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Letters in Drug Design & Discovery

Editor-in-Chief

ISSN (Print): 1570-1808
ISSN (Online): 1875-628X

Research Article

Design, Synthesis and In Vitro Evaluation of 4-Oxo-6-Substituted Phenyl- 2-Thioxo1,2,3,4-Tetrahydropyrimidine-5-Carbonitrile Derivatives as HIV Integrase Strand Transfer Inhibitors

Author(s): Pankaj Wadhwa*, Priti Jain and Hemant R. Jadhav

Volume 18, Issue 4, 2021

Published on: 22 October, 2020

Page: [387 - 395] Pages: 9

DOI: 10.2174/1570180817999201022193325

Price: $65

Abstract

Aim: To design, synthesis and in vitro evaluation of 4-oxo-6-substituted phenyl-2- thioxo1,2,3,4-tetrahydropyrimidine-5-carbonitrile derivatives as HIV integrase strand transfer inhibitors.

Background: Human immunodeficiency virus-1 (HIV-1), a member of retroviridae family, is the primary causative agent of acquired immunodeficiency syndrome (AIDS). Three enzymes viz: integrase (IN), reverse transcriptase (RT) and protease play important role in its replication cycle. HIV-1 integrase is responsible for the incorporation of viral DNA into human chromosomal DNA by catalyzing two independent reactions, 3′-processing (3′-P) and strand transfer (ST), which are observed as the “point of no-return” in HIV infection.

Objective: To develop inhibitors against HIV integrase strand transfer step.

Methods: Our previous results indicated that tetrahydro pyrimidine-5-carboxamide derivatives are potent HIV-1 IN inhibitors (unpublished results from our laboratory). Taking clue from above studies and our own experience, we hypothesized 4-oxo-6-substituted phenyl-2-thioxo1,2,3,4- tetrahydropyrimidine-5-carbonitrile analogues (14a to 14n) as inhibitors of HIV-1 Integrase strand transfer. Prototype compound 14 can be viewed as hybrid structure having characteristics of dihydropyrimidine derivatives 10-12 and tyrphostin 13.

Results: A total of fourteen derivatives of 4-oxo-6-substituted phenyl-2-thioxo-1,2,3,4-tetrahydropyrimidine- 5-carbonitrile (14a-14n) were synthesized and evaluated using HIV-1 Integrase Assay Kit (Xpressbio Life Science Products, USA). The percentage inhibition of all compounds was investigated at 10 μM concentration and IC50 value of few highly active compounds was studied. The obtained results were validated by in silico molecular docking study using Glide (maestro version 9.3, Schrödinger suite) in extra precision (XP) mode.

Conclusion: Fourteen 4-oxo-6-substituted phenyl-2-thioxo 1,2,3,4-tetrahydropyrimidine-5-carbonitrile analogues were synthesized and evaluated for HIV-1 IN inhibitory activity. Three compounds 14a, 14e, and 14h exhibited significant percentage inhibition of HIV-1 IN. There was good in vitro - in silico correlation. However, none of the derivative was active against HIV-1 and HIV-2 below their cytotoxic concentration. It needs to be seen whether these compounds can be explored further for their anti-HIV or cytotoxic potential.

Keywords: HIV-1 integrase, docking studies, anti-HIV, strand transfer inhibitors, tetrahydropyrimidine-5-carbonitriles.

Graphical Abstract
[1]
Wilen, C.B.; Tilton, J.C.; Doms, R.W. Molecular mechanisms of HIV entry. Adv. Exp. Med. Biol., 2012, 726, 223-242.
[http://dx.doi.org/10.1007/978-1-4614-0980-9_10] [PMID: 22297516]
[2]
Chiu, T.K.; Davies, D.R. Structure and function of HIV-1 integrase. Curr. Top. Med. Chem., 2004, 4(9), 965-977.
[http://dx.doi.org/10.2174/1568026043388547] [PMID: 15134551]
[3]
Nair, V.; Chi, G. HIV integrase inhibitors as therapeutic agents in AIDS. Rev. Med. Virol., 2007, 17(4), 277-295.
[http://dx.doi.org/10.1002/rmv.539] [PMID: 17503547]
[4]
Pace, P.; Rowley, M. Integrase inhibitors for the treatment of HIV infection. Curr. Opin. Drug Discov. Devel., 2008, 11(4), 471-479.
[PMID: 18600564]
[5]
Su, M.; Tan, J.; Lin, C.Y. Development of HIV-1 integrase inhibitors: recent molecular modeling perspectives. Drug Discov. Today, 2015, 20(11), 1337-1348.
[http://dx.doi.org/10.1016/j.drudis.2015.07.012] [PMID: 26220090]
[6]
Patel, R.V.; Keum, Y.S.; Park, S.W. Sketching the historical development of pyrimidones as the inhibitors of the HIV integrase. Eur. J. Med. Chem., 2015, 97, 649-663.
[http://dx.doi.org/10.1016/j.ejmech.2014.07.005] [PMID: 25084622]
[7]
Sharma, V.; Chitranshi, N.; Agarwal, A.K. Significance and biological importance of pyrimidine in the microbial world. Int. J. Med. Chem., 2014, 2014202784
[http://dx.doi.org/10.1155/2014/202784]] [PMID: 25383216]
[8]
Selvam, T. S.; James, C. R.; Dniandev, P. V.; Valzita, S.K. A mini review of pyrimidine and fused pyrimidine marketed drugs., Research in Pharmacy, 2012, 2, 01-09..
[9]
Wadhwa, P.; Jain, P.; Jadhav, H.R.; Rudrawar, S. Quinoline, Coumarin and other heterocyclic analogues Based HIV-1 integrase inhibitors. Curr. Drug Discov. Technol., 2018, 15(1), 2-19.
[PMID: 28558629]
[10]
Summa, V.; Petrocchi, A.; Matassa, V.G.; Gardelli, C.; Muraglia, E.; Rowley, M.; Paz, O.G.; Laufer, R.; Monteagudo, E.; Pace, P. 4,5-dihydroxypyrimidine carboxamides and N-alkyl-5-hydroxypyrimidinone carboxamides are potent, selective HIV integrase inhibitors with good pharmacokinetic profiles in preclinical species. J. Med. Chem., 2006, 49(23), 6646-6649.
[http://dx.doi.org/10.1021/jm060854f] [PMID: 17154493]
[11]
Petrocchi, A.; Koch, U.; Matassa, V.G.; Pacini, B.; Stillmock, K.A.; Summa, V. From dihydroxypyrimidine carboxylic acids to carboxamide HIV-1 integrase inhibitors: SAR around the amide moiety. Bioorg. Med. Chem. Lett., 2007, 17(2), 350-353.
[http://dx.doi.org/10.1016/j.bmcl.2006.10.054] [PMID: 17107799]
[12]
Ramajayam, R.; Mahera, N.B.; Neamati, N.; Yadav, M.R.; Giridhar, R. Synthesis and anti-HIV-1 integrase activity of cyano pyrimidinones. Arch. Pharm. (Weinheim), 2009, 342(12), 710-715.
[http://dx.doi.org/10.1002/ardp.200900066] [PMID: 19899101]
[13]
Rajamaki, S.; Innitzer, A.; Falciani, C.; Tintori, C.; Christ, F.; Witvrouw, M.; Debyser, Z.; Massa, S.; Botta, M. Exploration of novel thiobarbituric acid, rhodamine and thiohydantoin-based HIV-1 integrase inhibitors. Bioorg. Med. Chem. Lett., 2009, 19(13), 3615-3618.
[http://dx.doi.org/10.1016/j.bmcl.2009.04.132] [PMID: 19447621]
[14]
Mazumder, A.; Gazit, A.; Levitzki, A.; Nicklaus, M.; Yung, J.; Kohlhagen, G.; Pommier, Y. Effects of tyrphostins, protein kinase inhibitors, on human immunodeficiency virus type 1 integrase. Biochemistry, 1995, 34(46), 15111-15122.
[http://dx.doi.org/10.1021/bi00046a018] [PMID: 7578125]
[15]
Debyser, Z.; Cherepanov, P.; Pluymers, W.; De Clercq, E. Assays for the evaluation of HIV-1 integrase inhibitors. Methods Mol. Biol., 2001, 160, 139-155.
[http://dx.doi.org/10.1385/1-59259-233-3:139] [PMID: 11265279]
[16]
Goldgur, Y.; Craigie, R.; Cohen, G.H.; Fujiwara, T.; Yoshinaga, T.; Fujishita, T.; Sugimoto, H.; Endo, T.; Murai, H.; Davies, D.R. Structure of the HIV-1 integrase catalytic domain complexed with an inhibitor: A platform for antiviral drug design. Proc. Natl. Acad. Sci. USA, 1999, 96(23), 13040-13043.
[http://dx.doi.org/10.1073/pnas.96.23.13040] [PMID: 10557269]
[17]
Friesner, R.A.; Murphy, R.B.; Repasky, M.P.; Frye, L.L.; Greenwood, J.R.; Halgren, T.A.; Sanschagrin, P.C.; Mainz, D.T. Extra precision glide: Docking and scoring incorporating a model of hydrophobic enclosure for protein-ligand complexes. J. Med. Chem., 2006, 49(21), 6177-6196.
[http://dx.doi.org/10.1021/jm051256o] [PMID: 17034125]
[18]
Tang, J.; Maddali, K.; Dreis, C.D.; Sham, Y.Y.; Vince, R.; Pommier, Y.; Wang, Z. N-3 hydroxylation of pyrimidine-2, 4-diones yields dual inhibitors of HIV reverse transcriptase and integrase. ACS Med. Chem. Lett., 2011, 2(1), 63-67.
[http://dx.doi.org/10.1021/ml1002162] [PMID: 21499541]

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