Facile synthesis, antibacterial activity, in silico molecular docking analysis, and pharmacokinetic properties of N-methyl anthranilate-based compounds.

Abstract

In this work, a diverse series of 2-(methylamino)benzohydrazide-derived heterocyclic compounds were synthesized from the natural methyl N-methyl anthranilate (methyl 2-(methylamino)benzoate (DMA)), isolated from petitgrain mandarin (PGM) essential oil, which served as a key starting material throughout all synthetic routes. The target compounds were obtained via a simple and efficient synthetic protocol, providing yields in the range of 58-98%. The synthesized series included Schiff base derivatives 3a-g, 4,5-dihydro-1,3,4-oxadiazole derivatives, 4a-f, spiro[indoline-3,2'-[1,3,4]oxadiazol]-2-one derivative 9, oxadiazole derivative 6, 13, oxadiazole thioglycoside derivatives 15a,b; 16a,b, and triazole derivatives 18a,b. Structural elucidation of the synthesized derivatives was confirmed through elemental analyses and spectroscopic techniques (IR, 1H NMR,13C NMR, and mass spectrometry). The in vitro antimicrobial activity of the synthesized compounds was evaluated against a panel of Gram-positive, Gram-negative bacteria and pathogenic fungi in comparison with standard drugs. Schiff base derivative 3c displayed outstanding broad-spectrum antimicrobial efficacy. The triazole derivatives 18a and 18b demonstrated notable antimicrobial activity against both bacterial and fungal strains. Notably, compound 18b exhibited notable in vitro antibacterial and antifungal activities against selected microorganisms, with MIC values reaching 1.57 μg/mL. Structure-activity relationship (SAR) analysis revealed that antimicrobial potency was strongly influenced by both the nature of substituents and the type of heterocyclic ring system. The incorporation of imine groups (as found in Schiff base derivatives) and hydrogen-bond-forming functionalities was found to enhance antibacterial activity, whereas cyclization to the corresponding dihydro-oxadiazole and oxadiazole rings resulted in a reduction of the antibacterial potency. In contrast, cyclization into a triazole ring markedly improved antifungal properties. Molecular docking studies were performed using AutoDock 4.0 against dihydrofolate reductase, revealing predicted binding affinities in the range of -8.40 to -9.65 kcal/mol. Drug-likeness properties for the most active compounds were assessed using SwissADME and pkCSM. The tested compounds complied with Lipinski's Rule of Five without any violations. ADMET predictions suggested generally favorable intestinal absorption and drug-like characteristics, while identifying several potential liabilities, including predicted CYP inhibition, Ames positivity for 4a, hERG II inhibition for 18a and 18b, and hepatotoxicity for 18b. These computational predictions require experimental validation. MD simulations were performed to further explore the dynamic behavior of the selected compounds within the investigated binding site. Collectively, these findings highlight compound 3c as a promising antibacterial lead and suggest compounds 18a and 18b as potential antifungal candidates, all warranting further investigation in the broader context of combating antimicrobial resistance.

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