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Medicinal Chemistry

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ISSN (Print): 1573-4064
ISSN (Online): 1875-6638

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General Research Article

Design, Synthesis and In Vitro Evaluation of Novel Anti-HIV 3-Pyrazol-3- yl-Pyridin-2-One Analogs

Author(s): Sanjay Kumar, Shiv Gupta, Shraddha Gaikwad, Leila F. Abadi, Late K. K. Bhutani, Smita Kulkarni* and Inder P. Singh*

Volume 15, Issue 5, 2019

Page: [561 - 570] Pages: 10

DOI: 10.2174/1573406414666181106125539

Price: $65

Abstract

Background: Natural products have shown potent anti-HIV activity, but some of these also possess toxicity. The pharmacophoric fragments of these natural products have scope of combination with other pharmacophoric fragment and derivatization to reduce toxicity and increase the potency. Combination of natural product fragments from different classes of anti–HIV compounds may lead to a new class of potent anti–HIV agents.

Objective: Design, in silico prediction of drug-likeness, ADMET properties and synthesis of pyrazol– pyridones. Evaluation of the anti–HIV–1 activity of synthesized pyrazol–pyridones.

Methods: Pyrazol–pyridones were designed by combining reported anti–HIV pharmacophoric fragments. Designed molecules were synthesized after in silico prediction of drug-likeness and ADMET properties. Compounds were evaluated for activity against HIV–1VB59 and HIV–1UG070.

Results: QED value of designed pyrazol–pyridones was greater than the known drug zidovudine. The designed compounds were predicted to be noncarcinogenic and nonmutagenic in nature. Seventeen novel pyrazol–pyridones were synthesized with good yield. Compound 6q and 6l showed activity with IC50 values 6.14 µM and 15.34 µM against HIV–1VB59 and 16.21 µM and 18.21 µM against HIV–1UG070, respectively.

Conclusion: Compound 6q was found to be most potent among the synthesized compounds with a therapeutic index of 54.31against HIV–1VB59. This is the first report of anti–HIV–1 activity of pyrazol–pyridone class of compounds. Although the anti–HIV–1 activity of these compounds is moderate, this study opens up a new class for exploration of chemical space for anti–HIV–1 activity.

Keywords: Pyrazol–pyridone, anti–HIV, drug-likeness, QED, ADMET, HIV–1VB51, HIV–1UG070.

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[1]
WHO. HIV/AIDS. Available at: http://www.who.int/mediacentre/factsheets/ fs360/en/ (Accessed on Mar. 17, 2018).
[2]
Singh, I.P.; Bodiwala, H.S. Recent advances in anti-HIV natural products. Nat. Prod. Rep., 2010, 27, 1781-1800.
[3]
Bodiwala, H.S.; Sabde, S.; Gupta, P.; Mukherjee, R.; Kumar, R.; Garg, P.; Bhutani, K.K.; Mitra, D.; Singh, I.P. Design and synthesis of caffeoyl-anilides as portmanteau inhibitors of HIV-1 integrase and CCR5. Bioorg. Med. Chem., 2011, 19, 1256-1263.
[4]
Sun, X.; Fan, N.; Xu, W.; Sun, Y.; Xie, X.; Guo, Y.; Ma, L.; Liu, J.; Wang, X. Design, synthesis and biological evaluation of caffeoyl benzanilides as dual inhibitors of HIV integrase and CCR5. MedChemComm, 2016, 7, 2028-2032.
[5]
Cheng, M.J.; Lee, K.H.; Tsai, I.L.; Chen, I.S. Two new sesquiterpenoids and anti-HIV principles from the root bark of Zanthoxylum ailanthoides. Bioorg. Med. Chem., 2005, 13, 5915-5920.
[6]
Goldman, M.E.; Nunberg, J.H.; O’brien, J.A.; Quintero, J.C.; Schleif, W.A.; Freund, K.F.; Gaul, S.L.; Saari, W.S.; Wai, J.S.; Hoffman, J.M. Pyridinone derivatives: Specific human immunodeficiency virus type 1 reverse transcriptase inhibitors with antiviral activity. Proc. Natl. Acad. Sci. USA, 1991, 88, 6863-6867.
[7]
Saari, W.S.; Hoffman, J.M.; Wai, J.S.; Fisher, T.E.; Rooney, C.S.; Smith, A.M.; Thomas, C.M.; Goldman, M.E.; O’brien, J.A. 2-Pyridinone derivatives: A new class of nonnucleoside, HIV-1-specific reverse transcriptase inhibitors. J. Med. Chem., 1991, 34, 2922-2925.
[8]
Hoffman, J.M.; Smith, A.M.; Rooney, C.S.; Fisher, T.E.; Wai, J.S.; Thomas, C.M.; Bamberger, D.L.; Barnes, J.L.; Williams, T.M. Synthesis and evaluation of 2-pyridinone derivatives as HIV-1-specific reverse transcriptase inhibitors. 4. 3-[2-(Benzoxazol-2-yl) ethyl]-5-ethyl-6-methylpyridin-2 (1H)-one and analogs. J. Med. Chem., 1993, 36, 953-966.
[9]
Himmel, D.M.; Das, K.; Clark, A.D.; Hughes, S.H.; Benjahad, A.; Oumouch, S.; Guillemont, J.; Coupa, S.; Poncelet, A.; Csoka, I. Crystal structures for HIV-1 reverse transcriptase in complexes with three pyridinone derivatives: A new class of non-nucleoside inhibitors effective against a broad range of drug-resistant strains. J. Med. Chem., 2005, 48, 7582-7591.
[10]
Davey, R.T.; Dewar, R.L.; Reed, G.F.; Vasudevachari, M.; Polis, M.A.; Kovacs, J.A.; Falloon, J.; Walker, R.E.; Masur, H.; Haneiwich, S.E. Plasma viremia as a sensitive indicator of the antiretroviral activity of L-697,661. Proc. Natl. Acad. Sci. USA, 1993, 90, 5608-5612.
[11]
Saag, M.S.; Emini, E.A.; Laskin, O.L.; Douglas, J.; Lapidus, W.I.; Schleif, W.A.; Whitley, R.J.; Hildebrand, C.; Byrnes, V.W.; Kappes, J.C. A short-term clinical evaluation of L-697,661, a non-nucleoside inhibitor of HIV-1 reverse transcriptase. N. Engl. J. Med., 1993, 329, 1065-1072.
[12]
Wei, Z-Y.; Liu, J-C.; Zhang, W.; Li, Y-R.; Li, C.; Zheng, C-J.; Piao, H-R. Synthesis and antimicrobial evaluation of (Z)-5-((3-phenyl-1H-pyrazol-4-yl) methylene)-2-thioxothiazolidin-4-one derivatives. Med. Chem., 2016, 12, 751-759.
[13]
Mamolo, M.G.; Zampieri, D.; Falagiani, V.; Vio, L.; Banfi, E. Synthesis and antimycobacterial activity of 5-aryl-1-isonicotinoyl-3-(pyridin-2-yl)-4, 5-dihydro-1H-pyrazole derivatives. II Farmaco, 2001, 56, 593-599.
[14]
Zhang, C.Y.; Liu, X.H.; Wang, B.L.; Wang, S.H.; Li, Z.M. Synthesis and antifungal activities of new pyrazole derivatives via 1, 3-dipolar cycloaddition reaction. Chem. Biol. Drug Des., 2010, 75, 489-493.
[15]
Meta, E.; Brullo, C.; Tonelli, M.; Franzblau, S.; Wang, Y.; Ma, R.; Baojie, W.; Orena, B.; Pasca, M.; Bruno, O. Pyrazole and imidazo [1, 2-b] pyrazole derivatives as new potential anti-tuberculosis agents. Med. Chem., 2019, 15, 17-27.
[16]
Mojzych, M.; Tarasiuk, P.; Karczmarzyk, Z.; Juszczak, M.; Rzeski, W.; Fruzinski, A.; Wozny, A. Synthesis, structure and antipro-liferative activity of new pyrazolo [4, 3-e] triazolo [4, 5-b][1, 2, 4] triazine derivatives. Med. Chem., 2018, 14, 53-59.
[17]
Gavriil, E-S.; Lougiakis, N.; Pouli, N.; Marakos, P.; Skaltsounis, A-L.; Nam, S.; Jove, R.; Horne, D.; Gioti, K.; Pratsinis, H. Synthesis and antiproliferative activity of new pyrazolo [3, 4-c] pyridines. Med. Chem., 2017, 13, 365-374.
[18]
Storer, R.; Ashton, C.J.; Baxter, A.D.; Hann, M.M.; Marr, C.L.; Mason, A.M.; Mo, C-L.; Myers, P.L.; Noble, S.A.; Penn, C.R. The synthesis and antiviral activity of 4-fluoro-1-β-D-ribofuranosyl-1H-pyrazole-3-carboxamide. Nucleosides Nucleotides Nucleic Acids, 1999, 18, 203-216.
[19]
Johns, B.A.; Gudmundsson, K.S.; Allen, S.H. Pyrazolo [1, 5-a] pyridine antiherpetics: Effects of the C3 substituent on antiviral activity. Bioorg. Med. Chem. Lett., 2007, 17, 2858-2862.
[20]
Ramirez-Prada, J.; Robledo, S.M.; Vélez, I.D.; Del Pilar Crespo, M.; Quiroga, J.; Abonia, R.; Montoya, A.; Svetaz, L.; Zacchino, S.; Insuasty, B. Synthesis of novel quinoline-based 4, 5-dihydro-1H-pyrazoles as potential anticancer, antifungal, antibacterial and antiprotozoal agents. Eur. J. Med. Chem., 2017, 131, 237-254.
[21]
Faria, J.V.; Vegi, P.F.; Miguita, A.G.C.; Dos Santos, M.S.; Boechat, N.; Bernardino, A.M.R. Recently reported biological activities of pyrazole compounds. Bioorg. Med. Chem., 2017, 25, 5891-5903.
[22]
Genin, M.J.; Biles, C.; Keiser, B.J.; Poppe, S.M.; Swaney, S.M.; Tarpley, W.G.; Yagi, Y.; Romero, D.L. Novel 1, 5-diphenyl-pyrazole nonnucleoside HIV-1 reverse transcriptase inhibitors with enhanced activity versus the delavirdine-resistant P236L mutant: Lead identification and SAR of 3-and 4-substituted derivatives. J. Med. Chem., 2000, 43, 1034-1040.
[23]
Mowbray, C.E.; Burt, C.; Corbau, R.; Gayton, S.; Hawes, M.; Perros, M.; Tran, I.; Price, D.A.; Quinton, F.J.; Selby, M.D.; Stupple, P.A.; Webster, R.; Wood, A. Pyrazole NNRTIs 4: selection of UK-453,061 (lersivirine) as a development candidate. Bioorg. Med. Chem. Lett., 2009, 19, 5857-5860.
[24]
Abadi, A.H.; Eissa, A.A.; Hassan, G.S. Synthesis of novel 1,3,4-trisubstituted pyrazole derivatives and their evaluation as antitumor and antiangiogenic agents. Chem. Pharm. Bull. , 2003, 51, 838-844.
[25]
Flower, R.J. The development of COX2 inhibitors. Nat. Rev. Drug Discov., 2003, 2, 179-191.
[26]
Chamberlain, E.F.; Wang, C.; Shi, H.; Adams, C.D.; Ma, Y. Oxidative removal and kinetics of fipronil in various oxidation systems for drinking water treatment. J. Agric. Food Chem., 2010, 58, 6895-6899.
[27]
Bebernitz, G.R.; Argentieri, G.; Battle, B.; Brennan, C.; Balkan, B.; Burkey, B.F.; Eckhardt, M.; Gao, J.; Kapa, P.; Strohschein, R.J. The effect of 1, 3-diaryl-[1H]-pyrazole-4-acetamides on glucose utilization in ob/ob mice. J. Med. Chem., 2001, 44, 2601-2611.
[28]
Armarego, W.L.; Chai, C. Purification of labotatory chemicals; Elsevier: New York, 2012.
[29]
Tetko, I.V.; Gasteiger, J.; Todeschini, R.; Mauri, A.; Livingstone, D.; Ertl, P.; Palyulin, V.A.; Radchenko, E.V.; Zefirov, N.S.; Makarenko, A.S. Virtual computational chemistry laboratory-design and description. J. Comput. Aided Mol. Des., 2005, 19, 453-463.
[30]
Bickerton, G.R.; Paolini, G.V.; Besnard, J.; Muresan, S.; Hopkins, A.L. Quantifying the chemical beauty of drugs. Nat. Chem., 2012, 4, 90-98.
[31]
Cheng, F.; Li, W.; Zhou, Y.; Shen, J.; Wu, Z.; Liu, G.; Lee, P.W.; Tang, Y. admetSAR: A comprehensive source and free tool for assessment of chemical ADMET properties. J. Chem. Inf. Model., 2012, 52, 3099-3105.
[32]
Mosmann, T. Rapid colorimetric assay for cellular growth and survival: Application to proliferation and cytotoxicity assays. J. Immunol. Methods, 1983, 65, 55-63.
[33]
Gupta, S.; Kumar, S.; Jariwala, N.; Bhadane, D.; Bhutani, K.K.; Kulkarni, S.; Singh, I.P. in silico prioritization, synthesis and in vitro evaluation of Tembamide analogs for anti-HIV activity. Lett. Drug Des. Discov., 2017, 14, 1455-1464.
[34]
Drugbank. Available at: https://www.drugbank.ca/drugs/DB00495 (Accessed on Aug. 20, 2018).
[35]
Drugbank. Available at: https://www.drugbank.ca/drugs/DB00238 (Accessed on Aug. 20, 2018).
[36]
Ene, L.; Duiculescu, D.; Ruta, S.M. How much do antiretroviral drugs penetrate into the central nervous system? J. Med. Life, 2011, 4, 432-439.
[37]
Milanetti, E.; Raimondo, D.; Tramontano, A. Prediction of the permeability of neutral drugs inferred from their solvation properties. Bioinformatics, 2015, 32, 1163-1169.
[38]
AIDS info. Available at: https://aidsinfo.nih.gov/ (Accessed on Mar. 17, 2018).
[39]
Toxnet. Available at: http://hivinsite.ucsf.edu/InSite?page=ar-00-02 (Accessed on Aug. 20, 2018).
[40]
Available at: https://toxnet.nlm.nih.gov/cgi-bin/sis/search/a?dbs+hsdb:@term+@ DOCNO+7164 (Accessed on Aug. 20, 2018).
[41]
Walton, E.; Rodin, J.; Stammer, C.; Holly, F. Synthesis of L-Valyl-L-tryosyl-L-tyrosyl-Lisoleucyl-L-histidyl-L-prolyl-L-phenylalanine methyl ester dihydrochloride. J. Org. Chem., 1961, 26, 1657-1658.
[42]
Showalter, H.; Haskell, T.H. Functionalization of substituted 2‐(1H) pyridones. I. A novel synthesis of a-arylgyloxylates and related systems. J. Het. Chem, 1981, 18, 367-370.
[43]
Rai, P.; Srivastava, M.; Singh, J.; Singh, J. Molecular iodine: A green and inclusive catalyst for the synthesis of highly functionalized 1,3,5-trisubstituted pyrazoles in aqueous medium. RSC Advances, 2014, 4, 779-783.

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