Design, Synthesis, and Evaluation of Triazolyl Quinoline Derivatives as Potential Antimalarial Agents

The present study aims to develop novel antimalarial and antimicrobial agents by synthesizing a series of 25 triazolyl quinoline carboxylate derivatives via azide-alkyne 1,3-dipolar cycloaddition, starting from isatin and p-fluoroacetophenone. Structural characterization was performed using IR, ¹H NMR, ¹³C NMR, and mass spectrometry. The synthesized hybrids were evaluated for their in vitro antimalarial activity against the chloroquine-sensitive Plasmodium falciparum 3D7 strain. Among them, compounds 6e, 6h, and 6i exhibited notable potency, with IC₅₀ values ranging from 1.364 to 1.518 µM, underscoring their potential as promising antimalarial candidates. Furthermore, compounds 6g, 6h, 6m, and 8a demonstrated broad-spectrum antimicrobial activity, while 6d, 6e, 6h, 8c, 8h, and 8k showed strong antioxidant potential through effective OH and DPPH radical scavenging. In silico ADME profiling using SwissADME and DeepPK revealed favorable pharmacokinetic properties and compliance with Lipinski's rule of five, suggesting good oral bioavailability. Density functional theory (DFT) calculations provided insights into the electronic structures, and molecular docking studies confirmed strong binding interactions with P. falciparum falcipain-2 protease. Collectively, these findings highlight the therapeutic promise of this compound class as multifunctional agents targeting malaria and microbial infections.