2,3-Diphenyltetrahydrofurans (DPTF) - A new class of stereogenic diarylheterocycles as potential COX-2 inhibitors - Computational evaluation of COX-2-DPTF binding behaviour

Abstract

<span style="color:black;mso-bidi-language:HI">Based on the reported COX-2 selectivity of α<span style="color:#1C1C1C;mso-bidi-language:HI">,<span style="color:black;mso-bidi-language:HI">β-diarylheterocycles based NSAIDs' - a new class of 2,3-diphenyltetrahydrofurans (DPTF) possessing COOH, CH₂OH or CH_{<span style="color:#1C1C1C;mso-bidi-language:HI">2</span>}<span style="color:black;mso-bidi-language:HI">NH₂ groups at C-5 and three chiral centers C-2, C-3 and C-5 have been designed. In total 12 title compounds have been studied for their binding in the active sites of COX-2 and COX-1 enzymes<span style="color:#333333;mso-bidi-language:HI">. <span style="color:black; mso-bidi-language:HI">For comparison, the binding behavior of known COX-2 selective (rofecoxib, celecoxib, valdecoxib) and nonselective (aspirin, ibuprofen) drugs has also been studied. The trends of COX-2 selectivity of known NSAIDs' are parallel with their reported results<span style="color:#1C1C1C;mso-bidi-language:HI">. <span style="color:black; mso-bidi-language:HI">In general, DPTF derivatives show binding energies in COX-2 active site better than rofecoxib and comparable to aspirin and poor binding energies in COX-1 active sites pointing towards these molecules being selective COX-2 inhibitors. The stereochemistries at C-2, C-3 and C-5 carbons of DPTF derivatives considerably affect their bindings in the active sites of COX-1 and COX-2 and the COX-2 selectivity. The ligands with configuration <span style="mso-bidi-font-family:Arial;color:black;mso-bidi-language:HI">(2<i>S</i>, 3<i>R</i>, <span style="color:black;mso-bidi-language:HI">5<i>S</i>) show higher selectivity for COX-2 over COX-1 in comparison to other configurational isomers.

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