Synthesis and studies of calcium channel blocking and antioxidant activities of novel 4-pyridinium and/or N-propargyl substituted 1,4-dihydropyridine derivatives

Abstract

The novel 1,4-dihydropyridine derivatives containing the cationic pyridine moiety at the position 4, and the N -propargyl group as a substituent at position 1 of the 1,4-DHP cycle were designed, synthesised, and assessed in biological tests. Among all the novel compounds, the 4-( N -dodecyl) pyridinium group-containing compounds 11 (without the N -propargyl group) and 12 (with the N -propargyl group) demonstrated the highest calcium antagonistic properties against neuroblastoma SH-SY5Y (IC 50 about 5–14 μM) and the vascular smooth muscle A7r5 cell (IC 50 – 0.6–0.7 μM) lines, indicating that they predominantly target the L-type calcium channels. These compounds showed a slight total antioxidant activity. At concentrations close to those of L-type calcium channel blocking ones, compound 12 did not affect mitochondrial functioning; also, no toxicity was obtained in vivo. The N -propargyl group as a substituent at position 1 of the 1,4-DHP cycle did not essentially influence the compounds’ activity. The 4-( N -dodecyl) pyridinium moiety-containing compounds can be considered as prototype molecules for further chemical modifications and studies as cardioprotective/neuroprotective agents.