Dataset Information

In vitro and in silico assessment of new beta amino ketones with antiplasmodial activity.

ABSTRACT:

Background

Based on the current need for new drugs against malaria, our study evaluated eight beta amino ketones in silico and in vitro for potential antimalarial activity.

Methods

Using the Brazilian Malaria Molecular Targets (BraMMT) and OCTOPUS® software programs, the pattern of interactions of beta-amino ketones was described against different proteins of P. falciparum and screened to evaluate their physicochemical properties. The in vitro antiplasmodial activities of the compounds were evaluated using a SYBR Green-based assay. In parallel, in vitro cytotoxic data were obtained using the MTT assay.

Results

Among the eight compounds, compound 1 was the most active and selective against P. falciparum (IC50 = 0.98 µM; SI > 60). Six targets were identified in BraMMT that interact with compounds exhibiting a stronger binding energy than the crystallographic ligand: P. falciparum triophosphate phosphoglycolate complex (1LYX), P. falciparum reductase (2OK8), PfPK7 (2PML), P. falciparum glutaredoxin (4N0Z), PfATP6, and PfHT.

Conclusions

The physicochemical properties of compound 1 were compatible with the set of criteria established by the Lipinski rule and demonstrated its potential as a drug prototype for antiplasmodial activity.

SUBMITTER: Krombauer GC

PROVIDER: S-EPMC9549944 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Publications

In vitro and in silico assessment of new beta amino ketones with antiplasmodial activity.

Krombauer Gabriela Camila GC Guedes Karla de Sena KS Banfi Felipe Fingir FF Nunes Renata Rachide RR Fonseca Amanda Luisa da ALD Siqueira Ezequias Pessoa de EP Bellei Jéssica Côrrea Bezerra JCB Scopel Kézia Katiani Gorza KKG Varotti Fernando de Pilla FP Sanchez Bruno Antônio Marinho BAM

Revista da Sociedade Brasileira de Medicina Tropical 20220926

<h4>Background</h4>Based on the current need for new drugs against malaria, our study evaluated eight beta amino ketones in silico and in vitro for potential antimalarial activity.<h4>Methods</h4>Using the Brazilian Malaria Molecular Targets (BraMMT) and OCTOPUS® software programs, the pattern of interactions of beta-amino ketones was described against different proteins of P. falciparum and screened to evaluate their physicochemical properties. The in vitro antiplasmodial activities of the comp ...[more]

PMID: 36169491

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Project description:In tropical and subtropical areas, malaria stands as a profound public health challenge, causing an estimated 247 million cases worldwide annually. Given the absence of a viable vaccine, the timely and effective treatment of malaria remains a critical priority. However, the growing resistance of parasites to currently utilized drugs underscores the critical need for the identification of new antimalarial therapies. Here, we aimed to identify potential new drug candidates against Plasmodium falciparum, the main causative agent of malaria, by analyzing the transcriptomes of different life stages of the parasite and identifying highly expressed genes. We searched for genes that were expressed in all stages of the parasite's life cycle, including the asexual blood stage, gametocyte stage, liver stage, and sexual stages in the insect vector, using transcriptomics data from publicly available databases. From this analysis, we found 674 overlapping genes, including 409 essential ones. By searching through drug target databases, we discovered 70 potential drug targets and 75 associated bioactive compounds. We sought to expand this analysis to similar compounds to known drugs. So, we found a list of 1557 similar compounds, which we predicted as actives and inactives using previously developed machine learning models against five life stages of Plasmodium spp. From this analysis, two compounds were selected, and the reactions were experimentally evaluated. The compounds HSP-990 and silvestrol aglycone showed potent inhibitory activity at nanomolar concentrations against the P. falciparum 3D7 strain asexual blood stage. Moreover, silvestrol aglycone exhibited low cytotoxicity in mammalian cells, transmission-blocking potential, and inhibitory activity comparable to those of established antimalarials. These findings warrant further investigation of silvestrol aglycone as a potential dual-acting antimalarial and transmission-blocking candidate for malaria control.

Dataset Information

In vitro and in silico assessment of new beta amino ketones with antiplasmodial activity.

Background

Methods

Results

Conclusions

Publications

In vitro and in silico assessment of new beta amino ketones with antiplasmodial activity.

Similar Datasets

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