New Iron Twist to Chloroquine─Upgrading Antimalarials with Immunomodulatory and Antimicrobial Features

Abstract

Herein, upgraded chloroquine (CQ) derivatives capable of overcoming Plasmodium resistance and, at the same time, suppressing excessive immune response and risk of concurrent bacteremia were developed. Twelve new ferrocene− CQ hybrids tethered with a small azathia heterocycle (1,3thiazolidin-4-one, 1,3-thiazinan-4-one, or 5-methyl-1,3-thiazolidin-4-one) were synthesized and fully characterized. All hybrids were evaluated for their in vitro antiplasmodial, antimicrobial, and immunomodulatory activities. Additional assays were performed on selected hybrids to gain insights into their mode of action. Although only hybrid 4a was more potent than the parent drug toward CQ-resistant Dd2 Plasmodium falciparum strain, several other hybrids (such as 6b, 6c, and 6d) manifested substantially improved antimicrobial and immunomodulatory properties. Interesting structure−activity relationship data were obtained, hinting at future research for the development of new multitarget chemotherapies for malaria and other infectious diseases complicated by drug resistance, bacterial co-infection, and immune-driven pathology issues.

Chloroquine and cinchonine affect rat vascular smooth muscle tonus through calcium channels – in silico and in vitro approaches

“…Chloroquine application has serious side effects such as gastrointestinal disturbances, itching, headache, visual disturbances, and cardiotoxicity (2). The mortality rate of malaria has increased recently due to widespread resistance of Plasmodium to main antimalarial drugs, including CQ, and invasive bacterial co-infections (4).…”