RESUMEN
The beneficial action of nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with the inhibition of cyclooxygenase-2 (COX-2), whereas their harmful side effects are associated with the inhibition of COX-1. In order to understand a meaningful comparison of both classical NSAIDs and newer COX-2 drugs, a series of molecules from varied classes of COX-2 inhibitors was studied by the application of three-dimensional quantitative structure-activity relationships (3D-QSAR) using molecular descriptors obtained by genetic function approximation. The features responsible for the dual inhibition of COX-1 and COX-2 and the selective inhibition of COX-2 with factors contributing to the maintenance of optimum selectivity were identified. The QSAR models revealed the importance of thermodynamic, electronic, structural, and molecular shape analysis parameters, which can reasonably modulate the selectivity pattern to avoid unsolicited side effects. An improved understanding to rationalize the COX-1 and COX-2 binding profiles could be gained to develop safe drug design methods.
Asunto(s)
Antiinflamatorios no Esteroideos/química , Antiinflamatorios no Esteroideos/farmacología , Ciclooxigenasa 1/metabolismo , Ciclooxigenasa 2/metabolismo , Inhibidores de la Ciclooxigenasa/química , Inhibidores de la Ciclooxigenasa/farmacología , Ciclooxigenasa 1/genética , Ciclooxigenasa 2/genética , Diseño de Fármacos , Concentración 50 Inhibidora , Estructura Molecular , Relación Estructura-Actividad CuantitativaRESUMEN
Novel curcumin analogs were synthesized using Knoevenagel condensation to convert enolic diketones of curcumin into non-enolizable ones and Schiff bases were prepared using a bioactive thiosemicarbazide pharmacophore. Copper(II) conjugates of all synthesized ligands were prepared and structurally characterized as well as evaluated for their potential of inhibiting TNF-induced NF-kappaB activation and proliferation in human leukemic KBM-5 cells wherein compound 13 was found to be more potent than curcumin. Compounds were further examined on other tumor cell lines such as Jurkat, H1299, and MM1, respectively.