Synthesis and Evaluation of Pharmacological Activities of 3, 5‐Dialkyl 1, 4‐Dihydro‐2, 6‐Dimethyl‐4‐Nitroimidazole‐3, 5‐Pyridine Dicarboxylates

Abstract

New analogues of nifedipine, in which the 2-nitrophenyl group at position 4 is replaced by a 1-methyl-5-nitro-2-imidazolyl substituent, were synthesized. The symmetrical dialkyl 1, 4-dihydro-2, 6-dimethyl-4-(1-methyl-5-nitro-2-imidazolyl)-3, 5-pyridinedicarboxylates were prepared by a classical Hantzsch condensation. The asymmetrical analogues were synthesized using a procedure reported by Iwanami that involved the condensation of alkylacetoacetate with methyl-, ethyl- or isopropyl3-aminocrotonate and 1-methyl-5-nitroimidazole-2-carboxaldehyde. Calcium channel antagonist activities were determined in vitro using a guinea pig ileum longitudinal smooth muscle (GPILSM)assay. Many compounds exhibited superior, or equipotent, calcium antagonist activity (IC(50) = 10(-10) to 10(-13) M range) relative to the reference drug nifedipine (IC(50) = 1.09 +/- 0.12 x 10(-11) M). Antinociceptive effects of some compounds were evaluated by the mouse tail-flick assay in vivo. Results demonstrate that some of the compounds were active as an antinociceptive.

Dihydropyridine Derivatives to Overcome Atypical Multidrug Resistance: Design, Synthesis, QSAR Studies, and Evaluation of Their Cytotoxic and Pharmacological Activities

“…The discovery of the DHP class of Ca 2+ channel blockers (CCBs) has represented a major therapeutic advance in treatment of cardiovascular disease such as hypertension, angina, and other spastic smooth muscle disorder (5–7). Recently, CCBs were identified as one of the first classes of drugs acting as MDR inhibitors (8–10).…”

β-Enaminonitriles in heterocylic synthesis: Synthesis of new tetrahydropyridinethione, pyridopyrimidines, pyridotriazines and dihydropyridines

“…nifadipine drug. [6][7][8][9][10][11][12][13] In continuation of this work we investigated the behaviour of 3aminocrotononitrile (1) towards some electrophilic reagents such as arylidenemalononitriles and arylidinecyanothioacetamides. Thus, it has been found that 3-aminocrotononitrile (1) reacted with arylidenmalononitriles 19a-c and arylidinecyanothioacetamides 19d,e to give dihydropyridine derivatives 24a-e. Establishing structure 24 was based on its spectral data and authentic specimen prepared from the reaction of 1 with the corresponding aldehydes derivatives 25a-e.…”

Dihydropyridines and Multidrug Resistance: Previous Attempts, Present State, and Future Trends

“…The discovery that the 1,4‐dihydropyridine class of calcium channel antagonists inhibits Ca 2+ influx represented a major therapeutic advancement in the treatment of cardiovascular disease including hypertension, angina pectoris, and other spastic smooth muscle disorders (61–63). Moreover, some other biological applications were reported for DHPs making them a reliable class for widespread drug development (63–66).…”