Login Register Cart 0
Generic placeholder image

Current Computer-Aided Drug Design

Editor-in-Chief

ISSN (Print): 1573-4099
ISSN (Online): 1875-6697

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

Non Nucleoside Reverse Transcriptase Inhibitors, Molecular Docking Studies and Antitubercular Activity of Thiazolidin-4-one Derivatives

Author(s): Trupti S. Chitre*, Shital M. Patil, Anagha G. Sujalegaonkar, Kalyani D. Asgaonkar, Vijay M. Khedkar, Dinesh R. Garud, Prakash C. Jha, Sharddha Y. Gaikwad, Smita S. Kulkarni, Amit Choudhari and Dhiman Sarkar

Volume 15, Issue 5, 2019

Page: [433 - 444] Pages: 12

DOI: 10.2174/1573409915666181221102903

Price: $65

Abstract

Background: Management of Co-existence of Acquired immunodeficiency syndrome and Tuberculosis has become a global challenge due to the emergence of resistant strains and pill burden.

Objective: Hence the aim of the present work was to design and evaluate compounds for their dual activity on HIV-1 and Tuberculosis (TB).

Methods: A series of seven, novel Thiazolidin-4-one derivatives were synthesized and evaluated for their anti-HIV and anti-tubercular activity along with Molecular docking studies. All the seven compounds displayed promising activity against the replication of HIV-1 in cell-based assays. The four most active compounds were further evaluated against X4 tropic HIV-1UG070 and R5 tropic HIV-1VB59 primary isolates. The binding affinity of all the designed compounds for HIV-RT and Mycobacterium tuberculosis Enol Reductase (MTB InhA) was gauged by molecular docking studies which revealed crucial thermodynamic interactions governing their binding.

Results: The CC50 values for the test compounds were in the range of, 15.08-34.9 μg/ml, while the IC50 values were in the range of 16.1-27.13(UG070; X4) and 12.03-23.64 (VB59; R5) μg/ml. The control drug Nevirapine (NVP) exhibited CC50 value of 77.13 μg/ml and IC50 value of 0.03 μg/ml. Amongst all these compounds, compound number 3 showed significant activity with a TI value of 2.167 and 2.678 against the HIV-1 X4 and the R5 tropic virus respectively. In anti-mycobacterial screening, the compounds proved effective in inhibiting the growth of both log phase and starved MTB cultures.

Conclusion: Compound 3 has been found to be active against HIV-1 as well as MTB.

Keywords: Non nucleoside reverse transcriptase, human immunodeficiency virus-1, anti-HIV-1 activity, antitubercular activity, molecular docking, thiazolidin-4-ones.

« Previous Next »
Graphical Abstract

[1]
Banerjee, D.; Yogeshwari, P.; Bhat, P.; Thomas, A.; Srividya, M.; Sriram, D. Novel isatinyl thiosemicarbazones derivatives as potential molecule to combat HIV-TB co-infection. Eur. J. Med. Chem., 2011, 46, 106-121.
[2]
Sarafianos, S.G.; Das, K.; Hughes, S.H.; Arnold, E. Taking aim at a moving target: Designing drugs to inhibit drug-resistant HIV-1 reverse transcriptases. Curr. Opin. Struct. Biol., 2004, 14, 716-730.
[3]
Murugesan, V.; Makwana, N.; Suryawanshi, R.; Saxena, R.; Tripathi, R.; Paranjape, R.; Kulkarni, S.; Katti, S.B. Rational design and synthesis of novel thiazolidin-4-ones as non-nucleoside HIV-1 reverse transcriptase inhibitors. Bioorg. Med. Chem., 2014, 22, 3159-3170.
[4]
Esposito, F.; Corona, A.; Tramontano, E. HIV-1 reverse transcriptase still remains a new drug target: Structure, function, classical inhibitors, and new inhibitors with innovative mechanisms of actions. Mol. Biol. Int., 2012, 2012586401
[5]
Banerjee, A.; Dubnau, E.; Quemard, A.; Balasubramanian, V.; Um, K.S.; Wilson, T.; Collins, D.; de Lisle, G.; Jacobs, W.R., Jr InhA, a gene encoding a target for isoniazid and ethionamide in Mycobacterium tuberculosis. Sci, 1994, 263, 227-230.
[6]
Vilcheze, C.; Morbidoni, H.R.; Weisbrod, T.R.; Iwamoto, H.; Kuo, M.; Sacchettini, J.C.; Jacobs, W.R. Inactivation of the inhA-encoded fatty acid synthase II (FASII) enoyl-acyl carrier protein reductase induces accumulation of the FASI end products and cell lysis of Mycobacterium smegmatis. J. Bacteriol., 2000, 182, 4059-4067.
[7]
Ren, J.; Stammers, D.K. HIV reverse transcriptase structures: Designing new inhibitors and understanding mechanisms of drug resistance. Trends Pharmacol. Sci., 2005, 260, 4-7.
[8]
Barreca, M.L.; Chimirri, A.; De Luca, L.; Monforte, A.M.; Monforte, P.; Rao, A.; Zappalà, M.; Balzarini, J.; De Clercq, E.; Pannecouque, C.; Witvrouw, M. Discovery of 2,3-diaryl-1,3-thiazolidin-4-ones as potent anti-HIV-1 agents. Bioorg. Med. Chem. Lett., 2001, 11, 1793-1796.
[9]
Rao, A.; Balzarini, J.; Carbone, A.; Chimirri, A.; De Clercq, E.; Monforte, A.M.; Monforte, P.; Pannecouque, C.; Zappalà, M. 2-(2,6-Dihalophenyl)-3-(pyrimidin-2-yl)-1,3-thiazolidin-4-ones as non-nucleoside HIV-1 reverse transcriptase inhibitors. Antiviral Res., 2004, 63, 79-84.
[10]
Rawal, R.K.; Tripathi, R.; Katti, S.B.; Pannecouque, C.; De Clercq, E. Design, synthesis, and evaluation of 2-aryl-3-heteroaryl-1,3-thiazolidin-4-ones as anti-HIV agents. Bioorg. Med. Chem., 2007, 15, 1725-31.
[11]
Rawal, R.K.; Tripathi, R.; Katti, S.B.; Pannecouque, C.; De Clercq, E. Synthesis and evaluation of 2-(2,6-dihalophenyl)-3-pyrimidinyl-1,3-thiazolidin-4-one analogues as anti-HIV-1 agents. Bioorg. Med. Chem., 2007, 15, 3134-31342.
[12]
Rawal, R.K.; Tripathi, R.K.; Katti, S.B.; Pannecouque, C.; De Clercq, E. Synthesis and biological evaluation of 2,3-diaryl substituted-1,3-thiazolidin-4-ones as anti-HIV agents. Med. Chem., 2007, 3, 355-363.
[13]
Rawal, R.K.; Tripathi, R.; Katti, S.B.; Pannecouque, C.; De Clercq, E. Design and synthesis of 2-(2,6-dibromophenyl)-3-heteroaryl-1,3-thiazolidin-4-ones as anti-HIV agents. Eur. J. Med. Chem., 2008, 430, 2800-2806.
[14]
Balzarini, J.; Orzeszko, B.; Maurin, J.K.; Orzeszko, A. Synthesis and anti-HIV studies of 2-adamantyl-substituted thiazolidin-4-ones. Eur. J. Med. Chem., 2007, 42, 993-1003.
[15]
Balzarini, J.; Orzeszko-Krzesinska, B.; Maurin, J.K.; Orzeszko, A. Synthesis and anti-HIV studies of 2- and 3-adamantyl-substituted thiazolidin-4-ones. Eur. J. Med. Chem., 2009, 44, 303-311.
[16]
Tripathi, A.C.; Gupta, S.J.; Fatima, G.N.; Sonar, P.K.; Verma, A.; Saraf, S.K. 4-Thiazolidinones: the advances continue. Eur. J. Med. Chem., 2014, 72, 52-77.
[17]
Pawar, V.; Lokwani, D.; Bhandari, S.; Mitra, D.; Sabde, S.; Bothara, K.; Madgulkar, A. Design of potential reverse transcriptase inhibitor containing Isatin nucleus using molecular modeling studies. Bioorg. Med. Chem., 2010, 18, 3198-3211.
[18]
Akkurt, M.; Çelik, I.; Demir, H.; Özkırımlı, S.; Büyükgüngörd, O.N. -[2-(4-Chlorophenyl)-5-methyl-4-oxo-1,3-thiazolidin-3-yl]pyridine-3-carboxamide. Acta Crystallogr. Sect. E Struct. Rep. Online, 2011, 6(4), 745-746.
[19]
Küçükgüzel, S.G.; Oruç, E.E.; Rollas, S.; Sahin, F.; Özbek, A. Synthesis, characterisation and biological activity of novel 4-thiazolidinones, 1,3,4-oxadiazoles and some related compounds. Eur. J. Med. Chem., 2002, 37(3), 197-206.
[20]
Krishna, S.M.; Padmalatha, Y.; Ravindranath, L.K. Thiazolidinone as a core unit biological evaluation agent. Int. J. Med. Pharm. Res, 2015, 3(2), 999-1003.
[21]
Shanthi, V.; Ramanathan, K. Identification of potential inhibitor targeting enoyl-acyl carrier protein reductase (InhA) in Mycobacterium tuberculosis:a computational approach. Biotechnology, 2014, 4, 253-261.
[22]
Cichero, E.; Cesarini, S.; Spallarossa, A.; Mosti, L.; Fossa, P. Acylthiocarbamates as non-nucleoside HIV-1 reverse transcriptase inhibitors: docking studies and ligand-based CoMFA and CoMSIA analyses. J. Mol. Model., 2009, 15(7), 871-884.
[23]
Cichero, E.; Fossa, P. Docking-based 3D-QSAR analyses of pyrazole derivatives as HIV-1 non-nucleoside reverse transcriptase inhibitors. J. Mol. Model., 2012, 18, 1153-1182.
[24]
Deep, A.; Jain, S.; Sharma, P.C.; Mittal, S.K.; Phogat, P.; Malhotra, M. Synthesis, characterization and antimicrobial evaluation of 2, 5-disubstituted-4-thiazolidinone derivatives. Arab. J. Chem., 2014, 7, 287-291.
[25]
Desai, N.; Dodiya, A.M. Synthesis, characterization and antimicrobial screening of quinoline based quinazolinone-4-thiazolidinone heterocycles. Arab. J. Chem., 2014, 7, 906-913.
[26]
Geonnotti, A.R.; Bilska, M.; Yuan, X.; Ochsenbauer, C.; Edmonds, T.G.; Kappes, J.C.; Liao, H.; Haynes, B.F.; Montefiori, D.C. Differential inhibition of human immunodeficiency virus type 1 in peripheral blood mononuclear cells and TZM-bl cells by endotoxin-mediated chemokine and gamma interferon production. AIDS Res. Hum. Retroviruses, 2010, 26, 279-291.
[27]
Khopkar, P.; Mallav, V.; Chidrawar, S.; Kulkarni, S. Comparative evaluation of the Abbott HIV-1 RealTime assay with the Standard Roche COBAS(R) Amplicor HIV-1 Monitor(R) Test, v1.5 for determining HIV-1 RNA levels in plasma specimens from Pune, India. J. Virol. Methods, 2013, 191, 82-87.
[28]
Said, M.; Chinchansure, A.; Nawale, L.; Durge, A.; Wadhwani, A.; Kulkarni, S.S.; Sarkar, D.; Joshi, S. A new butenolide cinnamate and other biological active chemical constituents from Polygonum Glabrum. Nat. Prod. Res., 2015, 25(22), 2080-2086.
[29]
Singh, U.; Akhtar, S.; Mishra, A.; Sarkar, D. A novel screening method based on menadione mediated rapid reduction of tetrazolium salt for testing of anti-mycobacterial agents. J. Microbiol. Meth, 2011, 84, 202-207.
[30]
Friesner, R.A.; Banks, J.L.; Murphy, R.B.; Halgren, T.A.; Klicic, J.J.; Mainz, D.T.; Repasky, M.P.; Knoll, E.H.; Shelley, M.; Perry, J.K.; Shaw, D.E.; Francis, P.; Shenkin, P.S. Glide: A new approach for rapid, accurate docking and scoring. 1. Method and assessment of docking accuracy. J. Med. Chem., 2004, 47, 1739-1749.
[31]
Halgren, T.A.; Murphy, R.B.; Friesner, R.A.; Beard, H.S.; Frye, L.L.; Pollard, W.T.; Banks, J.L. Glide: A new approach for rapid, accurate docking and scoring. 2. Enrichment factors in data base screening. J. Med. Chem., 2004, 47, 1750-1759.

Rights & Permissions Print Cite
Article Metrics
79
3
© 2024 Bentham Science Publishers | Privacy Policy