Design, synthesis, in silico, and in vitro evaluation of 3-phenylpyrazole acetamide derivatives as antimycobacterial agents.
Nikhil B GaikwadKrishna NirmaleSantosh K SahooMohammad N AhmadGrace KaulManjulika ShuklaSrinivas NanduriArunava Das GuptaSidharth ChopraVenkata Madhavi YaddanapudiPublished in: Archiv der Pharmazie (2020)
Mycobacterium tuberculosis (Mtb) is one of the most dangerous pathogens affecting immunocompetent and immunocompromised patients worldwide. Novel molecules, which are efficient and can reduce the duration of therapy against drug-resistant strains, are an urgent unmet need of the hour. In our current study, a series of new 2-(3-phenyl-1H-pyrazol-1-yl)acetamide and N'-benzylidene-2-(3-phenyl-1H-pyrazol-1-yl)acetohydrazide derivatives were designed, synthesized, and evaluated for their antimycobacterial potential. The biological evaluation revealed that 6b, 6m, 6l, 7a, and 7k exhibited selective and potent inhibitory activity against Mtb. Furthermore, compounds 6m and 7h were found to be nontoxic to Vero cells with CC50 of greater than 20 and 80 mg/ml, respectively, and exhibited promising selectivity indices (SI) of greater than 666 and 320, respectively. All derivatives exhibited excellent ADME (absorption, distribution, metabolism, and excretion) properties in silico. Also, all the derivatives were found compliant with Lipinski's rule of five, showing their druggability profile. Molecular docking insights of these derivatives have shown outstanding binding energies on the mycobacterial membrane protein large transporters. These results indicate that this scaffold may lead to a potential antimycobacterial drug candidate in the discovery of antitubercular agents.
Keyphrases
- molecular docking
- mycobacterium tuberculosis
- drug resistant
- molecular dynamics simulations
- pulmonary tuberculosis
- structure activity relationship
- multidrug resistant
- end stage renal disease
- ejection fraction
- acinetobacter baumannii
- newly diagnosed
- chronic kidney disease
- induced apoptosis
- blood pressure
- high throughput
- escherichia coli
- transcription factor
- human health
- small molecule
- peritoneal dialysis
- stem cells
- cell death
- emergency department
- dna binding
- drug induced
- electronic health record
- antimicrobial resistance
- intensive care unit
- single cell
- ionic liquid