Evaluation of novel 1,4-dihydropyridine spirooxindole as antitumor, anti-inflammatory, and antioxidant agents.

Abstract

A novel series of 2-oxo-1'H-spiro[indoline-3,4'-pyridine]-3',5'-dicarbonitrile derivatives (5a-e, 6a-d) was successfully synthesized via an efficient one-pot, three-component reaction of N-alkylisatins, malononitrile, and secondary amines (morpholine or thiomorpholine). The chemical structures of all target compounds were unambiguously characterized using ¹H NMR, ¹³C NMR, 2D NMR techniques (COSY, HMQC, HMBC), and high-resolution mass spectrometry (HRMS). In malignancies' adherent monolayers, optimal differential antiproliferation effects of sub-25 µM IC₅₀ values were attained by 5a and 6b (colorectal CaCo2 and lung A549), 5b (A549 and skin melanoma A375), 5c and 5d (mammary T47D and colorectal SW480), 5e (SW480), 6a (colorectal HT29) and 6d (colorectal HCT116 and A549). Among all physiologically regulated immunomodulatory 9 spirooxindoles derivatives, 6c was ascribed the maximal efficacy of 0.45 µM IC₅₀ value in LPS-primed RAW 264.7 macrophages. Distinctively, 6a displayed superior antioxidative capacity in DPPH radical scavenging compared with the others. Collectively these findings highlight 1,4-dihydropyridine spirooxindoles as promising multifunctional leads for anticancer and anti-inflammatory drug development with a high therapeutic safety window.