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System for Efficacy and Cytotoxicity Screening of Inhibitors Targeting Intracellular Mycobacterium tuberculosis

System for Efficacy and Cytotoxicity Screening of Inhibitors Targeting Intracellular Mycobacterium tuberculosis

Published on: April 5, 2017

Synthesis, Biological Evaluation, Molecular Docking Studies and ADMET Prediction of Oxindole-based Hybrids for the

Vaishali Pavalbhai Patel¹, Rati Kailash Prasad Tripathi², Snigdha Das Mandal³

¹Parul Institute of Pharmacy & Research, Parul University Department of Quality Assurance Vadodara India.

Current Computer-Aided Drug Design

|November 1, 2024

Abstract

Introduction:

With a projected mortality toll of 1.4 million in 2019, tuberculosis (TB) continues to be a significant public health concern around the world. Studies of novel treatments are required due to decreased bioavailability, increased toxicity, increased side effects, and resistance of several first- and second-line TB therapies, including isoniazid and ethionamide.

Methods:

This study reports the synthesis of oxindole-based hybrids as potent InhA inhibitors targeting Mycobacterium tuberculosis. The synthesized compounds (5a-5e and 8a-8c) were evaluated for their anti-mycobacterial activity against Mycobacterium tuberculosis and nontuberculous mycobacteria (NTMs), viz. M. abscessus (ATCC 19977), M. fortuitum (ATCC 6841), and M. chelonae (ATCC 35752) using the Microplate Alamar Blue Assay (MABA). Molecular docking studies were performed using AutoDock Vina to explore the binding interactions of these compounds with the InhA enzyme (PDB: 2NSD). Additionally, biochemical and histopathological studies were conducted to assess the hepatotoxicity of the lead compounds. Insilico molecular properties and ADMET properties of the synthesized compounds were predicted using SwissADME and Deep-PK online tools to assess their drug-likeness.

Results:

Among the tested compounds, 8b exhibited significant anti-mycobacterial activity with a minimum inhibitory concentration (MIC = 1 μg/mL) comparable to the reference drug ethambutol. Further, the compound demonstrated a binding affinity and orientation similar to the reference inhibitor 4PI, indicating its potential as a potent InhA inhibitor, and was found to be stabilized within the binding pocket of InhA through H-bonding, hydrophobic and van der Waal's interactions. Besides, the compounds hepatotoxicity assessment studies depicted that 8b showed no significant liver dysfunction or damage to liver tissues. Additionally, 8b adhered to Lipinski's rule of five and Veber's rule, displaying favourable pharmacokinetic and drug-like properties, including high human intestinal absorption, distribution, and acceptable metabolic stability and excretion.

Conclusion:

Compound 8b emerged as a promising candidate for further optimization and development as a therapeutic agent for tuberculosis, offering a new avenue for tackling tuberculosis.

Insights

A novel oxindole-based compound, 8b, shows potent anti-mycobacterial activity against tuberculosis. This promising candidate exhibits favorable drug-like properties and low toxicity, offering a new therapeutic avenue.

Area of Science:

Medicinal Chemistry
Drug Discovery
Antimicrobial Agents

Background:

Tuberculosis (TB) remains a global health threat with 1.4 million projected deaths in 2019.
Existing TB therapies face challenges including reduced efficacy, toxicity, and emerging resistance.
Novel treatment strategies are crucial to combat drug-resistant and persistent forms of TB.

Purpose of the Study:

To synthesize and evaluate novel oxindole-based hybrids as potential inhibitors of InhA.
To assess the anti-mycobacterial activity of synthesized compounds against Mycobacterium tuberculosis and nontuberculous mycobacteria (NTMs).
To investigate the binding interactions, safety profile, and drug-likeness of promising compounds.

Main Methods:

Synthesis of oxindole-based compounds (5a-5e, 8a-8c).
Antimycobacterial activity testing using Microplate Alamar Blue Assay (MABA).
Molecular docking studies with InhA enzyme (PDB: 2NSD) and assessment of hepatotoxicity, pharmacokinetic, and ADMET properties.

Main Results:

Compound 8b demonstrated significant anti-mycobacterial activity (MIC = 1 μg/mL), comparable to ethambutol.
Molecular docking revealed potent InhA inhibition via H-bonding and hydrophobic interactions.
Compound 8b exhibited no significant hepatotoxicity and favorable drug-like properties (Lipinski's and Veber's rules).

Conclusions:

Compound 8b is a promising candidate for further development as a novel anti-tuberculosis therapeutic agent.
The study highlights oxindole-based hybrids as a viable strategy for developing new TB treatments.
Further optimization of compound 8b could lead to a new class of drugs to combat tuberculosis.

Read full analysis

Keywords:

ADMET InhA inhibitors Tuberculosis hepatotoxicity studies molecular docking oxindole-based hybrids

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