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Current Bioactive Compounds

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ISSN (Print): 1573-4072
ISSN (Online): 1875-6646

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Research Article

Synthesis, Molecular Docking and In-silico Admet Screening of New Benzothiazole-Linked Pyrazole Prototype Derivatives: Validation of Resistant Strains and their Biological Activity

Author(s): Kyatham Ramadevi*, Dommati Ashok, K.S.K. Rao Patnaik, Mohammad Arif Pasha and Raju Bathula

Volume 19, Issue 6, 2023

Published on: 16 November, 2022

Article ID: e180822207633 Pages: 20

DOI: 10.2174/1573407218666220818112448

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Abstract

Background: The necessity for newer anti-microbial medications with prototypes has arisen as a result of the prevalence of infections caused by resistant strains of microorganisms.

Objective: A series of nine novel benzothiazole-linked pyrazole prototype derivatives were synthesized in multistep reactions and evaluated for anti-microbial and anti-fungal activities. The druglikeness along with physicochemical properties of synthesized compounds were determined by docking the ligands with resistant strains.

Methods: Synthesis of benzothiazole and pyrazole prototype derivatives was carried out by a sequence of reactions to attain the hydrazine carboxamide derivatives. All the synthesized compounds were characterized and evaluated for their anti-bacterial and anti-fungal activities against carbapenem-resistantresistant Pseudomonas aeruginosa (CP-PA), carbapenem-resistantresistant Klebsiella pneumoniae (CP-KP), cephalosporin-resistant Clostridium difficile (CR-CD), macrolide- resistantresistant Streptococcus pyogenes (MR-SP), Voriconazole-resistant Aspergillus Niger (VR-AN) and Fluconazole-resistant Candida glabrata (FR-CG). Physico-chemical parameters were done by Medchem DesignerTM software version 5.5 and ADMET parameters by pkCSM online tool. Furthermore, molecular docking was accomplished with PyRx 0.8 by AutoDock Vina program.

Results: All the synthesized derivatives were characterized and evaluated for their anti-bacterial activity, which shows the significant activity of 6i with MIC 36.17 μM on CP-PA, MIC 36.86 μM on CP-KP, MIC 38.45 μM on CR-CD, and MIC 37.09 μM on MR-SP, with respect to ciprofloxacin with an average of MIC 32 μM for all resistant bacterial strains. The prototype derivatives were also evaluated for their anti-fungal activity, in which derivative 6i was found to be significant with MIC 35.27 μM for VR-AN, MIC 34.78 μM for FR-CG, and MIC values of 25.60 μM and 27.08 μM for Nystatin for all fungal-resistant strains. In-silico predicted parameters for synthesized prototype derivatives stood to be drug-like.

Conclusion: From the novel benzothiazole and pyrazole hybrid derivatives, compound 6i was found to be effective for anti-microbial and anti-fungal drugs and hence can be further explored for dual activities. Furthermore, derivatization was made to synthesize further potent derivatives for anti-microbial and anti-fungal treatments.

Keywords: Benzothiazole, Pyrazole, resistant strains, anti-microbial activity, anti-fungal activity, in-silico studies.

Graphical Abstract

[1]
Golkar, Z.; Bagasra, O.; Pace, D.G.; Bacteriophage Therapy, D. Bacteriophage therapy: A potential solution for the antibiotic resistance crisis. J. Infect. Dev. Ctries., 2014, 8(2), 129-136.
[http://dx.doi.org/10.3855/jidc.3573] [PMID: 24518621]
[2]
CDC. Centers for disease control and prevention, office of infectious disease antibiotic resistance threats in the United States. Available from: http://www.cdc.gov/drugresistance/threat-report-2013
[3]
Spellberg, B.; Gilbert, D.N. The future of antibiotics and resistance: A tribute to a career of leadership by John Bartlett. Clin. Infect. Dis., 2014, 59(Suppl. 2), S71-S75.
[http://dx.doi.org/10.1093/cid/ciu392] [PMID: 25151481]
[4]
Doi, Y. Treatment options for carbapenem-resistant gram-negative bacterial infections. Clin. Infect. Dis., 2019, 69(Suppl. 7), S565-S575.
[http://dx.doi.org/10.1093/cid/ciz830] [PMID: 31724043]
[5]
Reyes, J.; Aguilar, A.C.; Caicedo, A. Carbapenem-resistant Klebsiella pneumoniae: Microbiology key points for clinical practice. Int. J. Gen. Med., 2019, 12, 437-446.
[http://dx.doi.org/10.2147/IJGM.S214305] [PMID: 31819594]
[6]
Spigaglia, P. Recent advances in the understanding of antibiotic resistance in Clostridium difficile infection. Ther. Adv. Infect. Dis., 2016, 3(1), 23-42.
[http://dx.doi.org/10.1177/2049936115622891] [PMID: 26862400]
[7]
Silva-Costa, C.; Friães, A.; Ramirez, M.; Melo-Cristino, J. Macrolide-resistant Streptococcus pyogenes: Prevalence and treatment strategies. Expert Rev. Anti Infect. Ther., 2015, 13(5), 615-628.
[http://dx.doi.org/10.1586/14787210.2015.1023292] [PMID: 25746210]
[8]
Ansari, A.; Ali, A.; Asif, M.; Shamsuzzaman, S. Review: Biologically active pyrazole derivatives. New J. Chem., 2016, 41(1), 16-41.
[http://dx.doi.org/10.1039/C6NJ03181A]
[9]
Moore, K.W.; Bonner, K.; Jones, E.A.; Emms, F.; Leeson, P.D.; Marwood, R.; Patel, S.; Patel, S.; Rowley, M.; Thomas, S.; Carling, R.W. 4-N-linked-heterocyclic piperidine derivatives with high affinity and selectivity for human dopamine D4 receptors. Bioorg. Med. Chem. Lett., 1999, 9(9), 1285-1290.
[http://dx.doi.org/10.1016/S0960-894X(99)00169-9] [PMID: 10340615]
[10]
Patra, P.K.; Sree, P.C.; Pradesh, A. Synthesys and screening of analgesic activity of some novel pyrazole. Int. J. Pharm. Sci. Res., 2014, 5(5), 1874-1883.
[11]
Nargund, L.V.G.; Hariprasad, V.; Reedy, G.R. Synthesis and anti-inflammatory activity of fluorinated phenyl styryl ketones and N-phenyl-5-substituted aryl-3-p-(fluorophenyl) pyrazolins and pyrazoles. J. Pharm. Sci., 1992, 81(9), 892-894.
[http://dx.doi.org/10.1002/jps.2600810910] [PMID: 1432635]
[12]
Penning, T.D.; Talley, J.J.; Bertenshaw, S.R.; Carter, J.S.; Collins, P.W.; Docter, S.; Graneto, M.J.; Lee, L.F.; Malecha, J.W.; Miyashiro, J.M.; Rogers, R.S.; Rogier, D.J.; Yu, S.S.; Anderson, G.D.; Burton, E.G.; Cogburn, J.N.; Gregory, S.A.; Koboldt, C.M.; KPerkins, W.E.; Seibert, K.; Veenhuizen, A.W.; Zhang, Y.Y.; Isakson, P.C. Synthesis and biological evaluation of the 1,5-diarylpyrazole class of cyclooxygenase-2 inhibitors: Identification of 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]be-nze nesulfonamide (SC-58635, celecoxib). J. Med. Chem., 1997, 40(9), 1347-1365.
[http://dx.doi.org/10.1021/jm960803q] [PMID: 9135032]
[13]
Szabó, G.; Varga, B.; Páyer-Lengyel, D.; Szemzo, A.; Erdélyi, P.; Vukics, K.; Szikra, J.; Hegyi, E.; Vastag, M.; Kiss, B.; Laszy, J.; Gyertyán, I.; Fischer, J. Chemical and biological investigation of cyclopropyl containing diaryl-pyrazole-3-carboxamides as novel and potent cannabinoid type 1 receptor antagonists. J. Med. Chem., 2009, 52(14), 4329-4337.
[http://dx.doi.org/10.1021/jm900179y] [PMID: 19527048]
[14]
Alvarado, M.; Goya, P.; Macías-González, M.; Pavón, F.J.; Serrano, A.; Jagerovic, N.; Elguero, J.; Gutiérrez-Rodríguez, A.; García-Granda, S.; Suardíaz, M.; Rodríguez de Fonseca, F. Antiobesity designed multiple ligands: Synthesis of pyrazole fatty acid amides and evaluation as hypophagic agents. Bioorg. Med. Chem., 2008, 16(23), 10098-10105.
[http://dx.doi.org/10.1016/j.bmc.2008.10.023] [PMID: 18952442]
[15]
Kees, K.L.; Fitzgerald, J.J., Jr; Steiner, K.E.; Mattes, J.F.; Mihan, B.; Tosi, T.; Mondoro, D.; McCaleb, M.L. New potent antihyperglycemic agents in db/db mice: Synthesis and structure-activity relationship studies of (4-substituted benzyl) (trifluoromethyl)pyrazoles and -pyrazolones. J. Med. Chem., 1996, 39(20), 3920-3928.
[http://dx.doi.org/10.1021/jm960444z] [PMID: 8831758]
[16]
Ali, S.A.; Awad, S.M.; Said, A.M.; Mahgoub, S.; Taha, H.; Ahmed, N.M. Design, synthesis, molecular modelling and biological evaluation of novel 3-(2-naphthyl)-1-phenyl-1H-pyrazole derivatives as potent antioxidants and 15-Lipoxygenase inhibitors. J. Enzyme Inhib. Med. Chem., 2020, 35(1), 847-863.
[http://dx.doi.org/10.1080/14756366.2020.1742116] [PMID: 32216479]
[17]
Liu, J-J.; Zhao, M.Y.; Zhang, X.; Zhao, X.; Zhu, H-L. Pyrazole derivatives as antitumor, anti-inflammatory and antibacterial agents. Mini Rev. Med. Chem., 2013, 13(13), 1957-1966.
[http://dx.doi.org/10.2174/13895575113139990078] [PMID: 23937232]
[18]
Vijesh, A.M.; Isloor, A.M.; Shetty, P.; Sundershan, S.; Fun, H.K. New pyrazole derivatives containing 1,2,4-triazoles and benzoxazoles as potent antimicrobial and analgesic agents. Eur. J. Med. Chem., 2013, 62, 410-415.
[http://dx.doi.org/10.1016/j.ejmech.2012.12.057] [PMID: 23385092]
[19]
Ningaiah, S.; Bhadraiah, U.K.; Keshavamurthy, S.; Javarasetty, C. Novel pyrazoline amidoxime and their 1,2,4-oxadiazole analogues: Synthesis and pharmacological screening. Bioorg. Med. Chem. Lett., 2013, 23(16), 4532-4539.
[http://dx.doi.org/10.1016/j.bmcl.2013.06.042] [PMID: 23850201]
[20]
Paramashivappa, R.; Phani Kumar, P.; Subba Rao, P.V.; Srinivasa Rao, A. Design, synthesis and biological evaluation of benzimidazole/benzothiazole and benzoxazole derivatives as cyclooxygenase inhibitors. Bioorg. Med. Chem. Lett., 2003, 13(4), 657-660.
[http://dx.doi.org/10.1016/S0960-894X(02)01006-5] [PMID: 12639552]
[21]
Singh, H.P.; Sharma, C.S.; Gautam, C.P. Synthesis and pharmacological screening of some novel 2-arylhydrazino- and 2-aryloxypyrimido[2,1-b]benzothiazole derivatives. Am. J. Sci. Res., 2009, 4(4), 222-228.
[22]
Kaur, H.; Kumar, S.; Singh, I.; Saxena, K.K.; Kumar, A. Synthesis, characterization and biological activity of various substituted benzothiazole derivatives. Dig. J. Nanomater. Biostruct., 2010, 5(1), 67-76.
[23]
Sigmundová, I.; Zahradník, P.; Magdolen, P.; Bujdáková, H. Synthesis and study of new antimicrobial benzothiazoles substituted on heterocyclic ring. ARKIVOC, 2008, 2008(8), 183-192.
[http://dx.doi.org/10.3998/ark.5550190.0009.815]
[24]
Chawla, R.; Sahoo, U.; Arora, A.; Sharma, P.C.; Radhakrishnan, V. Microwave assisted synthesis of some novel 2-pyrazoline derivatives as possible antimicrobial agents. Acta Pol. Pharm., 2010, 67(1), 55-61.
[PMID: 20210079]
[25]
Akhtar, T.; Hameed, S.; Al-Masoudi, N.A.; Loddo, R.; La Colla, P. In vitro antitumor and antiviral activities of new benzothiazole and 1,3,4-oxadiazole-2-thione derivatives. Acta Pharm., 2008, 58(2), 135-149.
[http://dx.doi.org/10.2478/v10007-008-0007-2] [PMID: 18515224]
[26]
Bowyer, P.W.; Gunaratne, R.S.; Grainger, M.; Withers-Martinez, C.; Wickramsinghe, S.R.; Tate, E.W.; Leatherbarrow, R.J.; Brown, K.A.; Holder, A.A.; Smith, D.F. Molecules incorporating a benzothiazole core scaffold inhibit the N-myristoyltransferase of Plasmodium falciparum. Biochem. J., 2007, 408(2), 173-180.
[http://dx.doi.org/10.1042/BJ20070692] [PMID: 17714074]
[27]
Huang, Q.; Mao, J.; Wan, B.; Wang, Y.; Brun, R.; Franzblau, S.G.; Kozikowski, A.P. Searching for new cures for tuberculosis: Design, synthesis, and biological evaluation of 2-methylbenzothiazoles. J. Med. Chem., 2009, 52(21), 6757-6767.
[http://dx.doi.org/10.1021/jm901112f] [PMID: 19817445]
[28]
Dubey, R.; Shrivastava, P.K.; Basniwal, P.K.; Bhattacharya, S.; Moorthy, N.S. 2-(4-aminophenyl) benzothiazole: A potent and selective pharmacophore with novel mechanistic action towards various tumour cell lines. Mini Rev. Med. Chem., 2006, 6(6), 633-637.
[http://dx.doi.org/10.2174/138955706777435706] [PMID: 16787373]
[29]
Shi, D.F.; Bradshaw, T.D.; Wrigley, S.; McCall, C.J.; Lelieveld, P.; Fichtner, I.; Stevens, M.F.G. Antitumor benzothiazoles. 3. Synthesis of 2-(4-aminophenyl)benzothiazoles and evaluation of their activities against breast cancer cell lines in vitro and in vivo. J. Med. Chem., 1996, 39(17), 3375-3384.
[http://dx.doi.org/10.1021/jm9600959] [PMID: 8765521]
[30]
Limbago, B. M100-S11, Performance standards for antimicrobial susceptibility testing. Clin. Microbiol. Newsl., 2001, 23(6), 49.
[http://dx.doi.org/10.1016/S0196-4399(01)88009-0]
[31]
Pfaller, M.A.; Haturvedi, V.; Espinel-Ingroff, A.; Ghannoum, M.A.; Gosey, L.L.; Odds, F.C.; Rex, J.H.; Rinaldi, M.G.; Sheehan, D.J.; Walsh, T.J.; Warnock, D.W. Reference Method for Broth Dilution Antifungal Susceptibility Testing of Yeasts ; Approved Standard-Second Edition Serving the World’s Medical Science Community Through Voluntary Consensus, 2002, 17(9)
[32]
Dallakyan, S.; Olson, A.J. Small-molecule library screening by docking with PyRx. Methods Mol. Biol., 2015, 1263, 243-250.
[http://dx.doi.org/10.1007/978-1-4939-2269-7_19] [PMID: 25618350]
[33]
Ke, W.; Bethel, C.R.; Thomson, J.M.; Bonomo, R.A.; van den Akker, F. Crystal structure of KPC-2: Insights into carbapenemase activity in class A β-lactamases. Biochemistry, 2007, 46(19), 5732-5740.
[http://dx.doi.org/10.1021/bi700300u] [PMID: 17441734]
[34]
Leiris, S.; Coelho, A.; Castandet, J.; Bayet, M.; Lozano, C.; Bougnon, J.; Bousquet, J.; Everett, M.; Lemonnier, M.; Sprynski, N.; Zalacain, M.; Pallin, T.D.; Cramp, M.C.; Jennings, N.; Raphy, G.; Jones, M.W.; Pattipati, R.; Shankar, B.; Sivasubrahmanyam, R.; Soodhagani, A.K.; Juventhala, R.R.; Pottabathini, N.; Pothukanuri, S.; Benvenuti, M.; Pozzi, C.; Mangani, S.; De Luca, F.; Cerboni, G.; Docquier, J.D.; Davies, D.T. SAR Studies leading to the identification of a novel series of metallo-β-lactamase inhibitors for the treatment of carbapenem-resistant enterobacteriaceae infections that display efficacy in an animal infection model. ACS Infect. Dis., 2019, 5(1), 131-140.
[http://dx.doi.org/10.1021/acsinfecdis.8b00246] [PMID: 30427656]
[35]
Ku, B.; Keum, C.W.; Lee, H.S.; Yun, H.Y.; Shin, H.C.; Kim, B.Y.; Kim, S.J. Crystal structure of SP-PTP, a low molecular weight protein tyrosine phosphatase from Streptococcus pyogenes. Biochem. Biophys. Res. Commun., 2016, 478(3), 1217-1222.
[http://dx.doi.org/10.1016/j.bbrc.2016.08.097] [PMID: 27545603]
[36]
Chambers, C.J.; Roberts, A.K.; Shone, C.C.; Acharya, K.R. Structure and function of a Clostridium difficile sortase enzyme. Sci. Rep., 2015, 5(1), 9449.
[http://dx.doi.org/10.1038/srep09449] [PMID: 25801974]
[37]
Lipinski, C.A. Lead- and drug-like compounds: The rule-of-five revolution. Drug Discov. Today. Technol., 2004, 1(4), 337-341.
[http://dx.doi.org/10.1016/j.ddtec.2004.11.007] [PMID: 24981612]

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