Synthesis, Characterization, Antimicrobial Activity and Molecular Modeling Studies of Novel Indazole-Benzimidazole Hybrids

resumo

Background/Objectives: In this work, a series of six new indazole-benzimidazole hybrids (M1-M6) were designed, synthesized, and fully characterized. The design of these compounds was based on the combination of two pharmacophoric units, indazole and benzimidazole, both known for their broad spectrum of biological activities. Methods: The molecular hybridization strategy was planned to combine these scaffolds through an effective synthetic pathway, using 6-nitroindazole, two 2-mercaptobenzimidazoles, and 1,3- or 1,5-dihaloalkanes as key precursors, affording the desired hybrids in good yields and with enhanced biological activity. Quantum chemical calculations were performed to investigate the structural, electronic, and electrostatic properties of M1-M6 molecules using Density Functional Theory (DFT) at the B3LYP/6-311++G(d,p) level. The antimicrobial activity efficacy of these compounds was assessed in vitro against four Gram-positive bacteria (Staphylococcus aureus, Enterococcus faecalis, Bacillus cereus, and Lactobacillus plantarum), four Gram-negative bacteria (Salmonella enteritidis, Escherichia coli, Campylobacter coli, Campylobacter jejuni), and four fungal strains (Saccharomyces cerevisiae, Candida albicans, Candida tropicalis, and Candida glabrata) using ampicillin and tetracycline as reference standard drugs. Results: Among the series, compound M6 exhibited remarkable antimicrobial activity, with minimum inhibitory concentrations (MIC) of 1.95 mu g/mL against S. cerevisiae and C. tropicalis, and 3.90 mu g/mL against S. aureus, B. cereus, and S. enteritidis, while the standards Ampicillin (AmB) (MIC >= 15.62 mu g/mL) and Tetracycline (TET) (MIC >= 7.81 mu g/mL) exhibited higher MIC values. To gain molecular insights into the compounds, an in silico docking study was performed to determine the interactions of M1-M6 ligands against the antimicrobial target beta-ketoacyl-acyl carrier protein (ACP) synthase III complexed with malonyl-COA (PDB ID: 1HNJ). Molecular modeling data provided valuable information on the structure-activity relationship (SAR) and the binding modes influencing the candidate ligand-protein recognition. Amino acid residues, such as Arg249, located in the solvent-exposed region, were essential for hydrogen bonding with the nitro group of the 6-nitroindazole moiety. Furthermore, polar side chains such as Asn274, Asn247, and His244 participated in interactions mediated by hydrogen bonding with the 5-nitrobenzimidazole moiety of these compound series. Conclusions: The hybridization of indazole and benzimidazole scaffolds produced compounds with promising antimicrobial activity, particularly M6, which demonstrated superior potency compared to standard antibiotics. Computational and docking analyses provided insights into the structure-activity relationships, highlighting these hybrids as potential candidates for antimicrobial drug development.

palavras-chave

PLANT-EXTRACTS; BASIS-SETS; DERIVATIVES; ACCURACY

categoria

Infectious Diseases; Pharmacology & Pharmacy

autores

Er-raqioui, R; Roudani, S; El Houssni, I; Gumede, NJ; Sert, Y; Mendes, RF; Chernyshov, D; Paz, FAA; Cavaleiro, JAS; Faustino, MDF; El Mostapha, R; Abouricha, S; Karrouchi, K; Neves, MDPMS; Moura, NMM

Grupos

G1 - Materiais Porosos e Nanossistemas

Projectos

CICECO-Aveiro Institute of Materials R&D Unit Pluriannual Funding (CICECO-Aveiro Institute of Materials)

Associated Laboratory CICECO-Aveiro Institute of Materials (LA/P/0006/2020)

agradecimentos

This research work received financial support from University of Aveiro and Fundac & atilde;o para a Ciencia e Tecnologia and Ministerio da Ciencia, Tecnologia e Ensino Superior (FCT/MCTES) to support the UID/50006/2025-Laboratorio Associado para a Quimica Verde-Tecnologias e Processos Limpos unit through national funds and, where applicable, was co-financed by the FEDER, within the PT2020 Partnership Agreement, and to the Portuguese NMR Network. This work was developed within the scope of the project CICECO Aveiro Institute of Materials, UID/50011/2025 (https://doi.org/10.54499/UID/50011/2025) & LA/P/0006/2020 (https://doi.org/10.54499/LA/P/0006/2020), financed by national funds through the FCT/MCTES (PIDDAC). NMM Moura gratefully acknowledges FCT for an Assistant Research Position under the Individual Scientific Employment Stimulus-6th Edition (2023.06495.CEECIND/CP2840/CT0031; https://doi.org/10.54499/2023.06495.CEECIND/CP2840/CT0031).