Benzimidazole-pyrazole hybrid antibacterial agent AJ01

Abstract

Composition comprising an antibacterial benzimidazole-pyrazole hybrid compound, N-(1H-Benzo[d]imidazol-2-yl)-1-(3-(4-Fluorphenyl)-1-phenyl-1H-pyrazole-4-yl)methanimin (AJ01), characterized at a minimum inhibitory concentration of 12.5 µg / ml against Staphylococcus aureus, including multi-resistant strains, and with predicted high affinity for bacterial target proteins.

Description

AREA OF INVENTION

[0001] The invention relates to low molecular weight antibacterial compositions comprising benzimidazole-pyrazole hybrid scaffolds and formulated for therapeutic use, with proven in vitro activity against Staphylococcus aureus and favorable drug-like and ADME properties for systemic administration. BACKGROUND OF THE INVENTION

[0002] Benzimidazole and pyrazole pharmacophores are intensively researched in medicinal chemistry due to their hydrogen-bonding capacity and their ability to target microbial enzymes and proteins. Scaffold structures inspired by natural products have significantly influenced the development of anti-infectives against resistant S. aureus strains, which require novel mechanisms of action and chemotypes. The formulation of topical and systemic drugs emphasizes stability, bioavailability, and gel / solution integrity. ADME-based design helps prioritize candidates with suitable absorption and lipophilicity that align with established oral or parenteral delivery paradigms in pharmaceutical development. A hybrid chemotype linking benzimidazole and pyrazole via a methanimine bridge exhibits a low double-digit µg / ml MIC against S.aureus, supported by docking-predicted target binding and acceptable in silico ADME values, addresses the urgent need for new antibacterial lead structures. SUMMARY OF THE INVENTION

[0003] The invention provides N-(1H-benzo[d]imidazol-2-yl)-1-(3-(4-fluorophenyl)-1-phenyl-1H-pyrazole-4-yl)methanimine (AJ01), a benzimidazole-pyrazole hybrid synthesized from benzimidazole and substituted pyrazole precursors linked via a methanimine bond. It exhibits potent antibacterial activity against S. aureus, including multidrug-resistant isolates, as demonstrated by a MIC assay at 12.5 µg / ml and strong docking-predicted binding (-10.1 kcal / mol) to bacterial target proteins. ADME profile analyses indicate high gastrointestinal absorption, acceptable lipophilicity, and a bioavailability value of 0.55, supporting its development potential. Compositions can be formulated as oral solid dosage forms or parenteral solutions with pharmaceutically acceptable excipients. DETAILED DESCRIPTION

[0004] AJ01 possesses a benzimidazole core (1H-benzo[d]imidazol-2-yl) linked via a methaniamine (-CH=N-) to a 1-phenyl-3-(4-fluorophenyl)-1H-pyrazole-4-yl unit. This forms a conjugated hybrid that enables π-π interactions and hydrogen bonding at bacterial protein binding sites, as suggested by docking studies with an affinity of -10.1 kcal / mol and important residual contacts. The synthetic route includes: (i) the preparation of the benzimidazole-2-amine intermediate by condensation and cyclization from o-phenylenediamine precursors; (ii) synthesis of 1-phenyl-3-(4-fluorophenyl)-1H-pyrazole-4-carbaldehyde by suitable hydrazone formation and cyclization; and (iii) Schiff base formation between benzimidazol-2-amine and pyrazole-4-carbaldehyde to give AJ01, followed by purification and structure elucidation by NMR / MS and HPLC purity for biological testing.Antibacterial in vitro evaluation includes determination of the minimum inhibitory concentration (MIC) against S. aureus by agar or broth microdilution. AJ01 exhibits an MIC of 12.5 µg / ml and retains its activity against multidrug-resistant strains. Kill rate or post-antibiotic effect studies can further refine the pharmacodynamics. In silico ADME simulations show high gastrointestinal absorption, a moderate logP value consistent with oral exposure, and a bioavailability value of 0.55. Medicinal chemistry guidelines for gel and solution stability serve as a basis for excipient selection in early formulations, while solid oral dosage forms aim for acceptable dissolution and homogeneity of concentration. Lead safety assessment excludes structural warning signals and predicts low acute toxicity using standard computational toxicology filters.Subsequent formulation strategies may include cyclodextrin solubilization or salt formation to improve water solubility while maintaining chemical stability. This is guided by development practices for topical and systemic gels / solutions. Comparative SAR extension around the methanimine bridge (e.g., electron-withdrawing substituents on the phenyl rings, heteroaryl substitution, reduced imine-to-amine variants) is considered to optimize potency, metabolic stability, and solubility. Docking and ADME screenings are used for prioritization prior to synthesis. Pharmaceutical compositions include capsules or tablets with excipients and disintegrants for oral administration or sterile solutions with appropriate cosolvents and buffers for parenteral administration. Carbopol-based topical gels are indicated for dermal infections with S.aureus is optional, taking into account stability and pH management techniques.

Claims

[1] Composition comprising an antibacterial benzimidazole-pyrazole hybrid compound, N-(1H-Benzo[d]imidazol-2-yl)-1-(3-(4-Fluorphenyl)-1-phenyl-1H-pyrazole-4-yl)methanimin (AJ01), characterized at a minimum inhibitory concentration of 12.5 µg / ml against Staphylococcus aureus, including multi-resistant strains, and with predicted high affinity for bacterial target proteins. [2] Composition according to claim 1, formulated with pharmaceutically acceptable excipients as an oral or parenteral composition, wherein the ADME profile indicates high gastrointestinal absorption, acceptable lipophilicity and a bioavailability value of approximately 0.55 to support systemic administration. [3] Composition according to claim 1 or 2, wherein the synthesis comprises the condensation of benzimidazol-2-amine with 1-phenyl-3-(4-fluorophenyl)-1H-pyrazole-4-carbaldehyde to form a methaniamine bond, followed by purification to pharmaceutical purity and confirmation by spectroscopic methods. [4] Composition according to any of the preceding claims, wherein pharmaceutical compositions further include stabilizers and solubilizers selected to ensure the stability of the solution or gel in accordance with established topical / systemic development practices, and wherein optional structure-activity variants are provided around phenyl substituents and the methanimine bond to optimize efficacy and ADME properties.