Benzothiazol Clubbed Imidazol-4-ones as Anti-fungal, Anti-tubercular and Anti-HIV-1 Agents: Their Synthesis and Molecular Docking Study

Author(s): Navin B. Patel*, Asif R. Shaikh, Vatsal M. Patel, Edgar E. Lara-Ramirez, Gildardo Rivera.

Journal Name: Letters in Drug Design & Discovery

Volume 16 , Issue 4 , 2019

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Graphical Abstract:


Background: The present work describes antimicrobial, antimycobacterium and anti HIV-1 evaluation of newly synthesized 5-(4-Substituted-benzylidene)-3-[4-(5-methyl-benzothiazol- 2-yl)-phenyl]-2-phenyl-3,5-dihydro-imidazol-4-one (4a-o). The docking studies were performed in order to predict the potential binding affinities.

Objective: The major aim of this study is to develop the new class of bezylidine candidate clubbed with benzothiazole with less toxicity and improved potency as antimicrobial, antitubercular and anti HIV-1.

Methods: The titled compounds were characterized by spectral studies (IR, 1H NMR, 13C NMR and Mass). In vitro antimycobacterium activity was carried out using Lowenstein-Jensen medium method and antimicrobial activity using the broth microdilution method. The anti HIV-1 reverse transcriptase activity was determined by the colorimetric MTT method and inhibition of virusinduced cytopathogenicity in MT-4 cells.

Results: Compound 4i (50 µM) showed better antifungal activity against A. clavatus. Compound 4g (50 µM) with 95% inhibition demonstrated good activity against M. tuberculosis H37Rv. Compound 4k showed CC50 (50 µM) against MT-4 (CD4+ Human T-cells containing an integrated HTLV-1 genome) cells by 50%, while 16 µM concentration value EC50 from the HIV-1 induced cytopathogenicity. Molecular docking study suggested that 4k interacted with the target with binding energy by Vina score (-10.3 Kcal/mol).

Conclusion: The preliminary in vitro evaluation results revealed that some of the compounds have promising antimicrobial activities as well as antitubercular potency. Among the various substituents on benzylidene, the nitro group was the most beneficial for improving the anti-HIV-1 activity. Docking result suggested that 4k compound could be acting as a non-competitive or weak inhibitor of Reverse Transcriptase (RT).

Keywords: Imidazolone, RT docking, antimicrobial, antitubercular, anti-HIV, cytopathogenicity.

Sunjic, V.; Parnham, M.J. Signposts to chiral drugs: organic synthesis in action; Springer Science & Business Media, 2011.
Shah, N.M.; Patel, M.P.; Patel, R.G. New N-arylamino biquinoline derivatives: Synthesis, antimicrobial, antituberculosis, and antimalarial evaluation. Eur. J. Med. Chem., 2012, 54, 239-247.
Sandhu, G.K. Tuberculosis: Current situation, challenges and overview of its control programs in India. J. Glob. Infect. Dis., 2011, 3(2), 143.
van de Vosse, E. Primary immunodeficiency leading to mycobacterial disease. Int. J. Mycobacteriol., 2015, 4, 63.
Nachega, J.B. Chaisson, R.E. Tuberculosis drug resistance: A global threat. Clin. Infect. Dis., 2003, 36(Suppl. 1), S24-S30.
Vandeputte, P.; Ferrari, S.; Coste, A.T. Antifungal resistance and new strategies to control fungal infections. Int. J. Micro., 2011, 2012
Hirsch, E.B. Tam, V.H. Impact of multidrug-resistant Pseudomonas aeruginosa infection on patient outcomes. Expert Rev. Pharmacoecon. Outcomes Res., 2010, 10(4), 441-451.
Klein, E.; Smith, D.L.; Laxminarayan, R. Hospitalizations and deaths caused by methicillin-resistant Staphylococcus aureus, United States, 1999-2005. Emerg. Infect. Dis., 2007, 13(12), 1840.
Swaminathan, S.; Padmapriyadarsini, C.; Narendran, G. HIV-associated tuberculosis: Clinical update. Clin. Infect. Dis., 2010, 50(10), 1377-1386.
Khan, K.M.; Mughal, U.R.; Khan, S.; Khan, S.; Perveen, S.; Choudhary, M.I. Synthesis and antibacterial and antifungal activity of 5-substituted imidazolones. Lett. Drug Des. Discov., 2009, 6(1), 69-77.
Patel, A.; Bari, S.; Talele, G.; Patel, J.; Sarangapani, M. Synthesis and antimicrobial activity of some new isatin derivatives. Iran. J. Pharm. Res., 2006, 4, 249-254.
Congiu, C.; Cocco, M.T.; Onnis, V. Design, synthesis, and in vitro antitumor activity of new 1, 4-diarylimidazole-2-ones and their 2-thione analogues. Bioorg. Med. Chem. Lett., 2008, 18(3), 989-993.
El-Araby, M.; Omar, A.; Hassanein, H.H.; El-Helby, A-G.H.; Abdel-Rahman, A.A. Design, synthesis and in vivo anti-inflammatory activities of 2, 4-diaryl-5-4H-imidazolone derivatives. Molecules, 2012, 17(10), 12262-12275.
Thaker, K.; Zalavadiya, P.; Joshi, H. Synthesis of some new imidazolones and 1, 2, 4-triazoles bearing benzo [b] thiophene nucleus as antimicrobial agents. J. Sci. Islam. Repub. Iran, 2005, 16(2), 139-144.
Kamal, A.; Ramakrishna, G.; Raju, P.; Viswanath, A.; Ramaiah, M.J.; Balakishan, G.; Pal-Bhadra, M. Synthesis and anti-cancer activity of chalcone linked imidazolones. Bioorg. Med. Chem. Lett., 2010, 20(16), 4865-4869.
Amir, M.; Asif, S.; Ali, I.; Hassan, M.Z. Synthesis of benzothiazole derivatives having acetamido and carbothioamido pharmacophore as anticonvulsant agents. Med. Chem. Res., 2012, 21(9), 2661-2670.
Saeed, S.; Rashid, N.; Jones, P.G.; Ali, M.; Hussain, R. Synthesis, characterization and biological evaluation of some thiourea derivatives bearing benzothiazole moiety as potential antimicrobial and anticancer agents. Eur. J. Med. Chem., 2010, 45(4), 1323-1331.
Aiello, S.; Wells, G.; Stone, E.L.; Kadri, H.; Bazzi, R.; Bell, D.R.; Stevens, M.F.; Matthews, C.S.; Bradshaw, T.D.; Westwell, A.D. Synthesis and biological properties of benzothiazole, benzoxazole, and chromen-4-one analogues of the potent antitumor agent 2-(3, 4-dimethoxyphenyl)-5-fluorobenzothiazole (PMX 610, NSC 721648)(1). J. Med. Chem., 2008, 51(16), 5135-5139.
Bhavsar, D.; Trivedi, J.; Parekh, S.; Savant, M.; Thakrar, S.; Bavishi, A.; Radadiya, A.; Vala, H.; Lunagariya, J.; Parmar, M. Synthesis and in vitro anti-HIV activity of N-1, 3-benzo [d] thiazol-2-yl-2-(2-oxo-2H-chromen-4-yl) acetamide derivatives using MTT method. Bioorg. Med. Chem. Lett., 2011, 21(11), 3443-3446.
Al-Tel, T.H.; Al-Qawasmeh, R.A.; Zaarour, R. Design, synthesis and in vitro antimicrobial evaluation of novel Imidazo [1, 2-a] pyridine and imidazo [2, 1-b][1, 3] benzothiazole motifs. Eur. J. Med. Chem., 2011, 46(5), 1874-1881.
Rattan, A. Antimicrobials in laboratory medicine. Churchill BI; Livingstone: New Delhi, 2000, p. 85.
Navin, P.; Sarvil, P.; Amit, P.; Divyesh, P.; Dhansukh, R.; Moo-Puc, R.; Rivera, G. Synthesis and biological evaluation of newer 1, 3, 4-oxadiazoles incorporated with benzothiazepine and benzodiazepine moieties. Zeitschrift. Für. Naturforschung. C., 2017, 72(3-4), 133-146.
Patel, M.B.; Modi, N.R.; Raval, J.P.; Menon, S.K. Calix [4] arene based 1, 3, 4-oxadiazole and thiadiazole derivatives: Design, synthesis, and biological evaluation. Org. Biomol. Chem., 2012, 10(9), 1785-1794.
Collins, L.; Franzblau, S.G. Microplate alamar blue assay versus BACTEC 460 system for high-throughput screening of compounds against Mycobacterium tuberculosis and Mycobacterium avium. Antimicrob. Agents Chemother., 1997, 41(5), 1004-1009.
Danel, K.; Jørgensen, P.T.; Pedersen, E.B.; La Colla, P.; Collu, G. Loddo, R. Synthesis and anti‐HIV‐1 evaluation of new sonogashira‐modified emivirine (MKC‐442) analogues. Helv. Chim. Acta, 2009, 92(7), 1385-1403.
Desai, N.; Pandya, D.; Kotadiya, G.; Desai, P. Synthesis, antimicrobial and cytotoxic activity of 2-azetidinone derivatives of pyridyl benzimidazoles. Med. Chem. Res., 2014, 23(4), 1725-1741.
Patel, N.B.; Khan, I.H.; Pannecouque, C.; De Clercq, E. Anti-HIV, antimycobacterial and antimicrobial studies of newly synthesized 1, 2, 4-triazole clubbed benzothiazoles. Med. Chem. Res., 2013, 22(3), 1320-1329.
Trott, O.; Olson, A.J. AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J. Comput. Chem., 2010, 31(2), 455-461.
Lindberg, J.; Sigurðsson, S.; Löwgren, S.O.; Andersson, H.; Sahlberg, C.; Noreen, R.; Fridborg, K.; Zhang, H.; Unge, T. Structural basis for the inhibitory efficacy of efavirenz (DMP-266), MSC194 and PNU142721 towards the HIV-1 RT K103N mutant. Eur. J. Biochem., 2002, 269(6), 1670-1677.
Morris, G.M.; Huey, R.; Lindstrom, W.; Sanner, M.F.; Belew, R.K.; Goodsell, D.S.; Olson, A.J. AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility. J. Comput. Chem., 2009, 30(16), 2785-2791.

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Article Details

Year: 2019
Page: [382 - 391]
Pages: 10
DOI: 10.2174/1570180815666180712150050
Price: $58

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