Synthesis, anticonvulsant activity and molecular properties prediction of dialkyl 1-(di(ethoxycarbonyl)methyl)-2,6-dimethyl-4-substituted-1,4-dihydropyridine-3,5-dicarboxylates

• Published in: European journal of medicinal chemistry 2014-02, Vol.73, p.97-104
• Main Authors: Prasanthi, G., Prasad, K.V.S.R.G., Bharathi, K.
• Format: Article
• Language: English
• Subjects: Administration, Oral; Animals; Anticonvulsants - chemical synthesis; Anticonvulsants - chemistry; Anticonvulsants - therapeutic use; Anticonvulsants - toxicity; Diethylmalonyl; Dihydropyridines - chemical synthesis; Dihydropyridines - chemistry; Dihydropyridines - therapeutic use; Dihydropyridines - toxicity; Drug Design; Lipinski's “rule of five”; Male; Maximal electroshock method; Mice; Molecular Structure; Pyridine-3,5-dicarboxylates; Rats; Rats, Wistar; Seizures - drug therapy; Seizures - etiology; Structure-Activity Relationship; Subcutaneous pentylenetetrazole method; Toxicity Tests, Acute
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2013.12.001

The synthesis and anticonvulsant properties of new N-diethylmalonyl derivatives of nifedipine and other isosteric analogues (7a–7n) were described. Anticonvulsant screening was performed by subcutaneous pentylenetetrazole (scPTZ) and maximal electroshock (MES) induced seizures tests. Majority of the compounds were effective in scPTZ and MES screens. Compound 7k showed good activity displaying maximum protection, which may be due to the presence of styryl moiety at position 4 of 1,4-dihydropyridine nucleus and the methyl groups of diester functionality. Compounds 7a–7d, 7g, 7i and 7k obeyed the Lipinski's “rule of five” and have drug-likeness. Based on computational prediction of molecular and pharmacokinetic properties, it was found that the compounds have good oral absorption. [Display omitted] A series of dialkyl 1-(di(ethoxycarbonyl)methyl)-1,4-dihydro-2,6-dimethyl-4-substituted pyridine-3,5-dicarboxylates (7a–7n) were synthesized and evaluated for anticonvulsant activity by scPTZ and MES methods. Compound 7k displayed promising activity and also obeyed the Lipinski's rule of five. •A novel series of N-diethylmalonyl derivatives 7a–7n were synthesized.•Majority of the compounds were effective in MES and scPTZ induced seizure tests.•Compound 7k showed good activity which may be due to the presence of styryl moiety.•Compounds 7a–7d, 7g, 7i and 7k obeyed the Lipinski's “rule of five”.