Abstract
Background: Benzothiazoles are reported to have bioorganic and pharmaceutical chemistry applications.
Introduction: A series of substituted N-bromoamido-2-aminobenzothiazoles was synthesized from substituted anilines via 2-aminobenzothiazoles and it was further evaluated for its antimicrobial activity.
Methods: All the newly synthesized compounds were characterized by FT-IR, NMR and mass spectra and purity profiles were studied by HPLC analysis. The antimicrobial testing (MIC determination) was newly performed with agar micro-broth dilution method for these analogs.
Results: Among the synthesized compound 3b showed the highest activity with MIC value of 3.12 μg/mL against Bacillus, E. coli, S. aureus and Klebsiella and 6.25 μg/mL against C. albicans. The ADME properties as calculated by using Qikprop were found within acceptable range. Derivatives shows a good-moderate binding affinity towards target Cytochrome P450 14 alpha-sterol demethylase (CYP51) (PDB ID: 1EA1).
Conclusion: Our in-silico and in-vitro studies on a series of substituted aminobenzothiazoles may be helpful for further designing of more potent antimicrobials in future.
Keywords: 2-aminobenzothiazole, antimicrobial activity, molecular docking, antibacterials, 14 alpha-sterol demethylase, ADMET predictions.
Graphical Abstract
[1]
Suter, H.; Zutter, H. Studies concerning benzthiazoles as eventual oral antidiabetics Helv. Chim. Acta, 1967, 50(4), 1084-1086.
[http://dx.doi.org/10.1002/hlca.19670500415] [PMID: 5592027]
[http://dx.doi.org/10.1002/hlca.19670500415] [PMID: 5592027]
[2]
Hays, S.J.; Rice, M.J.; Ortwine, D.F.; Johnson, G.; Schwarz, R.D.; Boyd, D.K.; Copeland, L.F.; Vartanian, M.G.; Boxer, P.A. Substituted 2-benzothiazolamines as sodium flux inhibitors: quantitative structure-activity relationships and anticonvulsant activity. J. Pharm. Sci., 1994, 83(10), 1425-1432.
[http://dx.doi.org/10.1002/jps.2600831013] [PMID: 7884664]
[http://dx.doi.org/10.1002/jps.2600831013] [PMID: 7884664]
[3]
Sawhney, S.N.; Arora, S.K.; Singh, J.V.; Bansal, O.P.; Singh, S.P. synthesis and antiinflammatory activity of 2‐amino‐and 2‐alkylamino‐6‐benzothiazoleacetic acids, 4‐(2′‐benzothiazolylamino)‐,4‐(4′‐substituted‐2‐thiazolylamino)‐and 4‐(4′‐substituted‐3′‐alkyl‐δ4′‐thiazoline‐2′‐imino) phenylacetic acids. Indian J. Chem., 1978, 16B, 605.
[http://dx.doi.org/10.1002/chin.197852206]
[http://dx.doi.org/10.1002/chin.197852206]
[4]
Bensimon, G.; Lacomblez, L.; Meininger, V. A controlled trial of riluzole in amyotrophic lateral sclerosis. N. Engl. J. Med., 1994, 330(9), 585-591.
[http://dx.doi.org/10.1056/NEJM199403033300901] [PMID: 8302340]
[http://dx.doi.org/10.1056/NEJM199403033300901] [PMID: 8302340]
[5]
Foscolos, G.; Tsatsas, G.; Champagnac, A.; Pommier, M. Synthesis and pharmacodynamic study of new derivatives of benzothiazole Ann. Pharm. Fr., 1977, 35(7-8), 295-307.
[PMID: 603213]
[PMID: 603213]
[6]
Shirke, V.G.; Bobade, A.S.; Bhamaria, R.P.; Khadse, B.G.; Sengupta, S.R. Synthesis and antitubercular activity of some new 2-(substituted arylamino)-5, 6-disubstituted/6-substituted benzothiazoles. Indian Drugs, 1990, 27, 350-353.
[7]
Young, R.C.; Mitchell, R.C.; Brown, T.H.; Ganellin, C.R.; Griffiths, R.; Jones, M.; Rana, K.K.; Saunders, D.; Smith, I.R.; Sore, N.E. Development of a new physicochemical model for brain penetration and its application to the design of centrally acting H2 receptor histamine antagonists. J. Med. Chem., 1988, 31(3), 656-671.
[http://dx.doi.org/10.1021/jm00398a028] [PMID: 2894467]
[http://dx.doi.org/10.1021/jm00398a028] [PMID: 2894467]
[8]
Wang, J.; Feng, P.; Jiang, J.; Lu, Z.; Wang, L.; Bai, J.; Pan, Y. Synthesis of N-benzothiazol-2-yl-amides by a copper-catalyzed intramolecular cyclization process. Tetrahedron Lett., 2008, 49(3), 467-470.
[http://dx.doi.org/10.1016/j.tetlet.2007.11.100]
[http://dx.doi.org/10.1016/j.tetlet.2007.11.100]
[9]
Hartmann, R.; Frotscher, M.; Marchais‐Oberwinkler, S.; Oster, A.; Spadaro, A. PCT Int; Appl, 2012.
[10]
Cheung, A.W.H.; Brinkman, J.; Firooznia, F.; Flohr, A.; Grimsby, J.; Gubler, M.L.; Guertin, K.; Hamid, R.; Marcopulos, N.; Norcross, R.D.; Qi, L.; Ramsey, G.; Tan, J.; Wen, Y.; Sarabu, R. 4-Substituted-7-N-alkyl-N-acetyl 2-aminobenzothiazole amides: drug-like and non-xanthine based A2B adenosine receptor antagonists. Bioorg. Med. Chem. Lett., 2010, 20(14), 4140-4146.
[http://dx.doi.org/10.1016/j.bmcl.2010.05.056] [PMID: 20541935]
[http://dx.doi.org/10.1016/j.bmcl.2010.05.056] [PMID: 20541935]
[11]
Song, E.Y.; Kaur, N.; Park, M.Y.; Jin, Y.; Lee, K.; Kim, G.; Lee, K.Y.; Yang, J.S.; Shin, J.H.; Nam, K.Y.; No, K.T.; Han, G. Synthesis of amide and urea derivatives of benzothiazole as Raf-1 inhibitor. Eur. J. Med. Chem., 2008, 43(7), 1519-1524.
[http://dx.doi.org/10.1016/j.ejmech.2007.10.008] [PMID: 18023932]
[http://dx.doi.org/10.1016/j.ejmech.2007.10.008] [PMID: 18023932]
[12]
Yamazaki, K.; Kaneko, Y.; Suwa, K.; Ebara, S.; Nakazawa, K.; Yasuno, K. Synthesis of potent and selective inhibitors of Candida albicans N-myristoyltransferase based on the benzothiazole structure. Bioorg. Med. Chem., 2005, 13(7), 2509-2522.
[http://dx.doi.org/10.1016/j.bmc.2005.01.033]
[http://dx.doi.org/10.1016/j.bmc.2005.01.033]
[13]
Scheetz, M.E. I.I.; Carlson, D.G.; Schinitsky, M.R. Frentizole, a novel immunosuppressive, and azathioprine: their comparative effects on host resistance to Pseudomonas aeruginosa, Candida albicans, herpes simplex virus, and influenza (Ann Arbor) virus. Infect. Immun., 1977, 15(1), 145-148.
[PMID: 188761]
[PMID: 188761]
[14]
Tao, Z.F.; Hasvold, L.; Wang, L.; Wang, X.; Petros, A.M.; Park, C.H.; Boghaert, E.R.; Catron, N.D.; Chen, J.; Colman, P.M.; Czabotar, P.E.; Deshayes, K.; Fairbrother, W.J.; Flygare, J.A.; Hymowitz, S.G.; Jin, S.; Judge, R.A.; Koehler, M.F.; Kovar, P.J.; Lessene, G.; Mitten, M.J.; Ndubaku, C.O.; Nimmer, P.; Purkey, H.E.; Oleksijew, A.; Phillips, D.C.; Sleebs, B.E.; Smith, B.J.; Smith, M.L.; Tahir, S.K.; Watson, K.G.; Xiao, Y.; Xue, J.; Zhang, H.; Zobel, K.; Rosenberg, S.H.; Tse, C.; Leverson, J.D.; Elmore, S.W.; Souers, A.J. Discovery of a potent and selective BCL-XL inhibitor with in vivo activity. ACS Med. Chem. Lett., 2014, 5(10), 1088-1093.
[http://dx.doi.org/10.1021/ml5001867] [PMID: 25313317]
[http://dx.doi.org/10.1021/ml5001867] [PMID: 25313317]
[15]
Sawhney, S.N.; Boykin, D.W. Transmission of substituent effects in heterocyclic systems by carbon-13 nuclear magnetic resonance. Benzothiazoles. J. Org. Chem., 1979, 44(7), 1136-1142.
[http://dx.doi.org/10.1021/jo01321a024]
[http://dx.doi.org/10.1021/jo01321a024]
[16]
Dong, H.S.; Quan, B.; Chai, E.F.; Mao, X.R. The syntheses and crystal structure of novel 5-methyl-3-substituted-1, 2, 4-triazolo [3, 4-b] benzothiazoles. J. Mol. Struct., 2002, 608(1), 41-47.
[http://dx.doi.org/10.1016/S0022-2860(01)00923-1]
[http://dx.doi.org/10.1016/S0022-2860(01)00923-1]
[17]
Deshmukh, H.; Goud, H. Capacity Analysis of MIMO OFDM System using Water filling Algorithm. International Journal of Advanced Research in Computer Engineering & Technology. In: IJARCET; , 2012; p. 1.
[18]
Malik, J.K.; Manvi, F.V.; Nanjwade, B.K.; Singh, S. Synthesis and screening of some new 2-amino substituted benzothiazole derivatives for antifungal activity. Drug Invention Today, 2009, 1(1), 32-34.
[http://dx.doi.org/10.1016/j.dit.2013.03.005]
[http://dx.doi.org/10.1016/j.dit.2013.03.005]
[19]
Munirajasekhar, D.; Himaja, M.; Sunil, M. Synthesis and Anthelmintic activity of 2-Amino-6-substituted Benzothiazoles. Int. Res. J. Pharm., 2011, 2(1), 114-117.
[20]
Alang, G.; Kaur, R.; Singh, A.; Budhlakoti, P.; Singh, A.; Sanwal, R. Synthesis, Characterization and antifungal activity of certain (E)-1-(1-(substitutedphenyl) ethylidene)-2-(6-methylbenzo [d] thiazol-2-yl) hydrazine analogues. Int. J. Pharm. Biol. Arch., 2010, 1(1), 56-61.
[21]
Prajapati, N.P.; Vekariya, R.H.; Borad, M.A.; Patel, H.D. Recent advances in the synthesis of 2-substituted benzothiazoles: a review. RSC Advances, 2014, 4(104), 60176-60208.
[http://dx.doi.org/10.1039/C4RA07437H]
[http://dx.doi.org/10.1039/C4RA07437H]
[22]
Chow, A.W.; Bitler, S.P.; Penwell, P.E.; Osborne, D.J.; Wolfe, J.F. Synthesis and solution properties of extended chain poly (2, 6-benzothiazole) and poly (2, 5-benzoxazole). Macromolecules, 1989, 22(9), 3514-3520.
[http://dx.doi.org/10.1021/ma00199a002]
[http://dx.doi.org/10.1021/ma00199a002]
[23]
Naeimi, H.; Heidarnezhad, A. Efficient and facile protocol for one-pot synthesis of 2-amino-substituted benzothiazoles catalyzed by nano-BF 3/SiO 2 under mild conditions. Res. Chem. Intermed., 2016, 42(12), 7855-7868.
[http://dx.doi.org/10.1007/s11164-016-2566-z]
[http://dx.doi.org/10.1007/s11164-016-2566-z]
[24]
Mehra, S.C.; Zaman, S.; Khan, A.A. synthesis of alkyl/arylaminopropionyl-2-amino‐4‐phenylthiazole, 2‐aminobenzothiazole and 2‐amino (substituted) benzothiazole as potential local anesthetics. J. Indian Chem. Soc., 1980, 57, 829-832.
[25]
Bondock, S.; Fadaly, W.; Metwally, M.A. Recent trends in the chemistry of 2-aminobenzothiazoles. J. Sulfur Chem., 2009, 30(1), 74-107.
[http://dx.doi.org/10.1080/17415990802588033]
[http://dx.doi.org/10.1080/17415990802588033]
[26]
Rezki, N. A green ultrasound synthesis, characterization and antibacterial evaluation of 1, 4-disubstituted 1, 2, 3-triazoles tethering bioactive benzothiazole nucleus. Molecules, 2016, 21(4), 505.
[http://dx.doi.org/10.3390/molecules21040505] [PMID: 27096862]
[http://dx.doi.org/10.3390/molecules21040505] [PMID: 27096862]
[27]
Akella, S.S.; Kilambi, N.; Lakshmanan, M.; Sriram, R.; Thangapazham, S.; Gaddam, R. Preparation of acylated piperazines as histone deacetylase (HDAC) inhibitors for treating cancer, psoriasis and related diseases. US Patent 20070088043, 19, 2007.
[28]
Mali, S.N.; Chaudhari, H.K. Computational studies on imidazo [1, 2-a] pyridine-3-carboxamide analogues as antimycobacterial agents: common pharmacophore generation, atom-based 3d-qsar, molecular dynamics simulation, QikProp, molecular docking and prime MMGBSA approaches. Open Pharm. Sci. J., 2018, 5, 12-23.
[http://dx.doi.org/10.2174/1874844901805010012]
[http://dx.doi.org/10.2174/1874844901805010012]
[29]
Mali, S.N.; Chaudhari, H.K. Molecular modelling studies on adamantane-based Ebola virus GP-1 inhibitors using docking, pharmacophore and 3D-QSAR. SAR QSAR Environ. Res., 2019, 30(3), 161-180.
[http://dx.doi.org/10.1080/1062936X.2019.1573377] [PMID: 30786763]
[http://dx.doi.org/10.1080/1062936X.2019.1573377] [PMID: 30786763]
[30]
Mali, S.N.; Sawant, S.; Chaudhari, H.K.; Mandewale, M.C. In silico appraisal, Synthesis, Antibacterial screening and DNA cleavage for 1,2,5-thiadiazole derivative. Curr. Comput. Aided Drug Des., 2019, 15, 1.
[http://dx.doi.org/10.2174/1573409915666190206142756] [PMID: 30727910]
[http://dx.doi.org/10.2174/1573409915666190206142756] [PMID: 30727910]
[31]
Mishra, V.R.; Ghanavatkar, C.W.; Mali, S.N.; Qureshi, S.I.; Chaudhari, H.K.; Sekar, N. Design, synthesis, antimicrobial activity and computational studies of novel azo linked substituted benzimidazole, benzoxazole and benzothiazole derivatives. Comput. Biol. Chem., 2019, 78, 330-337.
[http://dx.doi.org/10.1016/j.compbiolchem.2019.01.003] [PMID: 30639681]
[http://dx.doi.org/10.1016/j.compbiolchem.2019.01.003] [PMID: 30639681]
[32]
Munirajasekhar, D.; Himaja, M.; Sunil, M. Targeting CYP51 for drug design by the contributions of molecular modeling. Fundam. Clin. Pharmacol., 2011, 31, 37-53.
[33]
Rabelo, V.W.; Santos, T.F.; Terra, L.; Santana, M.V.; Castro, H.C.; Rodrigues, C.R.; Abreu, P.A. Targeting CYP51 for drug design by the contributions of molecular modeling. Fundam. Clin. Pharmacol., 2017, 31(1), 37-53.
[http://dx.doi.org/10.1111/fcp.12230] [PMID: 27487199]
[http://dx.doi.org/10.1111/fcp.12230] [PMID: 27487199]
[34]
Podust, L.M.; Poulos, T.L.; Waterman, M.R. Crystal structure of cytochrome P450 14alpha -sterol demethylase (CYP51) from Mycobacterium tuberculosis in complex with azole inhibitors. Proc. Natl. Acad. Sci. USA, 2001, 98(6), 3068-3073.
[http://dx.doi.org/10.1073/pnas.061562898] [PMID: 11248033]
[http://dx.doi.org/10.1073/pnas.061562898] [PMID: 11248033]
[36]
Yuzo, T.; Jutaro, O.; Katsumi, K. Synthesis of nitrogen-containing ring compounds (106th report) About 2- (N-allyl glycyl) aminothiazole derivative. Yakugaku Zasshi, 1957, 77, 649-651.https://www.jstage.jst.go.jp/article/yakushi1947/77/6/77_6_649/_article/-char/ja/
[37]
Mishra, V.R.; Ghanavatkar, C.W.; Mali, S.N.; Chaudhari, H.K.; Sekar, N. Synthesis, bioactivities, DFT and in-silico appraisal of azo clubbed benzothiazole derivatives. J. Mol. Struct., 2019, 1192, 162-171.
[http://dx.doi.org/10.1016/j.molstruc.2019.04.123]
[http://dx.doi.org/10.1016/j.molstruc.2019.04.123]
[38]
Mishra, V.R.; Ghanavatkar, C.W.; Mali, S.N.; Chaudhari, H.K.; Sekar, N. Schiff base clubbed benzothiazole: synthesis, potent antimicrobial and MCF-7 anticancer activity, DNA cleavage and computational study. J. Biomol. Struct. Dyn., 2019, 38(6), 1-14.
[http://dx.doi.org/10.1080/07391102.2019.1621213] [PMID: 31107179]
[http://dx.doi.org/10.1080/07391102.2019.1621213] [PMID: 31107179]
Article Metrics
32