Generic placeholder image

Letters in Drug Design & Discovery

Editor-in-Chief

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

Research Article

Synthesis, Antimicrobial Evaluation and In silico Studies of Novel 2,4- disubstituted-1,3-thiazole Derivatives

Author(s): Mir Mohammad Masood, Mohammad Irfan, Shadab Alam , Phool Hasan, Aarfa Queen, Shifa Shahid, Muhammad Zahid, Amir Azam and Mohammad Abid*

Volume 16, Issue 2, 2019

Page: [160 - 173] Pages: 14

DOI: 10.2174/1570180815666180502120042

Price: $65

Abstract

Background: 2,4-disubstituted-1,3-thiazole derivatives (2a–j), (3a–f) and (4a–f) were synthesized, characterized and screened for their potential as antimicrobial agents. In the preliminary screening against a panel of bacterial strains, nine compounds showed moderate to potent antibacterial activity (IC50 = 13.7-90.8 μg/ml).

Methods: In the antifungal screening, compound (4c) displayed potent antifungal activity (IC50 = 26.5 µg/ml) against Candida tropicalis comparable to the standard drug, fluconazole (IC50 = 10.5 µg/ml). Based on in vitro antimicrobial results, compounds 2f, 4c and 4e were selected for further pharmacological investigations. Hemolytic activity using human red blood cells (hRBCs) and cytotoxicity by MTT assay on human embryonic kidney (HEK-293) cells revealed non-toxic nature of the selected compounds (2f, 4c and 4e). To ascertain their possible mode of action, docking studies with the lead inhibitors (2f, 4c and 4e) were performed using crystal structure coordinates of bacterial methionine aminopeptidases (MetAPs), an enzyme involved in bacterial protein synthesis and maturation.

Results: The results of in vitro and in silico studies provide a rationale for selected compounds (2f, 4c and 4e) to be carried forward for further structural modifications and structure-activity relationship (SAR) studies against these bacterial infections.

Conclusion: The study suggested binding with one or more key amino acid residues in the active site of Streptococcus pneumoniae MetAP (SpMetAP) and Escherichia coli MetAP (EcMetAP). In silico physicochemical properties using QikProp confirmed their drug likeliness.

Keywords: 2, 4-disubstituted-1, 3-thiazole, antimicrobial, hemolysis, cytotoxicity, docking, ADME.

Graphical Abstract

[1]
Grare, M.; Mourer, M.; Fontanay, S.; Regnouf-de-Vains, J-B.; Finance, C.; Duval, R.E. In VItro Activity of para-guanidinoethylcalix[4]arene against Susceptible and antibiotic-resistant gram-negative and gram-positive bacteria. J. Antimicrob. Chemother., 2007, 60, 575-581.
[2]
Roberts, M. Distribution of Macrolide, Lincosamide, Streptogramin, Ketolide and Oxazolidinone (MLSKO) resistance genes in gram-negative bacteria. Curr. Drug Target Infectious. Disord., 2004, 4, 207-215.
[3]
Tenover, F.C.; McDonald, L.C. Vancomycin-resistant staphylococci and enterococci: epidemiology and control. Curr. Opin. Infect. Dis., 2005, 18, 300-305.
[4]
Hover, B.M.; Kim, S-H.; Katz, M.; Charlop-Powers, Z.; Owen, J.G.; Ternei, M.A.; Maniko, J.; Estrela, A.B.; Molina, H.; Park, S.; Perlin, D.S.; Brady, S.F. Culture-independent discovery of the malacidins as calcium-dependent antibiotics with activity against multidrug-resistant gram-positive pathogens. Nat. Microbiol., 2018, 3, 415-422.
[5]
Liaras, K.; Geronikaki, A.; Glamočlija, J.; Ćirić, A.; Soković, M. Thiazole-based chalcones as potent antimicrobial agents. synthesis and biological evaluation. Bioorg. Med. Chem., 2011, 19, 3135-3140.
[6]
Hargrave, K.D.; Hess, F.K.; Oliver, J.T.N. -(4-Substituted-Thiazolyl)oxamic acid derivatives, new series of potent, orally active antiallergy agents. J. Med. Chem., 1983, 26, 1158-1163.
[7]
Patt, W.C.; Hamilton, H.W.; Taylor, M.D.; Ryan, M.J.; Taylor, D.G.; Connolly, C.J.C.; Doherty, A.M.; Klutchko, S.R.; Sircar, I. Structure-activity relationships of a series of 2-Amino-4-Thiazole-containing renin inhibitors. J. Med. Chem., 1992, 35, 2562-2572.
[8]
Sharma, R.N.; Xavier, F.P.; Vasu, K.K.; Chaturvedi, S.C.; Pancholi, S.S. Synthesis of 4-Benzyl-1,3-Thiazole derivatives as potential anti-inflammatory agents: an analogue-based drug design approach. J. Enzyme Inhib. Med. Chem., 2009, 24, 890-897.
[9]
Jaen, J.C.; Wise, L.D.; Caprathe, B.W.; Tecle, H.; Bergmeier, S.; Humblet, C.C.; Heffner, T.G.; Meltzer, L.T.; Pugsley, T.A. 4-(1,2,5,6-Tetrahydro-1-Alkyl-3-Pyridinyl)-2-Thiazolamines: A novel class of compounds with central dopamine agonist properties. J. Med. Chem., 1990, 33, 311-317.
[10]
Mayhoub, A.S.; Khaliq, M.; Botting, C.; Li, Z.; Kuhn, R.J.; Cushman, M. An investigation of phenylthiazole antiflaviviral agents. Bioorg. Med. Chem., 2011, 19, 3845-3854.
[11]
Cantrell, A.S.; Engelhardt, P.; Högberg, M.; Jaskunas, S.R.; Johansson, N.G.; Jordan, C.L.; Kangasmetsä, J.; Kinnick, M.D.; Lind, P.; Morin, J.M., Jr; Muesing, M.A.; Noreén, R.; Oberg, B.; Pranc, P.; Sahlberg, C.; Ternansky, R.J.; Vasileff, R.T.; Vrang, L.; West, S.J.; Zhang, H. Phenethylthiazolylthiourea (PETT) compounds as a new class of HIV-1 reverse transcriptase inhibitors. 2. Synthesis and further structure-activity relationship studies of PETT analogs. J. Med. Chem., 1996, 39, 4261-4274.
[12]
Ergenç, N.; Çapan, G.; Günay, N.S.; Özkirimli, S.; Güngör, M.; Özbey, S.; Kendi, E. Synthesis and hypnotic activity of new 4-Thiazolidinone and 2-Thioxo-4,5-Imidazolidinedione derivatives. Arch. Pharm. (Weinheim), 1999, 332, 343-347.
[13]
Carter, J.S.; Kramer, S.; Talley, J.J.; Penning, T.; Collins, P.; Graneto, M.J.; Seibert, K.; Koboldt, C.M.; Masferrer, J.; Zweifel, B. Synthesis and activity of sulfonamide-substituted 4,5-diaryl thiazoles as selective cyclooxygenase-2 inhibitors. Bioorg. Med. Chem. Lett., 1999, 9, 1171-1174.
[14]
Rudolph, J.; Theis, H.; Hanke, R.; Endermann, R.; Johannsen, L.; Geschke, F-U. Seco-Cyclothialidines: New concise synthesis, inhibitory activity toward bacterial and human DNA topoisomerases, and antibacterial properties. J. Med. Chem., 2001, 44, 619-626.
[15]
Özdemir, A.; Turan-Zitouni, G.; Asım Kaplancıklı, Z.; Revial, G.; Güven, K. Synthesis and antimicrobial activity of 1-(4-Aryl-2-thiazolyl)-3-(2-thienyl)-5-Aryl-2-pyrazoline derivatives. Eur. J. Med. Chem., 2007, 42, 403-409.
[16]
Quiroga, J.; Hernández, P.; Insuasty, B.; Abonía, R.; Cobo, J.; Sánchez, A.; Nogueras, M.; Low, J.N. Control of the reaction between 2-aminobenzothiazoles and mannich bases. synthesis of pyrido[2,1-b][1,3]benzothiazoles versus [1,3]benzothiazolo[2,3-B]quinazolines. J. Chem. Soc., Perkin Trans. 1, 2002, 57, 555-559.
[17]
Souza, M. de Almeida, M. de. Drogas Anti-HIV: Passado, presente E perspectivas futuras. Quim. Nova, 2003, 26, 366-372.
[18]
Hutchinson, I.; Jennings, S.A.; Vishnuvajjala, B.R.; Westwell, A.D.; Stevens, M.F.G. Antitumor Benzothiazoles. 16. synthesis and pharmaceutical properties of antitumor 2-(4-Aminophenyl) benzothiazole Amino Acid Prodrugs. J. Med. Chem., 2002, 45, 744-747.
[19]
Mylari, B.L.; Larson, E.R.; Beyer, T.A.; Zembrowski, W.J.; Aldinger, C.E.; Dee, M.F.; Siegel, T.W.; Singleton, D.H. Novel, potent aldose reductase inhibitors: 3,4-Dihydro-4-Oxo-3-[[5-(Trifluoromethyl)-2-Benzothiazolyl]methyl]-1-Phthalazineacetic acid (Zopolrestat) and congeners. J. Med. Chem., 1991, 34, 108-122.
[20]
Irfan, M.; Alam, S.; Manzoor, N.; Abid, M.; Manzoor, N.; Khan, L. Effect of quinoline based 1,2,3-Triazole and its structural analogues on growth and virulence attributes of candida albicans. PLoS One, 2017, 12, e0175710.
[21]
Masood, M.M.; Hasan, P.; Tabrez, S.; Ahmad, M.B.; Yadava, U.; Daniliuc, C.G.; Sonawane, Y.A.; Azam, A.; Rub, A.; Abid, M. Anti-leishmanial and cytotoxic activities of amino acid-triazole hybrids: synthesis, biological evaluation, molecular docking and in silico physico-chemical properties. Bioorg. Med. Chem. Lett., 2017, 27, 1886-1891.
[22]
Irfan, M.; Khan, S.I.; Manzoor, N.; Abid, M. Biological activities and in silico physico-chemical properties of 1,2,3-triazoles derived from natural bioactive alcohols. Anti-infective. Agents, 2016, 14, 126-131.
[23]
Aneja, B.; Irfan, M.; Kapil, C.; Jairajpuri, M.A.; Maguire, R.; Kavanagh, K.; Rizvi, M.M.A.; Manzoor, N.; Azam, A.; Abid, M.; Zhang, W.; Zhu, J.; Lü, J.; Sheng, C. Effect of novel triazole-amino acid hybrids on growth and virulence of candida species: in vitro and in vivo studies. Org. Biomol. Chem., 2016, 14, 10599-10619.
[24]
Masood, M.M.; Pillalamarri, V.K.; Irfan, M.; Aneja, B.; Jairajpuri, M.A.; Zafaryab, M.; Rizvi, M.M.A.; Yadava, U.; Addlagatta, A.; Abid, M. Diketo Acids and their amino acid/dipeptidic analogues as promising scaffolds for the development of bacterial methionine aminopeptidase inhibitors. RSC Adv, 2015, 5, 34173-34183.
[25]
Aneja, B.; Irfan, M.; Hassan, M.I.; Prakash, A.; Yadava, U.; Daniliuc, C.G.; Zafaryab, M.; Rizvi, M.M.A.; Azam, A.; Abid, M. Monocyclic β-lactam and unexpected oxazinone formation: synthesis, crystal structure, docking studies and antibacterial evaluation. J. Enzyme Inhib. Med. Chem., 2015, 1-19.
[26]
Irfan, M.; Aneja, B.; Yadava, U.; Khan, S.I.; Manzoor, N.; Daniliuc, C.G.; Abid, M. Synthesis, QSAR and anticandidal evaluation of 1,2,3-Triazoles derived from naturally bioactive scaffolds. Eur. J. Med. Chem., 2015, 93, 246-254.
[27]
Lowther, W.T.; Matthews, B.W. Structure and function of the methionine aminopeptidases. Biochim. Biophys. Acta - Protein Struct. Mol. Enzymol., 2000, 1477, 157-167.
[28]
Lipinski, C.A.; Lombardo, F.; Dominy, B.W.; Feeney, P.J. Experimental and computational approaches to estimate Solubility and permeability in drug discovery and development settings. Adv. Drug Deliv. Rev., 1997, 23, 3-25.
[29]
Wikler, M.A. Performance standards for antimicrobial susceptibility testing: seventeenth informational supplement. Clinical and Laboratory Standards Institute; CLSI, 2007.
[30]
Kumar, A.; Zafaryab, M.; Umar, A.; Rizvi, M.M.A.; Ansari, H.Z.A.F.; Ansari, S.G. Relief of oxidative stress using curcumin and glutathione functionalized ZnO nanoparticles in HEK-293 cell line. J. Biomed. Nanotechnol., 2015, 11, 1913-1926.
[31]
Trott, O.; Olson, A. AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J. Comput. Chem., 2010, 31, 455-461.
[32]
DeLano, W. The PyMOL User’s Manual; , 2002.
[33]
Schrödinger, L. QikProp, Version 5.1. New York, NY; , 2017.

© 2024 Bentham Science Publishers | Privacy Policy