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

In pursuit of novel anti-plasmodial agents, a library of triclosan-based dimers both with and without a 1<i>H</i>-1,2,3 triazole core were designed and synthesized in order to achieve a multitargeted approach. <i>In vitro</i> assessment against chloroquine-susceptible (3D7) and resistant (W2) <i>P. falciparum</i> 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 <i>P. falciparum</i>, 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 <i>P. falciparum</i> chloroquine resistance transporter (<i>Pf</i>CRT), respectively. <i>In silico</i> studies of the most potent compound revealed that it shows better binding affinity with <i>Pf</i>ACP and <i>Pf</i>CRT 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).