Abstract
Objective: synthesis of new 1, 3-diphenyl pyrazole derivatives 9(a-f) and 10(a-f) using molecular hybridization approach for antitubercular and cytotoxic studies.Methods: The structures of synthesized compounds were confirmed by 1H-NMR, 13C-NMR and mass spectra’s. The antitubercular activity of compounds and standard drugs were assessed against Mycobacterium tuberculosis using microplate Alamar Blue assay (MABA). The cytotoxic activities were performed by Sulforhodamine B (SRB) assay. The molecular docking and in silico ADME prediction were studied by using Schrodinger.Results: The results reveals that the compounds 9c, 9d, 10c and 10d exhibited substantial antitubercular potential with MIC < 20 μM. The cytotoxic studies revealed that the active compounds (9d, 10a, and 10d) are non-toxic to HeLa cancer cell lines with selectivity index >10. The molecular docking study was performed to study the binding orientation and affinity of synthesized compounds for InhA enzyme.Conclusion: The study explored that the 1, 3-diphenyl pyrazole hybrids coupled with well known antitubercular drugs could be a potential lead for antitubercular agents. In-silico molecular docking study helps to identify their corresponding intermolecular ligand-protein interactions with target enzyme. Also ADME prediction studies revealed that the compounds were in acceptable range to have pharmacokinetic parameters.
Highlights
Tuberculosis (TB) is a re-emerging global health threat caused by an infectious bacillus called Mycobacterium tuberculosis and is the second largest killer disease caused by a single infectious agent after the human immunodeficiency virus (HIV) [1]
World Health Organization (WHO) promoted a comprehensive tuberculosis management program known as DOTS (Directly Observed Treatment, Shortcourse)
Despite notable progress in antitubercular agents, multi-drug resistance tuberculosis (MDR-TB), extremely drug resistance tuberculosis (XDR-TB) and HIV co-infection are the major hurdles in control of tuberculosis infection [4]
Summary
Tuberculosis (TB) is a re-emerging global health threat caused by an infectious bacillus called Mycobacterium tuberculosis and is the second largest killer disease caused by a single infectious agent after the human immunodeficiency virus (HIV) [1]. World Health Organization (WHO) Global Tuberculosis Report 2016 suggested that, in 2015, there were an estimated 10.4 million new tuberculosis cases worldwide. People living with HIV accounted for 1.2 million (11 %) of all new tuberculosis cases [2]. World Health Organization (WHO) promoted a comprehensive tuberculosis management program known as DOTS (Directly Observed Treatment, Shortcourse). The discovery and development of new chemical entities with a novel mechanism of action, safe and efficacious drugs, and shorter duration of treatment are the desperate needs for infectious diseases research programs. Pioneering scientists had reported pyrazole and its derivatives for an extensive range of pharmacological activities such as antipyretic, analgesic, antimicrobial, anticancer, antitubercular, antiviral, antihypertensive, antioxidant, antidepressant, and anxiolytic [5,6,7]
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