Abstract
We have explored the possibility of using organometallic derivatives of cobalamin as a scaffold for the delivery of the same antimalarial drug to both erythro- and hepatocytes. This hybrid molecule approach, intended as a possible tool for the development of multi-stage antimalarial agents, pivots on the preparation of azide-functionalized drugs which, after coupling to the vitamin, are released with a 4-(4-ethynylphenyl)-triazole functionality. Three chloroquine and one imidazolopiperazine derivative (based on the KAF156 structure) were selected as model drugs. One hybrid chloroquine conjugate was extensively studied via fluorescent labelling for in vitro and in vivo bio-distribution studies and gave proof-of-concept for the design. It showed no toxicity in vivo (zebrafish model) as well as no hepatotoxicity, no cardiotoxicity or developmental toxicity of the embryos. All 4-(4-ethynylphenyl)-triazole derivatives of chloroquine were equally active against chloroquine-resistant (CQR) and chloroquine-sensitive (CQS) Plasmodium falciparum strains.
Highlights
Malaria is considered to be one of the most life-threatening and globally infectious diseases caused by a single-cell parasite called Plasmodium
Vitamin B12 (B12, Cbl) derivatives bearing antimalarial compounds were prepared by attaching releasable drugs at the cobalt ion via the synthetic protocol illustrated in
4-diethylamino-1-methylbutylamino chain appended at the quinoline core structure of chloroquine was replaced by a 2-azidoethyl chain (to give N-(2-azidoethyl)-7-chloroquinolin-4-amine, N3 -CQ) [31]
Summary
Malaria is considered to be one of the most life-threatening and globally infectious diseases caused by a single-cell parasite called Plasmodium (including P. falciparum, P. vivax, P. ovale, P. malariae). This disease has remained one of the leading causes of morbidity and mortality over the past centuries throughout the world. According to the World Health Organization (WHO) in 2016, there have been about 216 million cases of malaria and 445,000 deaths worldwide [1]. P. falciparum, the most lethal malaria species in humans, has become resistant to the most conventional antimalarial treatments, in turn resulting in a worldwide concern and the call for new strategies, and drugs that can act at different stages of the parasite life cycle [2,3,4].
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