Design, synthesis and mechanistic insights into triclosan derived dimers as potential anti-plasmodials†

Abstract

In pursuit of novel anti-plasmodial agents, a library of triclosan-based dimers both with and without a 1H-1,2,3 triazole core were designed and synthesized in order to achieve a multitargeted approach. In vitro assessment against chloroquine-susceptible (3D7) and resistant (W2) P. falciparum strains identified that two of the synthesized dimers containing triazole were the most potent in the series. The most potent of the synthesized compounds exhibited IC₅₀ values of 9.27 and 12.09 μM against the CQ-resistant (W2) and CQ-susceptible (3D7) strains of P. falciparum, with an RI of 0.77, suggesting little or no cross-resistance with CQ. Heme binding and molecular modelling studies revealed the most promising scaffold as a dual inhibitor for hemozoin formation and a P. falciparum chloroquine resistance transporter (PfCRT), respectively. In silico studies of the most potent compound revealed that it shows better binding affinity with PfACP and PfCRT compared to TCS. To the best of our knowledge, this is the first report of triclosan-based compounds demonstrating promising heme-inhibition behaviour, with binding values comparable to those of chloroquine (CQ).