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

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 Designer^TM 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.