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A Novel Hybrid of Chloroquine and Primaquine Linked by Gold(I): Multitarget and Multiphase Antiplasmodial Agent
Author(s) -
Souza Pereira Caroline,
Costa Quadros Helenita,
Magalhaes Moreira Diogo Rodrigo,
Castro William,
Santos De Deus Da Silva Romulo Ivisson,
Botelho Pereira Soares Milena,
Fontinha Diana,
Prudêncio Miguel,
Schmitz Vinicius,
Dos Santos Hélio F.,
Gendrot Mathieu,
Fonta Isabelle,
Mosnier Joel,
Pradines Bruno,
Navarro Maribel
Publication year - 2021
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.202000653
Subject(s) - primaquine , plasmodium berghei , malaria , chloroquine , plasmodium falciparum , antimalarial agent , plasmodium (life cycle) , pharmacology , in vivo , gametocyte , biology , drug , parasite hosting , immunology , microbiology and biotechnology , computer science , world wide web
Abstract Plasmodium parasites kill 435 000 people around the world every year due to unavailable vaccines, a limited arsenal of antimalarial drugs, delayed treatment, and the reduced clinical effectiveness of current practices caused by drug resistance. Therefore, there is an urgent need to discover and develop new antiplasmodial candidates. In this work, we present a novel strategy to develop a multitarget metallic hybrid antimalarial agent with possible dual efficacy in both sexual and asexual erythrocytic stages. A hybrid of antimalarial drugs (chloroquine and primaquine) linked by gold(I) was synthesized and characterized by spectroscopic and analytical techniques. The CQPQ‐gold(I) hybrid molecule affects essential parasite targets, it inhibits β‐hematin formation and interacts moderately with the DNA minor groove. Its interaction with PfTrxR was also examined in computational modeling studies. The CQPQ‐gold(I) hybrid displayed an excellent in vitro antimalarial activity against the blood‐stage of Plasmodium falciparum and liver‐stage of Plasmodium berghei and efficacy in vivo against P. berghei , thereby demonstrating its multiple‐stage antiplasmodial activity. This metallic hybrid is a promising chemotherapeutic agent that could act in the treatment, prevention, and transmission of malaria.