Integrated computational evaluation of novel benzimidazole scaffolds as dual COX-2 inhibitory and histamine H1 antagonistic activity

Abstract

Chronic inflammatory and hypersensitivity diseases are regulated by linked biochemical pathways where cyclooxygenase-2 (COX-2) and histamine H1 receptor are vital therapeutic targets. The current study sought to produce and computationally screen emerging benzimidazole derivatives as dual-acting agents with prime pharmacokinetic profiles. Eleven structurally varied benzimidazole analogues (SP1–SP11) were rationally proposed using a 2-phenyl-1H-benzimidazole scaffold with logical N-1 substitutions to examine structure–activity relationships. The physicochemical properties and drug-likeness profiles were assessed by SwissADME platform whereas toxicity prediction was carried out by ProTox-III. Glide XP based molecular docking studies were carried out against COX-2 (PDB: 5IKR) and histamine H1 receptor (PBD: 8X64) to study binding affinity and interaction patterns. All the computationally designed analogues adhered to Lipinski’s Rule of Five and Veber’s criteria, suggesting good oral bioavailability. ADMET studies predicted tolerable pharmacokinetic and toxicity traits for the overall series. From docking studies, SP2 and SP8 established maximum affinity towards COX-2 (GlideScores: − 8.032 and − 9.566 kcal/mol, better than the prototypical drug ibuprofen, − 5.779 kcal/mol). Equivalent trend was also detected for binding towards histamine H1 receptor with SP2 and SP11 producing superior docking (− 8.021 and − 8.627 kcal/mol). Important molecular inter-connections were hydrogen bonding, π–π stacking and hydrophobic stabilization in the receptor active sites. SP2, SP8, and SP11 emerge as computationally prioritized dual-target candidates, showing favorable predicted binding affinity toward both COX-2 and H1R alongside acceptable predicted drug-likeness, warranting experimental synthesis and biological validation before any conclusions about actual anti-inflammatory or antihistaminic activity can be drawn. This image outlines a three-step computational evaluation process for novel benzimidazole derivatives as dual COX-2 and histamine H1 receptor modulators. The first step, labeled "Design," involves benzimidazole derivatives named SP1 to SP11, represented by chemical structures. The second step, "In Silico Evaluation," includes assessments of drug-likeness and physicochemical properties using SwissADME, toxicity prediction with ProTox-III, and ADMET profiling, illustrated by a molecular structure, a radar chart, and a laptop screen showing the ProTox-III interface. The third step, "Molecular Docking," shows protein structures and their docked complexes, indicating the interaction between the benzimidazole derivatives and target proteins. Arrows indicate the sequence from design through evaluation to docking.