Malkeet Kumar, Anees Ahmad, Anna Caroline Campos Aguiar, Sarah El Chamy Maluf, Anwar Shamim, Mariana Ferrer, Guilherme E Souza, Marcos L Gazarini, Dhelio B Pereira, Thomas W von Geldern, Delphine Baud, Barry Jones, Susanta Kumar Mondal, Paul A Willis, Rafael Victorio Carvalho Guido, Luiz Carlos Dias
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引用次数: 0
Abstract
Malaria still stands out as one of the most devastating and prevalent diseases globally, where the rise of resistance to different antimalarial drugs in different regions has posed significant obstacles to global treatment and elimination. Consequently, there is a pressing need for the development of new antimalarial agents with novel modes of action. In this study, we report the identification and optimization of new indole-2-carboxamide derivatives where structural modifications have yielded new compounds 6x with enhanced potency (Pf3D7-IC50 ∼ 0.3 μM) and improved metabolic stability (hMics = 3 μL/min/mg), while also minimizing the human ether-a-go-go-related gene (hERG, IC50 > 20 μM) channel activity and cytotoxic effect on hepatic cells (CC50 > 30 μM). Mode-of-action investigations revealed that a representative compound from this series interfered with homeostasis of the parasite's digestive vacuole. However, cross-resistance was observed with resistant strains, which was linked to efflux pumps such as Plasmodium falciparum chloroquine resistance transporter (PfCRT). Despite this challenge, these indole-2-carboxamides provide versatile molecular templates for innovative medicinal chemistry to overcome cross-resistance while maintaining other attractive properties of this novel series.
期刊介绍：
ACS Bio & Med Chem Au is a broad scope open access journal which publishes short letters comprehensive articles reviews and perspectives in all aspects of biological and medicinal chemistry. Studies providing fundamental insights or describing novel syntheses as well as clinical or other applications-based work are welcomed.This broad scope includes experimental and theoretical studies on the chemical physical mechanistic and/or structural basis of biological or cell function in all domains of life. It encompasses the fields of chemical biology synthetic biology disease biology cell biology agriculture and food natural products research nucleic acid biology neuroscience structural biology and biophysics.The journal publishes studies that pertain to a broad range of medicinal chemistry including compound design and optimization biological evaluation molecular mechanistic understanding of drug delivery and drug delivery systems imaging agents and pharmacology and translational science of both small and large bioactive molecules. Novel computational cheminformatics and structural studies for the identification (or structure-activity relationship analysis) of bioactive molecules ligands and their targets are also welcome. The journal will consider computational studies applying established computational methods but only in combination with novel and original experimental data (e.g. in cases where new compounds have been designed and tested).Also included in the scope of the journal are articles relating to infectious diseases research on pathogens host-pathogen interactions therapeutics diagnostics vaccines drug-delivery systems and other biomedical technology development pertaining to infectious diseases.
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