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 anti-inflammatory agents. The in-silico ADMET study predicted a favorable pharmacokinetic profile and respect for Lipinski's Rule of Five. 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 COX-1 and COX-2 enzymes, with a relative preference for COX-2, predicting anti-inflammatory 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 significant inhibition of the carrageenan-induced paw edema in rats and probable inhibition of cyclooxygenase. Particularly, compounds 4e and 4h devoid of COOH group, which provoke serious gastrointestinal irritation, exhibited anti-inflammatory activity comparable to that of salicylic acid (ASA) and surpassed the effectiveness of DCF. 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 hours. The results also indicate good pharmacokinetic profile of the target compounds similar to ASA and DCF.