دورية أكاديمية
أعرض في EDS

Rational-Based Discovery of Novel β-Carboline Derivatives as Potential Antimalarials: From In Silico Identification of Novel Targets to Inhibition of Experimental Cerebral Malaria.

التفاصيل البيبلوغرافية
العنوان: Rational-Based Discovery of Novel β-Carboline Derivatives as Potential Antimalarials: From In Silico Identification of Novel Targets to Inhibition of Experimental Cerebral Malaria.
المؤلفون: Alves FM; Research Center on Biological Chemistry (NQBio), Federal University of São João Del Rei, Divinópolis 35501-296, Brazil., Bellei JCB; Research Center Parasitology, Departament of Parasitology, Microbiology and Immunology, Federal University of Juiz de Fora, Juiz de Fora 36036-900, Brazil., Barbosa CS; Research Center on Biological Chemistry (NQBio), Federal University of São João Del Rei, Divinópolis 35501-296, Brazil., Duarte CL; Research Center on Biological Chemistry (NQBio), Federal University of São João Del Rei, Divinópolis 35501-296, Brazil., Fonseca ALD; Research Center on Biological Chemistry (NQBio), Federal University of São João Del Rei, Divinópolis 35501-296, Brazil., Pinto ACS; Research Center on Biological Chemistry (NQBio), Federal University of São João Del Rei, Divinópolis 35501-296, Brazil., Raimundo FO; Research Center Parasitology, Departament of Parasitology, Microbiology and Immunology, Federal University of Juiz de Fora, Juiz de Fora 36036-900, Brazil., Carpinter BA; Research Center Parasitology, Departament of Parasitology, Microbiology and Immunology, Federal University of Juiz de Fora, Juiz de Fora 36036-900, Brazil., Lemos ASO; Research Center Parasitology, Departament of Parasitology, Microbiology and Immunology, Federal University of Juiz de Fora, Juiz de Fora 36036-900, Brazil., Coimbra ES; Research Center Parasitology, Departament of Parasitology, Microbiology and Immunology, Federal University of Juiz de Fora, Juiz de Fora 36036-900, Brazil., Taranto AG; Research Center on Biological Chemistry (NQBio), Federal University of São João Del Rei, Divinópolis 35501-296, Brazil., Rocha VN; Research Center of Pathology and Veterinary Histology, Departament of Veterinary Medicine, Federal University of Juiz de Fora, Juiz de Fora 36036-900, Brazil., de Pilla Varotti F; Research Center on Biological Chemistry (NQBio), Federal University of São João Del Rei, Divinópolis 35501-296, Brazil., Ribeiro Viana GH; Research Center on Biological Chemistry (NQBio), Federal University of São João Del Rei, Divinópolis 35501-296, Brazil., Scopel KKG; Research Center Parasitology, Departament of Parasitology, Microbiology and Immunology, Federal University of Juiz de Fora, Juiz de Fora 36036-900, Brazil.
المصدر: Pathogens (Basel, Switzerland) [Pathogens] 2022 Dec 13; Vol. 11 (12). Date of Electronic Publication: 2022 Dec 13.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: MDPI AG Country of Publication: Switzerland NLM ID: 101596317 Publication Model: Electronic Cited Medium: Print ISSN: 2076-0817 (Print) Linking ISSN: 20760817 NLM ISO Abbreviation: Pathogens Subsets: PubMed not MEDLINE
أسماء مطبوعة: Original Publication: Basel, Switzerland : MDPI AG, 2012-
مستخلص: Malaria is an infectious disease widespread in underdeveloped tropical regions. The most severe form of infection is caused by Plasmodium falciparum, which can lead to development of cerebral malaria (CM) and is responsible for deaths and significant neurocognitive sequelae throughout life. In this context and considering the emergence and spread of drug-resistant P. falciparum isolates, the search for new antimalarial candidates becomes urgent. β-carbolines alkaloids are good candidates since a wide range of biological activity for these compounds has been reported. Herein, we designed 20 chemical entities and performed an in silico virtual screening against a pool of P. falciparum molecular targets, the Brazilian Malaria Molecular Targets (BRAMMT). Seven structures showed potential to interact with PfFNR, PfPK7, PfGrx1, and PfATP6, being synthesized and evaluated for in vitro antiplasmodial activity. Among them, compounds 3−6 and 10 inhibited the growth of the W2 strain at µM concentrations, with low cytotoxicity against the human cell line. In silico physicochemical and pharmacokinetic properties were found to be favorable for oral administration. The compound 10 provided the best results against CM, with important values of parasite growth inhibition on the 5th day post-infection for both curative (67.9%) and suppressive (82%) assays. Furthermore, this compound was able to elongate mice survival and protect them against the development of the experimental model of CM (>65%). Compound 10 also induced reduction of the NO level, possibly by interaction with iNOS. Therefore, this alkaloid showed promising activity for the treatment of malaria and was able to prevent the development of experimental cerebral malaria (ECM), probably by reducing NO synthesis.
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فهرسة مساهمة: Keywords: antimalarial chemotherapy; cerebral malaria; experimental cerebral malaria; malaria; nitric oxide; β-carbolines alkaloids
تواريخ الأحداث: Date Created: 20221223 Latest Revision: 20230308
رمز التحديث: 20231215
مُعرف محوري في PubMed: PMC9781199
DOI: 10.3390/pathogens11121529
PMID: 36558863
قاعدة البيانات: MEDLINE
الوصف
تدمد:2076-0817
DOI:10.3390/pathogens11121529