Molecular modeling and protection against pentylenetetrazole-induced seizure of new 1,4-dihydropyridines containing 5(4)-imidazolyl substituent

Abstract

A group of symmetrical and asymmetrical esters of nifedipine analogs, in which the ortho-nitro phenyl group at position 4 was replaced by 2-ethyl(or H)-4(5)-chloro-5(4)-imidazolyl substituent, was designed and evaluated as anticonvulsant against pentylenetetrazole (PTZ)-induced seizure. Our molecular modeling studies reveals that 4-chloro tautomeric form is the main one and has good compatibility with nifedipine and that 4-H is syn-perpendicular. Docking studies reveal that the oxygen atoms of carbonyl group and the N3′ of imidazole ring of dihydropyridine form a hydrogen-bonding interaction with the receptor. The time-course of anticonvulsant' effect on PTZ-induced seizure threshold was assessed, and it showed that increasing the lipophilicity decreases the time need for maximum effect. All those mice, treated with intraperitoneal injection of 5, 10, and 20 mg/kg of these derivatives, exhibited increased seizure threshold as compared with control. Based on in vivo results of symmetrical and unsymmetrical ester series, increasing the length of the chain in C3- and C5-ester substituents increases the protection activity. The most active compounds were 2c and 3b, which were more active than the reference drug nifedipine, and compound 2e had comparable activity with nifedipine. QSAR studies indicate that size, hydrophobicity, and topology of DHPs have main effects in the respective biological activities of these compounds.