to CLQ in vitro [86] . Yao et al. [14] used physiologically-based pharmacokinetic models (PBPK) models to ensure the most efficacious concentrations of CLQ-OH and its safety profile, and found its EC 50 value to be 0.72 μM in vitro. Fantini et al. [74] used an assembly of structure-molecular modeling methods and found that CLQ-OH can prevent binding of the SARS-CoV-2 spike to gangliosides, which is helpful in understanding the mechanism of CLQ-OH as an anti-COVID-19 drug (Figs. 17, 18) .

Zhang et al. [87] systematically evaluated the treatment of COVID-19 with CLQ and CLQ-OH for efficacy and safety, and asserted a potential mechanism involving COVID-19-induced injury of multiple organs as well as the pharmacological effects of CLQ-OH on COVID-19 (Fig. 19) ; the authors concluded that COVID-19 is actually a multisystem disease, with respiratory symptoms as the major clinical manifestation. Therefore, the treatment of COVID-19 with CLQ and CLQ-OH should be evaluated systematically, and patients should be monitored carefully for cardiovascular conditions to prevent lethal adverse events. 

Based on clinical studies [88] , CLQ-OH is considered to be safer than CLQ. Gautret et al. [89] conducted a phase III clinical trial treating 80 mildly infected inpatients with CLQ-OH in combination with Azithromycin, demonstrating its therapeutic effect. Furthermore, the cost of this treatment is negligible. The suggested dose of CLQ-OH is 400 mg daily on the 1st day, then 200 mg daily for the next 3 days [90] . A total of 62 COVID-19 patients were assigned stochastically to the CLQ-OH (0.4 g daily, 0.2 g bid) and the control groups. After 5 days of treatment, patients in the CLQ-OH groups were clearly recovering in a shorter time [91] . To evaluate toxicity in patients who received high doses of CLQ-OH, a total of 63 patients were included [92] , 58 females and 5 males. The mean dosage of CLQ-OH was 3.9 mg/kg, but 14 patient had doses higher than 5 mg/kg. A total of 36 patients were treated with CLQ-OH for more than 5 days. 

Alexander et al. [98] first reported the synthesis of CLQ-OH (Scheme 4). I and II were refluxed in xylene to get III, then ammoniation and hydrogenation by Raney Nickel in high pressure obtained IV; finally, IV and V refluxed in phenol CLQ-OH. The overall yield of this procedure is as low as 17.6%, in step (b) intermediate (III) ammoniation and reduction by Raney Nickel requires high pressure, and in step (c) the solvent phenol is hard to recover. Hence, this method is unacceptable for large-scale production.

Ashok et al. [99] reported another synthetic route for the preparation of CLQ-OH (Scheme 5). Compound I was protected by ethylene glycol then reacted with III in refluxing toluene obtained IV, IV via deprotection, ammoniation and hydrogenation with Raney Nickel in high pressure to get VI, VI reacted with VII obtained CLQ-OH; finally, treatment of CLQ-OH with sulfuric acid yields CLQ-OH sulfate. The overall yield of this procedure is about approximately 40% via 

Method for preparation of CLQ-OH by Ashok et al. [99] six steps, but in step (d), the Raney Nickel reduction of intermediate (IV) requires high pressure, which is a potential safety hazard.

In 2010, Min et al. [100] reported a method for preparation of CLQ-OH (Scheme 6). I and II reacted in nitrogen conditions at high pressure obtained CLQ-OH with a yield of 78%; treatment sulfuric acid obtained CLQ-OH sulfate. This procedure led to CLQ-OH sulfate via two steps with an approximate total yield of 77%, but in step (a) the reaction proceeded in high pressure, which has safety implications.

Yu et al. [101] and Frank et al. [102] used continuous-flow method for highyield preparation of CLQ-OH (Scheme 7), which is not suitable for large-scale production. Iodization of I with hydroiodic acid and reaction with III in the presence of K 2 CO 3 yielded IV, then oxime was obtained with hydroxylamine, and hydrogenation using Raney Nickel in high pressure obtained VI; finally, VI and VII reacted at high temperature in base conditions yielded CLQ-OH. This procedure yielded CLQ-OH in mild conditions, but the final step using ethanol as a solvent at high temperature is unacceptable, as ethanol volatilizes easily. 

Favipiravir (T-705) has been developed by Toyama Chemical Co., Ltd (Tokyo, Japan) as a broad spectrum antiviral drug against RNA viruses [103] . It shows good efficacy in the treatment of influenza infections [104] and pathogenic avian influenza A (H5N1). Favipiravir was also used as a potential drug for Ebola virus [105] and severe influenza [106] , with EC 50 values of 0.014-0.55 μg/mL to seasonal influenza and oseltamivir-resistant virus [107] . Favipiravir has an antiviral effect on SARS-CoV-2 by inducing a reduction in virus-induced cytopathic effect [108] .

Observations show that Favipiravir induced the mutagenic effect responsible for the inhibition of replication; it was shown to act through lethal mutagenesis for several viruses, predominantly by competing with guanosine to cause transition mutations.

Favipiravir is a virus RdRp inhibitor. EC 90 values for H5N1 resistance are in the 1.3-7.7 µM range [109] . Research in a P388D1 cell-based system [110] showed that Favipiravir can clearly inhibit the generation of TNF-α. Shirak et al. [111] established an influenza infection animal model to study the activity of Favipiravir, and proved that Favipiravir was significantly effective in alleviating influenza infection in mice. Janowski et al. [112] demonstrated that Favipiravir has EC 50 values of 246 ± 76 µM (VA1), > 1000 µM (HAstV4) and 4.73 µM (IAV).

Survival and virological characteristics were observed [113] . Randomized, multicenter phase II [114] and phase III [115] trials demonstrated clinical efficacy and safety of Favipiravir in Influenza. Lou [116] assessed the antiviral activity of Favipiravir and Baloxavir against COVID-19. Patients were randomized and assigned into three groups: Baloxavir group: dose 80 mg daily orally on Day 1 and Day 4, for patients still positive in virological test, given again on Day 7; Favipiravir group: The first dose 1.600 g or 2.2 g, followed by dose 0.6 g, 3 times daily; Control group: Continue existing antiviral treatment. The results showed that Favipiravir did not have any dramatic efficiency against COVID-19 even at high concentration. Cai et al. [117] conducted an Open-Label Controlled trial to test the efficacy of Favipiravir compared to Lopinavir (LPV)/Ritonavir (RTV) as anti-COVID-19 agents. Patients were randomly allocated to Favipiravir group (dose 1.6 g twice a day for the 1st day; dose 0.6 g twice a day for 2-14 days) and LPV/RTV group (dose 0.4 g/0.1 g twice a day); the results showed that the Favipiravir group patients exhibited higher efficacy than the LPV/RTV group.

Takamatsu and Yonezawa [118] disclosed a method for producing Favipiravir and its intermediates in high yields (Scheme 8). Hydroxylation of I at room temperature in the presence of KOAc gives II. II reacted with III in the presence of ammonium hydroxide to give IV in 83.2% yield. Finally, cyan oxidation of IV by hydrogen peroxide in strong base solution gives Favipiravir in total yield of 74%. This procedure obtained Favipiravir via three steps under mild conditions. The process has the advantages of easy post-processing, low toxicity, and high yield for high purity of Favipiravir, and is suitable for large-scale production. Hara et al. [119] reported a method for producing Favipiravir via six steps (Scheme 9), witha total yield of 53% under mild conditions. Compound I reacted with glyoxal in the presence of NaOH solution at lower temperature to obtain II, bromination, chlorination and dehydration obtained IV, fluoro-substitution in the presence of KF and tetra-n-butylammonium bromide (TBAB) gives V, hydrolyzation of 2-fluoro group of V in sulfuric acid and 3-cyan group of VI in NaOH solution obtained Favipiravir. Liu et al. [120] reported a method for preparation of Favipiravir (Scheme 10) via 8 steps with a total yield of 24%. Esterification of I gave II, bromination by NBS obtained III, diazotization of III and hydrolyzation in the presence of ammonium hydroxide gave IV, ester group amidation obtained V, chlorination and dehydration obtained VI, fluoro-substitution chloro group of V in the presence of KF and TBAB got VII, hydrolyzation 3-cyan group of VII in the presence of hydrogen peroxide and 2-fluro group of VIII in weak base solution obtained Favipiravir. This procedure needs long steps and the diazotization reaction in step (c) has potential safety issues.

Li et al. [121] reported a method for preparation of Favipiravir (Scheme 11) via 4 steps with a total yield of less than 10%. Oxidation of I using hydrogen peroxide in the presence of HOAc gives II. Chlorination and dehydration of II obtained III, and then fluoro-substitution in presence of KF and TBAB gives 

Remdesivir (Fig. 20) also named GS-5734, is a broad-spectrum antiviral RdRp inhibitor against MERS, Ebola, SARS and the like. Research showed an EC 50 value of 0.77 μM in Vero E6 cells inhibiting COVID-19 [122] . Holshue [123] reported the first case of a US COVID-19 patient. After the COVID-19 spread worldwide in March, phase III clinical trials were launched in the US and other countries extensively. On 2 May, the FDA issued Remdesivir emergency use for COVID-19 treatment.

The HCV genome encodes two proteins, NS2 and NS5, that are important targets for drug design [124, 125] . The discovery of small molecules inhibiting virus replication has attracted more attention [25] . Abundant direct-acting antiviral (DAA) small molecules have been designed and tested in clinical trials over the last few decades. A number of DAAs have been proven to have anti-HCV activity. Nucleoside inhibitors (NIs) are the most outstanding due to their prominent therapeutic effect [126] . Most NIs used clinically are N-nucleosides, which have a 2′-C-Me in the sugar branch. The first 2′-C-Me branched N-nucleosides prepared in 1960s were used to treat HCV infection; their in vitro activity against HCV was test in the 2000s [127] . N-Nucleosides firstly metabolize into nucleoside triphosphates in cells, then link with the NS5B polymerase and insert into the viral RNA, inhibiting viral RNA extension and virus replication [128] . In 2012, Cho et al. [129] synthesized a few 2′-C-Me C-nucleosides targeting NS5B, and screened compound (1) as a HCV inhibitor (Fig. 21) . On the basis of compound (1), abundant analogues of compound (1) were synthesized to improve selectivity (Table 8 ) [130] .

Among these analogues of compound (1), it was found that compound (2) has perfect activity in the NS5B enzyme assay. Then compound (2) should be used as a lead nucleoside for further optimization (Table 9 ).

In 2013, Cho et al. [131] prepared the first HCV inhibitor C-nucleoside GS-6620 (Fig. 22) with high efficiency in phase I clinical trials.

In 2017, based on GS-6620, Siegel et al. [132] discovered and synthesized Remdesivir, and found it had good activity against Ebola virus. 

Remdesivir is RdRp inhibitor, suppressing virus genome replication [51] . RdRp controls the replication of virus RNA. Once Remdesivir metabolizes into the corresponding NTP, the latter competes with ATP for incorporation into the nascent RNA strand [133] , leading to termination of virus RNA synthesis and prevention of the growth of RNA. Even though the virus can probe and delete C-nucleosides, resulting in tolerance, Remdesivir appears to be able to overcome this problem and maintain efficiency [134] . Yin et al. [135] reported the complex structure of Remdesivir and SARS-CoV-2 RdRp, where Remdesivir was covalently inserted into RdRp. This complex structure supplies a mechanism whereby Remdesivir inhibits SARS-CoV-2 replication, providing a platform for development of new drugs against COVID-19 (Fig. 23 ). Remdesivir has EC 50 values about 0.07 μM for either SARS-CoV or MERS-CoV [136, 137] . Emmiede et al. [138] tested the efficiency of Remdesivir against MERS-CoV virus. The result showed that Remdesivir can clearly inhibit virus replication. Wang et al. [33] first examined the effect of Remdesivir against COVID-19 in Vero E6 cells and found an EC 50 value 0.77 μM for Remdesivir inhibiting COVID-19. Elfiky et al. [139] targeted a few anti-polymerase drugs targeting RdRp, and found Remdesivir, Sofosbuvir, Galidesivir and Tenofovir as potent drugs against COVID-19. Choy et al. [140] reported the efficiency of Remdesivir and three other drugs against COVID-19 in Vero E6 cells, with EC 50 values of 23.15 µM (Remdesivir), 26.63 µM (Lopinavir), 2.55 µM (Homorringtonine) and 0.46 µM (Emetine), respectively. Zhang et al. [141] found that the 1′-cyano group of Remdesivir has dual roles in inhibition of nucleotide addition and proofreading. Pruijssers et al. [142] reported that Remdesivir potently inhibits SARS-CoV-2 replication in human lung cells and primary human airway epithelial cultures (EC 50 = 0.01 µM), in Vero E6 cells (EC 50 = 1.65 µM), respectively. Wu et al. [143] found that Remdesivir and GS-441524 can inhibit cell proliferation and the expression of fibrotic markers (fibronectin, pSmad3, and aSMA) in NRK-49F and HK2 cells. Brandi et al. [144] used rhesus macaque model of COVID-19, and showed that Remdesivir can be used in transient lower respiratory tract disease. The complex structure of Remdesivir and SARS-CoV-2 RNA bound to RdRp complex. Image reproduced from Ref. [135] with permission from Wiley-VCH

The first case of a COVID-19 patient inthe US appeared in January 2020 [90] ; his condition improved after 8 days' Remdesivir treatment, and no obvious adverse effect was observed during the treatment. Stephanie et al. [145] 

The first generation [154] for the synthesis of Remdesivir was as follows (Scheme 12). Coupling I and II in the presence of n-BuLi, and chlorotrimethylsilane (TMSCl) or 1,2-bis(chlorodimethylsilyl)ethane, NaH, and n-BuLi at ultralow temperature gave III, cyanation of III by TMSCN in the presence of Lewis acid BF 3 -Et 2 O at ultralow temperature obtained IV, benzyl deprotection using BCl 3 gave V, V was reacted with VIII in the presence of NMI and OP(OMe) 3 to give VI, with Remdesivir finally achieved by chiral HPLC. In the first generation for synthesizing of Remdesivir, Remdesivir was obtained in total yield of less than 2%. The first four steps were conducted at −78 ℃ and the β-anomer VII was separated by chromatography [155] , which hindered this synthetic route from large-scale development.

Second generation [138] Remdesivir was synthesized diastereoselectively via 7 steps in total 4% yield which is still unacceptable but suitable for large-scale production (Scheme 13). Compound I reacted with II in the presence of TMSCl and Grignard reagent at low temperature yielded III, then cyanation of III using TMSCN and TMSOTf in the presence of TfOH at ultralow temperature obtained IV, benzyl deprotection using BCl 3 gave V, using 2,2-dimethoxypropane selectively protected two hydroxy of V to obtain VI, and then VI and X were reacted in the presence of DIPEA followed by deprotection to give Remdesivir.

Vieira et al. [156] described a route to synthesize a key Remdesivir intermediate (IV) by using a continuous flow chemistry method, providing improved control over the reaction conditions and increasing the diastereoselectivity (Scheme 14). Coupling of I and II in the presence of TMSCl and Grignard reagent catalyzed by NdCl 3 at low temperature obtained III in yields of 69%, and cyanation of III using TMSCN in the presence of TMSOTf and TfOH at lower temperatures obtained intermediate IV in yields of 78%. This synthetic route obtained the key intermediate IV in total yield 54% in two steps. But this process requires continuous flow conditions which is unacceptable in industrial production.

Xue et al. [157] disclosed an improved methodology for the key C-glycosylation step for synthssis of Remdesivir using i-Pr 2 NH as a cost-effective additive in yield 75% (Scheme 15). The reaction was conducted in the presence of i-Pr 2 NH, and n-BuLi at ultralow temperature within 2 h using III as a protecting amino group of I. This procedure is unacceptable in large-scale production due to the ultralow temperature conditions. Wang et al. [158] reported a gram-scale catalytic asymmetric synthesis of a key step of Remdisivir in high chiral purity and yield (Scheme 16). Compound I was reacted with II in the presence of 2,6-lutidine, and 4 Å MS catalyzed by chiral catalyst A at lower temperature gave III in 89% yield with chiral purity higher than 99%. III was then deprotected by 37% HCl to obtain Remdesivir at a yield of 73%. In this procedure, Remdesivir was synthesized asymmetrically in short steps in high yield under mild conditions at gram-scale, and is thus suitable for large-scale production.

Ruxolitinib is an FDA-approved targeting JAK1 and JAK2 inhibitor. It prevents the tyrosine phosphorylation of STAT1/3/5, which are downstream of cytokine receptors and drive T-ALL proliferation. Walker et al. [159] proved that Ruxolitinib and venetoclax worked synergistically to treat T-ALL in vitro, but were not effective in vivo. CXCR4-CXCL12 was implicated as the potential pathway that drives T-ALL infiltration into the central nervous system (CNS). By deleting the CXCR4 gene from T-ALL, they found prolonged survival in vivo with decreased neurologic clinical scores. Thus, T-ALL CNS infiltration should be blocked via CXCR4 inhibition. Ruxolitinib may be able to inhibit CXCR4 [160] (Fig. 24) .

The 7H-pyrrolo [2, 3] pyrimidine core of Ruxolitinib links to the hinge area of Cxc Chemokin Receptor 4 (CXCR4) by hydrogen bond, the nitrile function of Ruxolitinib binds to Ser936 by hydrogen bond, the pyrazole ring linking the side chain with the hinge binding adenine mimic acts as a structural template. Since it is not involved in direct interactions with the enzyme, bioisosteric replacement with a triazole ring is a promising strategy to increase synthetic accessibility.

In in vitro experiments, Ruxolitinib was diluted into 50 μM in DMSO. In in vivo studies, Ruxolitinib dissolved in DMSO was added to 5% DMA in H 2 O. To survey the relevance of the JAK/STAT and BCL2 pathways on T-ALL proliferation and cell survival, Jurkat (mature T-ALL) and Loucy (early precursor T-ALL with high BCL2 expression) were assessed following treatment with Ruxolitinib. These cell lines were treated with different doses of Ruxolitinib over 72 h and assessed using a trypan blue exclusion assay and MTT (3-(4, 5-dimethylthiazolyl-2)-2,5diphenyltetrazolium bromide) proliferation assay. Ruxolitinib decreased the survival and proliferation of both Jurkat and Loucy cell lines after 24, 48, and 72 h of treatment in 2.5 μM. Ruxolitinib failed to treat T-ALL in vivo because of leukemia CNS infiltration. In 2011, the FDA and European Food and Drug Administration (EFDA) approved Ruxolitinib first in class in treatment of myelofibrosis [161] . Tuttle et al. [162] used two mouse models to prove that interferon receptor genes are overexpressed in mice, and that JAK1 inhibitors can clearly restrain cytokine storm. Increased evidence proves that mortality with COVID-19 infections is caused mainly by the overexpression of a immune response to SARS-CoV-2, resulting in a cytokine storm and ARDS [163] . Many cytokines and chemokines involved in the cytokine storm employ JAKs for signal transduction. Cytokine analysis of COVID-19 patients shows that C-reactive protein (CRP) and interleukin (IL)-6 levels are significantly higher in patients who eventually died compared to those who survived [50] . Similar to some other mortal lung infections, the overexpression of immune response to the COVID-19 virus causes a cytokine storm, along with infiltration and activation of diverse immune cells, then generation secondary cell factors and chemotactic factors [164] . In this study, patients admitted to intensive care units (ICUs) showed significantly higher levels of IL-2, IL-10, IL-7, IP-10, MCP-1, MIP-1α, G-CSF, and TNF-α relative to non-ICU patients. All in all, these discoveries support the combination of antiviral treatment and targeted immunosuppression as a therapeutic program in COVID-19 [165] .

Several clinical trials have evaluated the safety and efficacy of Ruxolitinib of IL-6 and JAK/STAT signaling. Jung et al. [50] conducted a phase II clinical trial to (1) [166] . Cao et al. [167] carried out a phaseII clinical trial to treat severe COVID-19 patients using Ruxolitinib. A total of 20 patients were distributed to the Ruxolitinib and standard of care (SoC) group, 21 patients were distributed to placebo group (SoC treatment) randomly. The results showed that the patients in Ruxolitinib and SoC group recovered faster than the placebo group. Most importantly, there were no deaths in the Ruxolitinib and SoC group.

Rodgers et al. [168] synthesized racemic Ruxolitinib via three steps with a total yield of 48% (Scheme 17). Condensation of I with malonic acid in strong organic base condition obtained III, then III reacted with IV in the presence of 1,8-Diazabicyclo [5.4 .0]undec-7-ene (DBU) gave V; finally, V was deprotected by TFA to racemate Ruxolitinib with a total yield of 48%.

Haydl et al. [169] reported Rhodium-catalyzed asymmetric coupling of (I) with pyrazole derivatives (II) giving enantioenriched allylic pyrazoles, which can be used to synthesize the targeted drug Ruxolitinib (Scheme 18). They developed a Rhodium-catalyzed, enantioselective synthesis of (R)-Ruxolitinib in the presence of chiral ligand using cheap material I, II and V in high chiral purity and yield. Above all, there were only three reaction steps.

Deepshikha et al. [170] provided a method for preparation of Ruxolitinib and its phosphate giving a chiral purity of 99.96% but with a total yield as low as 5%, which is unacceptable (Scheme 19). In this synthetic route, I was protected by 2-(trimethylsilyl)ethoxymethyl chloride, then direct Suzuki coupling with III gave compound IV with a yield of 80.8% in two steps. IV reacted with V in base condition, Reagents and conditions: a) THF, t-BuOK, 0 o C, 64 h, yield 89%; b) CH3CN, DBU, rt, overnight, yield 93%; c) DCM, TFA, rt, 6 h, yield 58%.

Preparation of racemic Ruxolitinib by Rodgers et al. [168] deprotection with Lewis acid BF 3 -Et 2 O and treated with (+)-2,3-dibenzoyl-d-tartaric acid to obtain X with a yield as low as 7% in three steps. Finally, compound IV was chirally resolved and treated with phosphoric acid to give Ruxolitinib phosphate with yield 88% in two steps.

Zhang et al. [171] reported two methods for preparation of Ruxolitinib, which have characteristics such as high stereoselectivity, mild reaction conditions and convenient post treatment, avoiding use expensive asymmetric catalysts and suitable for industrial production (Schemes 20, 21). As shown in Scheme 20, condensation of I with malonic acid in weak organic base condition gave II, which directed ringclosure with hydrazine hydrate in quantitative yield to III. Chiral resolution of III by using d-tartaric acid then gave V. Methylation of VI using methylmagnesium bromide gave VII, then VIII was obtained via Vilsmeier-Haack reaction. VIII and IV or V refluxed in base or acid conditions obtained X, then acyl chlorination using oxalyl chloride and amidation obtained XII. Finally, dehydration of XII obtained Ruxolitinib.

As shown in Scheme 21, compound I was protected by 2-(trimethylsilyl)ethoxymethyl chloride to II. Methylation of II using methylmagnesium bromide gave III, then IV was obtained via Vilsmeier-Haack reaction. V and IV or V were refluxed in ethanol to obtain VI, and then amidation and dehydration gave VII. Finally, deprotection of VII obtained Ruxolitinib.

After the spread of COVID-19 worldwide, tens of thousands medical scientists and pharmacologists have made great efforts to search for potent drugs that can inhibit COVID-19, and they successfully found a few drugs like CLQ, CLQ-OH, Favipiravir and Remdesivir that are useful in the treatment of COVID-19 patients. But, in clinical trials to date, CLQ and CLQ-OH may increase mortality due to their 

Gram-scale synthesis of (R)-Ruxolitinib by Haydl et al. [169] high doses (CLQ 500 mg dose, twice daily; CLQ-OH 400-600 mg dose). Favipiravir has high efficiency in treating Chinese patients, but it also needed a high dose (600 mg dose, 2-3 times daily); especially, there is a lack of clinical data to prove its efficacy and safety outside of China. Gilead Sciences conducted clinical trials with Remdesivir after the spread of COVID-19 worldwide, and the FDA authorized Remdesivir for compassionate use in treating COVID-19 patients in May 2020. To date, COVID-19 patients who die with cytokine storm syndrome have higher levels of IL-6 in plasma; four JAK inhibitors, Ruxolitinib, Tofacitinib, Baricitinib and Upadacitinib, have proved useful in the treatment of COVID-19 patients. Most importantly, there were no deaths using Ruxolitinib to treat COVID-19 patients in a phase II clinical trial. 

Preparation of Ruxolitinib and its phosphate by Deepshikha et al. [170] As far as we know, there is no specific medicine for treatment of COVID-19 patients, but COVID-19 is still spreading rapidly worldwide. Combinations of antivirial drugs such as Remdesivir or GS-441524 and JAK inhibitor drugs may be a useful therapentic schedule to reduce mortality before a specific medicine appears.

In this review, we introduced lots of small molecules that exhibit potent activity in inhibiting COVID-19, especially CLQ, CLQ-OH, Favipiravir, Remdesivir and Ruxolitinib, presenting their biological activities, clinical trials and synthesis processes, which may help researchers to systematically understand the processes of these potential drugs. 

The epidemiology and pathogenesis of coronavirus disease (COVID-19) outbreak

The important role of polysaccharides from a traditional Chinese medicine-lung cleansing and detoxifying decoction against the COVID-19 pandemic. Carbohyd Polym

Vaccines for SARS-CoV-2: lessons from other coronavirus strains

COVID-19, an emerging coronavirus infection: advances and prospects in designing and developing vaccines, Reaction conditions: a) DMF, NaH, 2-(trimethylsilyl)ethoxymethyl chloride -10 to -20 o C, 2 h, yield 97.2%; b) Pd(bppf)2Cl2, THF, 3M methylmagnesium bromide, 60-65 o C, 2 h; c) DMF, POCl3, 80 o C, 3 h, b and c total yield 41.9%; d) EtOH, reflux 9 h, yield 79.6%; e) DMF, DCM, oxalyl chloride, 20-30 o C, 3 h, then aqueous ammonia, rt, yield 97.5%; f) DCM, NMP, phosphorus oxychloride, lower than 30 o C, 3 h

Scheme 21 Preparation of Ruxolitinib by Zhang et al. [171] synthetic route 2 immunotherapeutics, and therapeutics. Hum Vacc Immunother

Effectiveness of convalescent plasma therapy in severe COVID-19 patients

Challenges of convalescent plasma therapy on COVID-19

Convalescent plasma as a potential therapy for COVID-19

Research and development on therapeutic agents and vaccines for COVID-19 and related human coronavirus diseases

The potential for antibody-dependent enhancement of SARS-CoV-2 infection: translational implications for vaccine development

The clinical course and its correlated immune status in COVID-19 pneumonia

COVID-19: immunopathology and its implications for therapy

Ongoing clinical trials for the management of the COVID-19 pandemic

Breakthrough: chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies

In vitro antiviral activity and projection of optimized dosing design of hydroxychloroquine for the treatment of severe acute respiratory syndrome main point: hydroxychloroquine was found to be more potent than chloroquine at inhibiting SARS-CoV-2 in vitro

Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial

Toxicokinetics of hydroxychloroquine following a massive overdose

silico studies on therapeutic agents for COVID-19: drug repurposing approach. Life Sci

Broad-spectrum inhibition of coronavirus main and papain-like proteases by HCV drugs. Res Square

Evaluation of 19 antiviral drugs against SARS-CoV-2 infection

The in vitro antiviral activity of the anti-hepatitis C virus (HCV) drugs daclatasvir and sofosbuvir against SARS-CoV-2

In silico structure modelling of SARS-CoV-2 Nsp13 helicase and Nsp14 and repurposing of FDA approved antiviral drugs as dual inhibitors

Simeprevir potently suppresses SARS-CoV-2 replication and synergizes with remdesivir

A Nanoluciferase SARS-CoV-2 for rapid neutralization testing and screening of anti-infective drugs for COVID-19

Efficient culture of SARS-CoV-2 in human hepatoma cells enhances viability of the virus in human lung cancer cell lines permitting the screening of antiviral compounds

Nelfinavir inhibits replication of severe acute respiratory syndrome coronavirus 2 in vitro

Prediction of potential commercially inhibitors against SARS-CoV-2 by multi-task deep model

Lack of antiviral activity of darunavir against SARS-CoV-2

Maraviroc inhibits SARS-CoV-2 multiplication and S-protein mediated cell fusion in cell culture

COVID-19 therapy: what weapons do we bring into battle

Déjà Vu: stimulating open drug discovery for SARS-CoV-2

Search for SARS-CoV-2 inhibitors in currently approved drugs to tackle COVID-19 pandemia

The significance of natural product derivatives and traditional medicine for COVID-19

Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro

Mechanism of baricitinib supports artificial intelligence-predicted testing in COVID-19 patients

Camostat mesylate inhibits SARS-CoV-2 activation by TMPRSS2-related proteases and its metabolite GBPA exerts antiviral activity

Fight against novel coronavirus: a perspective of medicinal chemists

Advantages of the parent nucleoside GS-441524 over remdesivir for Covid-19 treatment

Discovery of SARS-CoV-2 antiviral drugs through large-scale compound repurposing

Structure of M pro from COVID-19 virus and discovery of its inhibitors

Structural basis for the inhibition of SARS-CoV-2 main protease by antineoplastic drug carmofur

Discovery of baicalin and baicalein as novel, natural product inhibitors of SARS-CoV-2 3CL protease in vitro

Structure-based design of antiviral drug candidates targeting the SARS-CoV-2 main protease

Crystal structure of SARS-CoV-2 main protease provides a basis for design of improved α-ketoamide inhibitors

Antiviral activity of glucosylceramide synthase inhibitors against SARS-CoV-2 and other RNA virus infections

Coronavirus disease 2019 (COVID-19): what we know

COVID-19: consider cytokine storm syndromes and immunosuppression

Pulmonary involvement in patients with hemophagocytic lymphohistiocytosis

Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China

The use of Janus kinase inhibitors in the time of SARS-CoV-2

Efficacy and safety of ruxolitinib in asian patients with myelofibrosis

Current knowledge about the antivirals remdesivir (GS-5734) and GS-441524 as therapeutic options for coronaviruses

Coronavirus infections more than just the common cold

Broad spectrum antiviral remdesivir inhibits human endemic and zoonotic delta-coronaviruses with a highly divergent RNA dependent RNA polymerase

Programmed ribosomal frameshifting in decoding the SARS-CoV genome

Therapeutic options for the 2019 novel coronavirus (2019-nCoV)

Learning from the past: possible urgent prevention and treatment options for severe acute respiratory infections caused by 2019-nCoV

Coronaviruses drug discovery and therapeutic options

Structure of SARS coronavirus spike receptor-binding domain complexed with receptor

An overview of coronaviruses including the SARS-2 coronavirus molecular biology, epidemiology and clinical implications

Computational design of peptides to block binding of the SARS-CoV-2 spike protein to human ACE2

Protein structure analysis of the interactions between SARS-CoV-2 spike protein and the human ACE2 receptor: from conformational changes to novel neutralizing antibodies

Computational alanine scanning and structural analysis of the SARS-CoV-2 spike protein/angiotensin-converting enzyme 2 complex

Inhibition of SARS-CoV-2 infections in engineered human tissues using clinical-grade soluble human ACE2

The current understanding and potential therapeutic options to combat COVID-19

Chloroquine is a potent inhibitor of SARS coronavirus infection and spread

Chloroquine inhibited ebola virus replication in vitro but failed to protect against infection and disease in the in vivo guinea pig model

In vitro inhibition of human influenza A virus replication by chloroquine

Chloroquine and hydroxychloroquine as inhibitors of human immuno-deficiency virus (HIV-1) activity

Anti-malaria drug chloroquine is highly effective in treating avian influenza A H5N1 virus infection in an animal model

A Systematic review on use of aminoquinolines for the therapeutic management of COVID-19: efficacy, safety and clinical trials

Chloroquine inhibits human CD4 + T-cell activation by AP-1 signaling modulation

Transcriptome-based network analysis reveals a spectrummodel of human macrophage activation

Zn 2+ inhibits coronavirus and arterivirus RNA polymerase activity in vitro and zinc ionophores block the replication of these viruses in cell culture

Structural and molecular modeling studies reveal a new mechanism of action of chloroquine and hydroxychloroquine against SARS-CoV-2 infection

Pharmaceutical care of chloroquine phosphate in elderly patients with coronavirus pneumonia (COVID-19)

Chloroquine dosing recommendations for pediatric COVID-19 supported by modeling and simulation

Chloroquine diphosphate in two different dosages as adjunctive therapy of hospitalized patients with severe respiratory syndrome in the context of coronavirus (SARS-CoV-2) infection: preliminary safety results of a randomized,double-blinded, phase IIb clinical trial (CloroCovid-19 Study)

Preliminary evidence fom a multicenter prospective observational study of the safety and efficacy of chloroquine for the treatment of COVID-19

Chloroquine for SARS-CoV-2: implications of its unique pharmacokinetic and safety properties

The risk of QTc-interval prolongation in COVID-19 patients treated with chloroquine

Could chloroquine/hydroxychloroquine be harmful in coronavirus disease 2019 (COVID-19) treatment?

Some 7-substituted 4-aminoquinoline derivatives

A new synthesis of chloroquine

Assembly of 4-aminoquinolines via palladium catalysis: a mild and convenient alternative to S N Ar methodology

Design and synthesis of hydroxyferroquine derivatives with antimalarial and antiviral activities

In vitro antiviral activity and projection of optimized dosing design of hydroxychloroquine for the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)

Pharmacological and cardiovascular perspectives on the treatment of COVID-19 with chloroquine derivatives

Cardiovascular risks of Hydroxychloroquine in treatment and prophylaxis of COVID-19 patients: a scientific statement from the Indian Heart Rhythm Society

Clinical and microbiological effect of a combination of hydroxychloroquine and azithromycin in 80 COVID-19 patients with at least a six-day follow up: a pilot observational study

Current targeted therapeutics against COVID-19: based on first-line experience in China

Efficacy of hydroxychloroquine in patients with COVID-19: results of a randomized clinical trial

Hydroxychloroquine dosing and toxicity: a real-world experience in Saudi Arabia of 63 patients

Excessive lysosomal ion-trapping of hydroxychloroquine and azithromycin

No evidence of rapid antiviral clearance or clinical benefit with the combination of hydroxychloroquine and azithromycin in patients with severe COVID-19 infection

Characterizing the adverse dermatologic effects of hydroxychloroquine: a systematic review

Hydroxychloroquine in patients with COVID-19: a systematic review and meta-analysis

Effect of combination therapy of hydroxychloroquine and azithromycin on mortality in COVID-19 patients

Continuous hydroxychloroquine or colchicine therapy does not prevent infection with SARS-CoV-2: insights from a large healthcare database analysis

7-Chloro-4-[5-(N-ethyl-N-2-hydroxyethylamino)-2-pentyl] aminoquinoline, its acid addition salts, and method of preparation

An improved process for the preparation of 7-chloro-4-(5-N-ethyl-N-2-hydroxyethylamine)-2-pentyl aminoquinoline and its intermediates

New preparation of hydroxychloroquine

High-yielding continuous-flow synthesis of antimalarial drug hydroxychloroquine

High-yielding continuous flow synthesis of antimalarial drug hydroxychloroquine

Favipiravir (T-705), a novel viral RNA polymerase inhibitor

vitro and in vivo activities of T-705 and oseltamivir against influenzavirus

T-705 (Favipiravir) activity against lethal H5N1 influenza A viruses

Clinical and virological characteristics of ebola virus disease patients treated with favipiravir (T-705)-Sierra Leone

A pharmacokinetics study of favipiravir in patients with severe influenza

vitro and in vivo activities of anti-influenza virus compound T-705

T-705 (favipiravir) suppresses tumor necrosis factor alpha production in response to influenza virus infection: a beneficial feature of T-705 as an anti-influenza drug

Favipiravir, an anti-influenza drug against life-threatening RNA virus infections

Antiviral activity of ribavirin and favipiravir against human astroviruses

Favipiravir strikes the SARS-CoV-2 at its Achilles Heel, the RNA polymerase

Dose-finding study of favipiravir in the treatment of uncomplicated influenza (2020) NCT01068912

Phase 3 Efficacy and safety study of favipiravir for treatment of uncomplicated in-fluenza in adults-T705. (2020) NCT02026349

Clinical outcomes and plasma concentrations of baloxavir marboxil and favipiravir in COVID-19 patients: an exploratory randomized

Experimental treatment with favipiravir for COVID-19: an open-label control study

Organic amine of 6-fluoro-3-hydroxy-2-pyrazinecarbonitrile and method for producing the same

Method for producing dichloropyrazine derivative

A method for preparation favipiravir

A method for preparation favipiravir

Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro

First case of 2019 novel coronavirus in the United States

Expert opinion on the treatment of patients with chronic hepatitis C

New developments in HCV therapy

Nucleotide prodrugs for HCV therapy

Inhibition of hepatitis C virus RNA replication by 2′-modified nucleoside analogs

Characterization of resistance to non-obligate chain-terminating ribonucleoside analogs that inhibit hepatitis C virus replication in vitro

Synthesis and characterization of 2'-C-Me branched C-nucleosides as HCV polymerase inhibitors

Synthesis and antiviral activity of a series of 1′-substituted 4-aza-7,9-dideazaadenosine C-nucleosides

Discovery of the first C-nucleoside HCV polymerase inhibitor (GS-6620) with demonstrated antiviral response in HCV infected patients

) for the treatment of ebola and emerging viruses

The antiviral compound remdesivir potently inhibits RNA-dependent RNA polymerase from Middle East respiratory syndrome coronavirus

Learning from the past: possible urgent prevention and treatment options for severe acute respiratory infections caused by 2019-nCoV

Structural basis for inhibition of the RNAdependent RNA polymerase from SARS-CoV-2 by remdesivir

Broadspectrum antiviral GS-5734 inhibits both epidemic and zoonotic coronaviruses

Coronavirus susceptibility to the antiviral remdesivir (GS-5734) is mediated by the viral polymerase and the proofreading exoribonuclease

Prophylactic and therapeutic remdesivir (GS-5734) treatment in the rhesus macaque model of MERS-CoV infection

Ribavirin, remdesivir, sofosbuvir, galidesivir, and tenofovir against SARS-CoV-2 RNA dependent RNA polymerase (RdRp): a molecular docking study

Remdesivir, lopinavir, emetine, and homoharringtonine inhibit SARS-CoV-2 replication in vitro

Role of 1'-ribose cyano substitution for remdesivir to effectively inhibit both nucleotide addition and proofreading in SARS-CoV-2 viral RNA replication

Remdesivir potently inhibits SARS-CoV-2 in human lung cells and chimeric SARS-CoV expressing the SARS-CoV-2 RNA polymerase in mice

Remdesivir inhibits renal fibrosis in obstructed kidneys

Clinical benefit of remdesivir in rhesus macaques infected with SARS-CoV-2

NIH Clinical Trial of Remdesivir to Treat COVID-19 Begins

National Library of Medicine Clinical Trials Registry (2020) A trial of remdesivir in adults with mild and moderate COVID-19

Clinical trial analysis of 2019-nCoV therapy registered in China

Compassionate use of remdesivir for patients with severe Covid-19

Remdesivir for the treatment of Covid-19 preliminary report

Remdesivir for 5 or 10 days in patients with severe Covid-19

) 1'-Substituted carba-nucleoside analogs for antiviral treatment

Practical synthesis of 1′-substituted tubercidin C-nucleoside

Development of a large-scale cyanation process using continuous flow chemistry en route to the synthesis of remdesivir

Improvement of the C-glycosylation step for the synthesis of remdesivir

Catalytic asymmetric synthesis of the anti-COVID-19 drugremdesivir

Efficacy of JAK1/2 and BCL2 inhibition on human T cell acute lymphoblastic leukemia in vitro and in vivo

Dissecting specificity in the janus kinases: the structures of JAK specific inhibitors complexed to the JAK1 and JAK2 protein tyrosine kinase domains

Comprehensive review of JAK inhibitors in myeloproliferative neoplasms

JAK1 inhibition blocks lethal sterile immune responses: implications for COVID-19 therapy

Into the eye of the cytokine storm

COVID-19: consider cytokine storm syndromes and immunosuppression

Could ruxolitinib be effective in patients with COVID-19 infection at risk of acute respiratory distress syndrome (ARDS)?

Ruxolitinib in treatment of severe coronavirus disease 2019 (COVID-19): a multicenter, singleblind, randomized controlled trial

Heteroaryl substituted pyrrolo[2,3-B]pyridines and pyrrolo[2,3-B]pyridines as janus kinese inhibitors

Regio-and enantioselective synthesis of N-substituted pyrazoles by rhodium-catalyzed asymmetric addition to allenes

Processes for the preparation of ruxolitinib phosphate

Synthesis process of ruxolitinib