EXPLORATION OF NICOTINOYL HYDRAZINE DERIVATIVES THROUGH IN SILICO STUDIES FOR NOVEL ANTI-TUBERCULAR DRUG DEVELOPMENT

AKASH HR; K. ARCHANA DEVI; S. BELIN; SENTHIL KUMAR P.; MOHD ABDUL BAQI; N. VENKATHESHAN; M. SUCHARITHA; KOPPULA JAYANTHI

doi:10.22159/ijap.2025v17i5.54697

Authors

AKASH HR Department of Pharmaceutical Chemistry, Arulumigu Kalasalingam College of Pharmacy, Kalasalingam Academy of Research and Education, Krishnan Koil, Tamil Nadu, India https://orcid.org/0009-0002-8912-5784
K. ARCHANA DEVI Department of Pharmaceutical Chemistry, Arulumigu Kalasalingam College of Pharmacy, Kalasalingam Academy of Research and Education, Krishnan Koil, Tamil Nadu, India
S. BELIN Department of Pharmaceutical Chemistry, Arulumigu Kalasalingam Collegeof Pharmacy, Kalasalingam Academy of Research and Education, Krishnan Koil, Tamil Nadu, India https://orcid.org/0009-0006-1256-7559
SENTHIL KUMAR P. Department of Pharmaceutical Chemistry, Arulumigu Kalasalingam College of Pharmacy, Kalasalingam Academy of Research and Education, Krishnan Koil, Tamil Nadu, India
MOHD ABDUL BAQI Department of Pharmaceutics, Arulumigu Kalasalingam College of Pharmacy, Kalasalingam Academy of Research and Education, Krishnan Koil, Tamil Nadu, India https://orcid.org/0009-0000-3711-3568
N. VENKATHESHAN Department of Pharmaceutical Chemistry, Arulumigu Kalasalingam College of Pharmacy, Kalasalingam Academy of Research and Education, Krishnan Koil, Tamil Nadu, India
M. SUCHARITHA Department of Pharmaceutics, Arulumigu Kalasalingam College of Pharmacy, Kalasalingam Academy of Research and Education, Krishnan Koil, Tamil Nadu, India https://orcid.org/0009-0007-8563-5417
KOPPULA JAYANTHI Department of Pharmaceutical Chemistry, Arulumigu Kalasalingam College of Pharmacy, Kalasalingam Academy of Research and Education, Krishnan Koil, Tamil Nadu, India https://orcid.org/0009-0003-9358-4278

DOI:

https://doi.org/10.22159/ijap.2025v17i5.54697

Keywords:

Enoyl-Acyl carrier protein reductase (INHA), Molecular docking, MM-GBSA, ADME, Tuberculosis, Isoniazid, Anti-tubercular agents

Abstract

Objective: This study explores the interactions of structurally novel nicotinoyl hydrazine derivatives with enoyl-acyl carrier protein reductase (INHA), a key enzyme involved in cellular metabolism regulation. The focus is on the tuberculosis (TB)-associated INHA pathway (PDB ID: 2NSD), aiming to evaluate the anti-tubercular potential of these compounds as inhibitors of the INHA catalytic subunit. Notably, these derivatives, particularly compound 6 (Benzyl nicotinoyl acetamide), feature a unique nicotinoyl hydrazine scaffold with functional groups distinct from known INHA inhibitors such as triclosan or diazaborines.

Methods: Molecular docking of the compounds was performed using the Glide module. An absorption, distribution, metabolism, and excretion (ADME) analysis was conducted using QikProp. The Prime Molecular Mechanics Generalized Born Surface Area (MM-GBSA) method was employed to calculate binding free energy.

Results: Ten compounds exhibited significant binding affinity and interactions, forming hydrogen and pi-cation bonds with key residues such as SER 84, LYS 163, ALA 22, GLY 14, LYS 165, PHE 142, SER 86, TYR 153, LYS 145, TYR 158, MET 167, PHE 168, SER 88, ILE 186, TYR 188, SER 20, PHE 148, and ILE 184 within the INHA catalytic subunit (PDB ID: 2NSD). Among these, Compound 6 demonstrated an exceptional Glide extra precision (XP) docking score of –10.74 kcal/mol and a binding free energy (ΔG_bind) of –109.48 kcal/mol, indicating stronger binding potential than the standard drug isoniazid. Prime MM-GBSA analysis further confirmed its promising binding affinities, with ΔBind (-109.48 kcal/mol), ΔLipo (-45.99 kcal/mol), and ΔVdW (-73.62 kcal/mol). The ligand consistently interacted with residues SER 88, SER 86, ILE 186, and TYR 188.

Conclusion: Benzyl nicotinoyl acetamide (Compound 6), with its structurally novel scaffold and potent binding metrics, exhibits significant potential as an INHA inhibitor. Characterized by functional groups such as a secondary amine (NH), ether (C-O-C), hydroxyl (OH), pyridine, carbonyl (C=O), and phenyl (C6H5), it shows potential application as an anti-tubercular agent, particularly for tuberculosis treatment.

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