Abstract
Targeting of cyclooxygenase-2 (COX-2) has emerged as a powerful tool for therapeutic intervention because the overexpression of this enzyme is synonymous with inflammation, cancer, and neurodegenerative diseases. Herein, a new series of 1,2,4-triazole Schiff bases scaffold with aryl and heteroaryl systems 9a–12d were designed, synthesized, structurally elucidated, and biologically evaluated as a potent COX-2 blocker. The rationale beyond the current study is to increase the molecule bulkiness allowing a selective binding to the unique hydrophobic pocket of COX-2. Among the triazole–thiazole hybrids, the one with the para-methoxy moiety linked to a phenyl ring 12d showed the highest In vitro selectivity by COX-2 inhibition assay (IC50 of 0.04 μM) and in situ anti-inflammatory activity when evaluated using the protein denaturation assay (IC50 of 0.88 μM) in comparison with commercially available selective COX-2 inhibitor, Celecoxib (IC50 of 0.05 μM). Towards the COX-2 selectivity, ligand-based three dimensional quantitative structures activity relationship (3D-QSAR) employing atomic-based and field-based approaches were performed and resulted in the necessity of triazole and thiazole/oxazole scaffolds for COX-2 blocking. Furthermore, the molecular modeling study indicated a high selectivity and promising affinity of our prepared compounds to COX-2, especially the hydrophobic pocket and the mouth of the active site holding hydrogen-bonding, hydrophobic, and electrostatic interactions. In Silico absorption, delivery, metabolism, and excretion (ADME) predictions showed that all the pharmacokinetic and physicochemical features are within the appropriate range for human use.
Highlights
Pain is an exceedingly severe issue in 90% of illnesses, from simple back pain to pain with multiple forms of cancer
Based on the previously mentioned studies, and in continuation of our interest in the synthesis of bioactive heterocycles, we describe the synthesis, in vitro evaluation as cyclooxygenase enzyme (COX)-1/COX-2 inhibitors, in situ anti-inflammatory activity for a new series of di/triaryl-1,2,4-triazoles Schiff bases hoping of reducing side effects with better selectivity and enhancing the anti-inflammatory activity
294.0 a IC50 value represents the compound concentration that is required to produce 50% inhibition of COX-1 or COX-2 which is the mean value of two determinations where the deviation from the mean is
Summary
Pain is an exceedingly severe issue in 90% of illnesses, from simple back pain to pain with multiple forms of cancer. Molecular docking studies and 3D-QSAR of active compounds were done to get the possible binding modes of the prepared compounds into COX-2 active site and to rationalize their activity These target compounds can be considered to be Celecoxib-like with some modifications include: (i) the replacement of the central pyrazole ring system with 1,2,4-triazole in a trial to avoid serious thromboembolic adverse effects previously reported with pyrazole derivatives [27] and to improve the drug solubility (ii) The methyl group at para position of phenyl moiety at pyrazole C3 was removed or replaced with different electronegative moieties as m-NO2, p-OCH3, O-OH to study the effect of various electronegative groups on COX-2 selectivity and anti-inflammatory activity. 294.0 a IC50 value represents the compound concentration that is required to produce 50% inhibition of COX-1 or COX-2 which is the mean value of two determinations where the deviation from the mean is
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