{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,13]],"date-time":"2026-04-13T04:56:36Z","timestamp":1776056196286,"version":"3.50.1"},"reference-count":86,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2025,11,13]],"date-time":"2025-11-13T00:00:00Z","timestamp":1762992000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"University of Aveiro and Funda\u00e7\u00e3o para a Ci\u00eancia e Tecnologia and Minist\u00e9rio da Ci\u00eancia, Tecnologia e Ensino Superior","award":["UID\/50006\/2025"],"award-info":[{"award-number":["UID\/50006\/2025"]}]},{"name":"project CICECO Aveiro Institute of Materials","award":["UID\/50011\/2025"],"award-info":[{"award-number":["UID\/50011\/2025"]}]},{"name":"project CICECO Aveiro Institute of Materials","award":["LA\/P\/0006\/2020"],"award-info":[{"award-number":["LA\/P\/0006\/2020"]}]},{"name":"FCT\/MCTES"},{"name":"FCT","award":["2023.06495.CEECIND\/CP2840\/CT0031"],"award-info":[{"award-number":["2023.06495.CEECIND\/CP2840\/CT0031"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antibiotics"],"abstract":"<jats:p>Background\/Objectives: In this work, a series of six new indazole-benzimidazole hybrids (M1\u2013M6) 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\u2013M6 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 \u00b5g\/mL against S. cerevisiae and C. tropicalis, and 3.90 \u00b5g\/mL against S. aureus, B. cereus, and S. enteritidis, while the standards Ampicillin (AmB) (MIC \u2265 15.62 \u00b5g\/mL) and Tetracycline (TET) (MIC \u2265 7.81 \u00b5g\/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\u2013M6 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\u2013activity relationships, highlighting these hybrids as potential candidates for antimicrobial drug development.<\/jats:p>","DOI":"10.3390\/antibiotics14111150","type":"journal-article","created":{"date-parts":[[2025,11,14]],"date-time":"2025-11-14T09:06:36Z","timestamp":1763111196000},"page":"1150","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Synthesis, Characterization, Antimicrobial Activity and Molecular Modeling Studies of Novel Indazole-Benzimidazole Hybrids"],"prefix":"10.3390","volume":"14","author":[{"given":"Redouane","family":"Er-raqioui","sequence":"first","affiliation":[{"name":"Laboratory of Molecular Chemistry Materials and Catalysis, Faculty of Sciences and Technics, Sultan Moulay Slimane University, B.P. 523, Beni-Mellal 23000, Morocco"},{"name":"LAQV-REQUIMTE, Department of Chemistry, University of Aveiro, Campus Universit\u00e1rio de Santiago, 3810-193 Aveiro, Portugal"},{"name":"Higher School of Technology, Sultan Moulay Slimane University, B.P. 336, 23200, Fkih Ben Salah 23000, Morocco"}]},{"given":"Sara","family":"Roudani","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Chemistry Materials and Catalysis, Faculty of Sciences and Technics, Sultan Moulay Slimane University, B.P. 523, Beni-Mellal 23000, Morocco"},{"name":"Higher School of Technology, Sultan Moulay Slimane University, B.P. 336, 23200, Fkih Ben Salah 23000, Morocco"}]},{"given":"Imane","family":"El Houssni","sequence":"additional","affiliation":[{"name":"BVPRT, BER Center, Faculty of Sciences, Mohammed V University, Rabat 08007, Morocco"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4213-5416","authenticated-orcid":false,"given":"Njabulo J.","family":"Gumede","sequence":"additional","affiliation":[{"name":"Department of Chemical and Physical Sciences, Faculty of Natural Sciences, Walter Sisulu University (WSU), Private Bag X01, Mthatha 4099, Eastern Cape, South Africa"}]},{"given":"Yusuf","family":"Sert","sequence":"additional","affiliation":[{"name":"Department of Physics, Yozgat Bozok University, 66100 Yozgat, Turkey"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8242-324X","authenticated-orcid":false,"given":"Ricardo F.","family":"Mendes","sequence":"additional","affiliation":[{"name":"CICECO\u2014Aveiro Institute of Materials, Department of Chemistry, University of Aveiro, Campus Universit\u00e1rio de Santiago, 3810-193 Aveiro, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7738-9358","authenticated-orcid":false,"given":"Dimitry","family":"Chernyshov","sequence":"additional","affiliation":[{"name":"European Synchrotron Radiation Facility, SNBL CS40220, 38043 Grenoble CEDEX 9, France"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2051-5645","authenticated-orcid":false,"given":"Filipe A. A.","family":"Paz","sequence":"additional","affiliation":[{"name":"CICECO\u2014Aveiro Institute of Materials, Department of Chemistry, University of Aveiro, Campus Universit\u00e1rio de Santiago, 3810-193 Aveiro, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5495-5126","authenticated-orcid":false,"given":"Jos\u00e9 A. S.","family":"Cavaleiro","sequence":"additional","affiliation":[{"name":"LAQV-REQUIMTE, Department of Chemistry, University of Aveiro, Campus Universit\u00e1rio de Santiago, 3810-193 Aveiro, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4423-3802","authenticated-orcid":false,"given":"Maria do Amparo F.","family":"Faustino","sequence":"additional","affiliation":[{"name":"LAQV-REQUIMTE, Department of Chemistry, University of Aveiro, Campus Universit\u00e1rio de Santiago, 3810-193 Aveiro, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2121-4708","authenticated-orcid":false,"given":"Rakib","family":"El Mostapha","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Chemistry Materials and Catalysis, Faculty of Sciences and Technics, Sultan Moulay Slimane University, B.P. 523, Beni-Mellal 23000, Morocco"},{"name":"Higher School of Technology, Sultan Moulay Slimane University, B.P. 336, 23200, Fkih Ben Salah 23000, Morocco"}]},{"given":"Said","family":"Abouricha","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Chemistry Materials and Catalysis, Faculty of Sciences and Technics, Sultan Moulay Slimane University, B.P. 523, Beni-Mellal 23000, Morocco"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8075-8051","authenticated-orcid":false,"given":"Khalid","family":"Karrouchi","sequence":"additional","affiliation":[{"name":"Laboratory of Analytical Chemistry and Bromatology, Faculty of Medicine and Pharmacy, Mohammed V University, Rabat 08007, Morocco"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7953-8166","authenticated-orcid":false,"given":"Maria da Gra\u00e7a P. 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