Design, Synthesis, and Biological Evaluation of New Ureido (Thioureido) Anthranilic Acid Isosteres: Molecular Docking, In Silico ADMET Predictions, and In Vivo Anti-Inflammatory Activity

Abstract

A novel series of anthranilic acid isosteres were designed and synthesized as antiinflammatory agents. The in silico absorption, distribution, metabolism, excretion, and toxicity (ADMET) study predicted a favorable pharmacokinetic profile and respect for Lipinski's rule of five. Density functional theory (DFT) calculations revealed an improvement in some target compounds' electronic parameters compared to diclofenac (DCF) and aspirin (ASA), predicting an improvement in their biological activity. Docking investigations demonstrated a strong affinity toward the cyclooxygenase (COX)-1 and COX-2 enzymes, with a relative preference for COX-2, predicting antiinflammatory activity. The MolDock scores were between -140.59 and -91.81 kcal/mol for COX-1 and between -148.10 and -108.9 kcal/mol for COX-2. The experimental pharmacological investigation confirmed these theoretical findings. Indeed, target compounds demonstrated a significant inhibition of the carrageenan-induced paw edema in rats and probable inhibition of COX. Particularly, compounds 4e and 4h devoid of COOH group, which provoke serious gastrointestinal irritation, exhibited antiinflammatory activity comparable to that of salicylic acid (ASA) and surpassed the effectiveness of DCF. Cpmpounds 4e and 4h showed 91.72% inhibition after 3h, against 91.03% and 83.44% for ASA and DCF, respectively, with a greater onset effect, and also surpassing the reference compounds after 1 and 2 h. The results also indicate good pharmacokinetic profile of the target compounds similar to ASA and DCF.

Keywords: absorption; and toxicity (ADMET); anthranilic acid isosteres; antiinflammatory activity; density functional theory (DFT); distribution; excretion; metabolism; molecular docking; non‐steroidal anti‐inflammatory drugs (NSAIDs).