Synthesis, Characterization, ‘ADMET-SAR’ Prediction, DPPH Assay, and Anti-Mycobacterium Study of 4-[(substituted benzyl) amino]benzohydrazides and its Hydrazones as the Acyl-CoA Carboxylase, AccD5 Inhibitors



Hydrazide-hydrazone derivatives have shown diverse biological activities, such as antitubercular (anti-TB), antibacterial, antifungal, anticancer, anti-inflammatory, antiviral, and antiprotozoal actions.



Hydrazide–hydrazones contain azomethine (–NH–N=CH–) group connected with carbonyl group and are believed to be responsible for various pharmaceutical applications. They aid in the synthesis of different five-membered heterocyclic systems, such as oxadiazole, triazoles, etc.



In the present study, various hydrazines/hydrazones were synthesized starting from 4-amino benzoic acid derivatives. Structures of all 9 newly synthesized compounds (6a-6d and 8a-8e) were further characterized by using various spectroscopic methods, such as 1H-NMR (Nuclear Magnetic Resonance), FT-IR (Fourier-transform infrared spectroscopy), Gas chromatography-mass spectrometry (GC-MS), etc. Furthermore, molecular docking analysis against the acyl-CoA carboxylase, AccD5 (PDB ID: 2A7S), was also carried out using the Glide module, which depicted good binding scores than standard drugs. The anti-tuberculosis activity of all the hydrazides and hydrazones (6a-6d and 8a-8e) were evaluated against the Mycobacterium tuberculosis H37 RV strain using the Alamar-Blue susceptibility (MABA) test. The activity was expressed as the minimum inhibitory concentration (MIC) in µg/mL values. The antioxidant activity was also carried out using a DPPH assay.



Our findings demonstrated highly encouraging in-vitro results (MABA assay, MIC: 1.2 µg/mL) of hydrazones as depicted by good antimycobacterial activity. The antioxidant results showed a moderate to a good percentage of DPPH inhibition. Our in-silico ADMET analysis further suggested good pharmacokinetic and toxicity-free profiles of synthesized analogues (6a-6d and 8a-8e).



Our results signify hydrazones/hydrazines as potential hit candidates against the future developments of potent and safer anti-TB agents.
