Abstract
Malaria is still one of the most dangerous infectious diseases and the emergence of drug resistant parasites only worsens the situation. A series of new tetrahydro-β-carbolines were designed, synthesized by the Pictet–Spengler reaction, and characterized. Further, the compounds were screened for their in vitro antiplasmodial activity against chloroquine-sensitive (D10) and chloroquine-resistant (W2) strains of Plasmodium falciparum. Moreover, molecular modeling studies were performed to assess the potential action of the designed molecules and toxicity assays were conducted on the human microvascular endothelial (HMEC-1) cell line and human red blood cells. Our studies identified N-(3,3-dimethylbutyl)-1-octyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b] indole-3-carboxamide (7) (a mixture of diastereomers) as the most promising compound endowed with the highest antiplasmodial activity, highest selectivity, and lack of cytotoxicity. In silico simulations carried out for (1S,3R)-7 provided useful insights into its possible interactions with enzymes essential for parasite metabolism. Further studies are underway to develop the optimal nanosized lipid-based delivery system for this compound and to determine its precise mechanism of action.
Highlights
Malaria is an infectious disease caused by the protozoan parasite of the genus Plasmodium, with Plasmodium falciparum and Plasmodium vivax being predominantly responsible for mortality and morbidity
(1a–e)(Figure were further with diverse amines in the presence carboline-3-carboxylic acids were further reacted with diverse amines in the presof 4-dimethylaminopyridine (DMAP), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC), 1-hydroxybenzotriazole (HOBt), and pyridine
Our studies led to the identification of a promising lead compound among a series of tetrahydro-β-carbolines that were designed and tested
Summary
Malaria is an infectious disease caused by the protozoan parasite of the genus Plasmodium, with Plasmodium falciparum and Plasmodium vivax being predominantly responsible for mortality and morbidity. In 2019, the global tally of malaria cases was 229 million, an annual estimate that has remained virtually unchanged over the last 4 years [1]. In October of 2021, the WHO has recommended Mosquirix, the RTS,S/AS01 malaria vaccine, for the prevention of. P. falciparum malaria in children living in regions with moderate to high transmission [2]. Disruptions to continued access to effective antimalarial treatment could lead to considerable loss of life [3]. First-line malaria treatments include several artemisinin-based combination therapies (ACTs), such as artemether-lumefantrine (AL), artesunate-amodiaquine (AS-AQ), artesunate-sulfadoxine-pyrimethamine (AS+SP), artesunate-mefloquine (AS-MQ), and dihydroartemisinin-piperaquine (DHA-PPQ). The malaria problem is evolving, dynamic, Int. J.
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