key: cord-0802737-qf4v2uc2 authors: Seliem, Israa A.; Panda, Siva S.; Girgis, Adel S.; Moatasim, Yassmin; Kandeil, Ahmed; Mostafa, Ahmed; Ali, Mohamed A.; Nossier, Eman S.; Rasslan, Fatma; Srour, Aladdin M; Sakhuja, Rajeev; Ibrahim, Tarek S.; Abdel-samii, Zakaria K.M.; Al-Mahmoudy, Amany M.M. title: New quinoline-triazole conjugates: Synthesis, and antiviral properties against SARS-CoV-2 date: 2021-06-23 journal: Bioorg Chem DOI: 10.1016/j.bioorg.2021.105117 sha: 6c989779d731e76e54c656fd4293de4d3aab8422 doc_id: 802737 cord_uid: qf4v2uc2 At present therapeutic options for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) are very limited. We designed and synthesized three sets of small molecules using quinoline scaffolds. A series of quinoline conjugates (10a-l, 11a-c, and 12a-e) by incorporating 1,2,3-triazole were synthesized via a modified microwave-assisted click chemistry technique. Among the synthesized conjugates, 4-((1-(2-chlorophenyl)-1H-1,2,3-triazol-4-yl)methoxy)-6-fluoro-2-(trifluoromethyl)quinoline (10g) and 6-fluoro-4-(2-(1-(4-methoxyphenyl)-1H-1,2,3-triazol-4-yl)ethoxy)-2-(trifluoromethyl)quinoline (12c) show high potency against SARS-CoV-2. The selectivity index (SI) of compounds 10g and 12c also indicates the significant efficacy compared to the reference drugs. fluoro-2-(trifluoromethyl)quinoline (10g) and 6-fluoro-4-(2-(1-(4-methoxyphenyl)-1H-1,2,3triazol-4-yl)ethoxy)-2-(trifluoromethyl)quinoline (12c) show high potency against SARS-CoV-2. The selectivity index (SI) of compounds 10g and 12c also indicates the significant efficacy compared to the reference drugs. Keywords: Quinoline; triazole; click chemistry, SARS-CoV-2; molecular docking In December 2019, an unknown viral infection was identified in a local fish and wild animal market of Wuhan city (China). 1 Since then, the virus has rapidly spread across mainland China followed by the rest of the world. 2,3 On Feb 11, 2020, the WHO identified the virus as the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). The viral infection disease is called as 2019-new coronavirus disease , and in March 2020 declared the coronavirus outbreak a global pandemic. 4 As of April 2021, COVID-19 has affected more than 152 million people with 3.18 million deaths worldwide. As of now, there is no potential antiviral drug available for the treatment of COVID-19. However, a few vaccines have received approval from FDA to control the pandemic. The drug repurposing approach was considered the most accessible pathway for exploring drugs to control the global pandemic. Several drugs that were considered for repurposing to control the COVID-19 pandemic include chloroquine (CQ) and hydroxychloroquine (HCQ) (Fig. 1 ). These exhibited promising responses accompanied with serious side effects (ventricular arrhythmias, retinopathy, QT prolongation, or cardiac-related toxicity). [5] [6] [7] [8] [9] [10] [11] Recently, a few quinolone-based small molecules reported their antiviral properties against SARS-CoV-2. 12-20 New drug development is expensive, time-consuming, and challenging processes. In the current scenario, molecular hybridization of bioactive moieties is a powerful and attractive rational drug design strategy for new drug development because of several advantages such as a) to achieve selectivity; b) gain desired activity; c) multiple pharmacological targets; d) lower possible cytotoxicity. Our group has actively engaged in developing drug conjugates and hybrid conjugates by this approach. [21] [22] [23] [24] [25] [26] In the present study, we have designed and synthesized a set of novel quinoline-triazole conjugates with potential antiviral properties against SARS-CoV-2 using the 'click' chemistry approach employing various azides and the alkyne component of the propargyl linked quinolines. We considered the quinoline scaffold from the repurposed drugs (chloroquine and hydroxychloroquine) and triazole because of their importance in the drug development process and well-known for diversified biological properties. [27] [28] [29] [30] [31] Besides, the presence of electronegative fluorine atoms may alter the physicochemical properties of the molecule significantly. This may improve the stability, reducing the cytotoxicity, in addition to enhancing the overall therapeutic efficacy in our designed molecules. 32 The synthetic protocol was developed for the synthesis of the targeted quinoline-triazole conjugates (Fig. 2 ) by adopting the well-established Cu-mediated click chemistry of alkynes 5, 6, and 8 with varied azides 10. The precursor alkynes 5, 6, and 8 were synthesized by treating a solution of 6-(un)substituted-2-(trifluoromethyl)quinolin-4(1H)-ones 3 in DMF with propargyl bromide (4) or 4-bromobut-1-yne (7) in the presence of potassium carbonate (K2CO3) at room temperature. 33 (Scheme 1). The azides of aromatic amines 1b-f were synthesized using the previously reported method. 25 A solution of compounds 3a-d in DMF on reaction with propargyl bromide (4) or 4bromobut-1-yne (7) in the presence of potassium carbonate (K2CO3) at 20 °C for 6 h gave predominately O-substituted quinolines. However, in the case of 3a and 3c on treatment with propargyl bromide 4, we got both N-substituted quinolones and O-substituted quinolines in a good ratio, which were isolated by column chromatography (5a,b, and 6a,b). We also observed the formation of N-substituted quinolones as a minor product when we treated 4-bromobut-1-yne (7) with 3a-d. The formation of O-substituted quinolones is move favored over N-substituted quinolines because of the steric and electronic properties of the CF3 group. The detailed investigation was reported by Raić-Malić and coworkers. 34 Scheme 1. Synthesis of alkynes 5, 6, and 8. Alkynes 5, 6, and 8 were treated with aromatic azides 9 adopting a modified click chemical technique in presence of CuSO4.5H2O and sodium D-isoascorbate in n-butanol-water mixture under microwave irradiation for 2 h at 100 °C to afford the desired corresponding conjugates 10al, 11a-c and 12a-e in good yields (Scheme 2). The reactions do work at room temperature but never go to completion even after 3 days. Our optimized reaction condition able to complete the reaction in 2 hours. All the synthesized compounds were fully characterized by spectroscopic techniques. CC50 relative to IC50 of the tested conjugate. From the observed biological properties (Table 1) In conclusion, we have synthesized three sets of triazole incorporated quinolone conjugates in good yields by an optimized facile reaction condition. Some conjugates showed promising antiviral activity against SARS-CoV-2. Compound 10g and 12c found the most effective agents for the SARS-CoV-2. The selectivity index (SI) of compounds also indicates significant efficacy compared to the reference drugs. We believe the initial investigation and the important scaffold could be further used as resources for the development of potential drug candidates for SARS-CoV-2. Melting points were determined on a capillary point apparatus equipped with a digital thermometer. NMR spectra were recorded in CDCl3, DMSO-d6, on Bruker NMR spectrometer operating at 500 MHz for 1 H (with TMS as an internal standard) and 125 MHz for 13 C. Highresolution mass spectra were recorded with TOF analyzer spectrometer by using electron spray mode. All microwave-assisted reactions were carried out with a single-mode cavity Discover Microwave Synthesizer (CEM Corporation, NC). The reaction mixtures were transferred into a 10 mL glass pressure microwave tube equipped with a magnetic stirrer bar. The tube was closed with a silicon septum and the reaction mixture was subjected to microwave irradiation (Discover mode; run time: 60 s; Power Max-cooling mode). oxyquinolines 6a,c 26, 33 To a suspension of corresponding quinolone 3a-d (1 equiv.) in N, N-dimethylformamide (DMF; 10 ml), K2CO3 (1.5 equiv.) was added. After stirring for 30 min, propargyl bromide 4 (1 equiv.) was added and the reaction mixture was stirred for 6 hours. The solvent was removed under reduced pressure and the crude residue was purified by column chromatography. These compounds were characterized by comparing their spectroscopic data to the reported ones. 26, 33 To a suspension of corresponding quinolone 3a-d (1 equiv.) in N, N-dimethylformamide (DMF; 10 ml), K2CO3 (1.5 equiv.) was added. After stirring for 30 min, 4-bromobut-1-yne 7 (1 equiv.) was added and the reaction mixture was subjected to microwave irradiations for 6 hours. The crude mixture was diluted with water than solid formed filtered off and crystallized from ethanol. These compounds were characterized by comparing their spectroscopic data to the reported ones. 28 To a solution of quinoline (1 equiv.) in n-butanol/H2O (2: 1) (3 mL), CuSO4 (0.05 equiv.), and sodium D-isoascorbate monohydrate (0.15 equiv.) was added at room temperature. To this mixture, aryl azide (1.5 mmol) was added and the reaction mixture was subjected to microwave irradiations at 250 W for 2 hours. The crude mixture was diluted with water then extracted with EtOAc and the combined organic layer was dried over sodium sulfate, concentrated in a vacuum, and purified through column chromatography to give the pure quinoline-triazole derivatives in good yields. White ((1-(p-tolyl)-1H-1,2,3-triazol-4-yl) White microcrystals, m.p. 180-182 °C, yield 54% (0. -(p-tolyl)-1H-1,2,3-triazol-4-yl)methoxy)-2-(trifluoromethyl)quinoline (10l) 841, 722; 1 H NMR (CDCl3) δ: 8.08 (s, 1H), 8.03 (d, J = 9 4-Methoxyphenyl)-1H-1,2,3-triazol-4-yl)methyl)-2-(trifluoromethyl)quinolin-4(1H)-one (11a) Yellow microcrystals 66 (s, 2H), 3.83 (s, 3H). 13 C NMR (CDCl3) δ: 160 -Methoxyphenyl)-1H-1,2,3-triazol-4-yl)methyl)-2-(trifluoromethyl)quinolin-4(1H)-one (11b) White microcrystals Yellow microcrystals 66 (s, 2H), 3.83 (s, 3H), 2.42 (s, 3H). 13 C NMR (CDCl3) δ: 160 -Methoxyphenyl)-1H-1,2,3-triazol-4-yl)ethoxy)-2-(trifluoromethyl)-1,4-dihydroquinoline (12a) Yellow microcrystals Hz, 1H), 7.82 (s, 1H), 7.74 (t, J = 7.1 Hz, 1H), 7.60-7.52 (m, 3H) 82 (s, 3H), 3.46 (t, J = 5.5 Hz, 2H). 13 C NMR (CDCl3) δ: 162.9 -fluorophenyl)-1H-1,2,3-triazol-4-yl)ethoxy)-2-(trifluoromethyl)-1,4-dihydroquinoline (12b) Yellow microcrystals -methoxyphenyl)-1H-1,2,3-triazol-4-yl)ethoxy)-2-(trifluoromethyl)-1,4-dihydroquinoline (12c) Yellow microcrystals Hz, 2H), 3.83 (s, 3H), 3.46 (t, J = 5.5 Hz, 2H). 13 C NMR (CDCl3) δ: 162.5 Yellow microcrystals 4-Methoxyphenyl)-1H-1,2,3-triazol-4-yl)ethoxy)-6-methyl-2-(trifluoromethyl)-1,4-dihydroquinoline (12e) 04 (s, 1H), 6.98 (d, J = 9 Outbreak of pneumonia of unknown etiology in Wuhan, China: the mystery and the miracle Early transmission dynamics in Wuhan, China, of novel coronavirus-Infected pneumonia Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study Clinical management of severe acute respiratory infection when novel coronavirus (nCoV) infection is suspected: interim guidance Drug repurposing approach to fight COVID-19 Inhibitors of SARS-CoV-2 entry: Current and future opportunities In vitro antiviral activity and projection of optimized dosing design of hydroxychloroquine for the treatment of severe 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Synthesis, antimalarial properties and 2D-QSAR studies of novel triazole-quinine conjugates Comprehensive review on the anti-bacterial activity of 1,2,3-triazole hybrids Synthesis and biological evaluation of novel 2-pyridinyl[1,2,3]triazoles as inhibitors of transforming growth factor β1 type 1 receptor Rapid discovery and structure-activity profiling of novel inhibitors of human immunodeficiency virus type 1 protease enabled by the copper(I)-catalyzed synthesis of 1,2,3-triazoles and their further functionalization Synthesis and biological evaluation of 4-aryl-5-cyano-2H-1,2,3-triazoles as inhibitor of HER2 tyrosine kinase Synthesis, HIV-RT inhibitory activity and SAR of 1-benzyl-1H-1,2,3-triazole derivatives of carbohydrates Fluorine and fluorinated motifs in the design and application of bioisosteres for drug design New trifluoromethyl quinolone derivatives: Synthesis and investigation of antimicrobial properties Quinoline and ferrocene conjugates: Synthesis, computational study and biological evaluations Crystal violet assay for determining viability of cultured cells FDA-approved drugs with potent in vitro antiviral activity against severe acute respiratory syndrome coronavirus 2 Molecular docking, molecular dynamics, and in vitro studies reveal the potential of angiotensin II receptor blockers to inhibit the COVID-19 main protease Structure of M pro from SARS-CoV-2 and discovery of its inhibitors We thank the Egyptian Cultural and Educational Bureau Scholarship. The authors also thank the Center for Undergraduate Research and Scholarship (CURS) and Translational Research Program (TRP) at Augusta University for financial support. A series of quinolone-triazole conjugates synthesized as potential antiviral agents for SARS-CoV2. Some of the conjugates are more potent than the standards.  A set of quinolone-triazole conjugates was designed and synthesized.  Some conjugates show promising antiviral properties against SARS-CoV2.  The selectivity index (SI) of the synthesized potent conjugates better than the reference drugs.  Potential conjugates could be further explored for the development of potential antiviral drug candidates.