Characterization of antimalarial activity of artemisinin-based hybrid drugs.

Autor:	Quadros HC; Instituto Gonçalo Moniz, Fundação Oswaldo Cruz (FIOCRUZ), Salvador, Brazil., Herrmann L; Organic Chemistry Chair I and Interdisciplinary Center for Molecular Materials (ICMM), Friedrich-Alexander-Universität of Erlangen-Nürnberg, Erlangen, Germany., Manaranche J; LCC-CNRS, Laboratoire de Chimie de Coordination, Université de Toulouse, CNRS, Toulouse, France.; MAAP, New Antimalarial Molecules and Pharmacological Approaches, Inserm ERL 1289, Toulouse, France.; Institut de Pharmacologie et de Biologie Structurale (IPBS), Université de Toulouse, CNRS, Université Toulouse III - Paul Sabatier (UPS), Toulouse, France., Paloque L; LCC-CNRS, Laboratoire de Chimie de Coordination, Université de Toulouse, CNRS, Toulouse, France.; MAAP, New Antimalarial Molecules and Pharmacological Approaches, Inserm ERL 1289, Toulouse, France.; Institut de Pharmacologie et de Biologie Structurale (IPBS), Université de Toulouse, CNRS, Université Toulouse III - Paul Sabatier (UPS), Toulouse, France., Borges-Silva MC; Instituto Gonçalo Moniz, Fundação Oswaldo Cruz (FIOCRUZ), Salvador, Brazil., Dziwornu GA; Drug Discovery and Development Centre (H3D), Department of Chemistry, University of Cape Town, Rondebosch, South Africa., D'Alessandro S; Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milan, Italy., Chibale K; Drug Discovery and Development Centre (H3D), Department of Chemistry, University of Cape Town, Rondebosch, South Africa.; South African Medical Research Council Drug Discovery and Development Research Unit, Department of Chemistry and Institute of Infectious Diseases and Molecular Medicine, University of Cape Town, Rondebosch, South Africa., Basilico N; Dipartimento di Scienze Biomediche, Chirurgiche e Odontoiatriche, Chirurgiche e Odontoiatriche, Universitá degli Studi di Milano, Milan, Italy., Benoit-Vical F; LCC-CNRS, Laboratoire de Chimie de Coordination, Université de Toulouse, CNRS, Toulouse, France.; MAAP, New Antimalarial Molecules and Pharmacological Approaches, Inserm ERL 1289, Toulouse, France.; Institut de Pharmacologie et de Biologie Structurale (IPBS), Université de Toulouse, CNRS, Université Toulouse III - Paul Sabatier (UPS), Toulouse, France., Tsogoeva SB; Organic Chemistry Chair I and Interdisciplinary Center for Molecular Materials (ICMM), Friedrich-Alexander-Universität of Erlangen-Nürnberg, Erlangen, Germany., Moreira DRM; Instituto Gonçalo Moniz, Fundação Oswaldo Cruz (FIOCRUZ), Salvador, Brazil.
Jazyk:	angličtina
Zdroj:	Antimicrobial agents and chemotherapy [Antimicrob Agents Chemother] 2024 Jul 09; Vol. 68 (7), pp. e0014324. Date of Electronic Publication: 2024 Jun 20.
DOI:	10.1128/aac.00143-24
Abstrakt:	In response to the spread of artemisinin (ART) resistance, ART-based hybrid drugs were developed, and their activity profile was characterized against drug-sensitive and drug-resistant Plasmodium falciparum parasites. Two hybrids were found to display parasite growth reduction, stage-specificity, speed of activity, additivity of activity in drug combinations, and stability in hepatic microsomes of similar levels to those displayed by dihydroartemisinin (DHA). Conversely, the rate of chemical homolysis of the peroxide bonds is slower in hybrids than in DHA. From a mechanistic perspective, heme plays a central role in the chemical homolysis of peroxide, inhibiting heme detoxification and disrupting parasite heme redox homeostasis. The hybrid exhibiting slow homolysis of peroxide bonds was more potent in reducing the viability of ART-resistant parasites in a ring-stage survival assay than the hybrid exhibiting fast homolysis. However, both hybrids showed limited activity against ART-induced quiescent parasites in the quiescent-stage survival assay. Our findings are consistent with previous results showing that slow homolysis of peroxide-containing drugs may retain activity against proliferating ART-resistant parasites. However, our data suggest that this property does not overcome the limited activity of peroxides in killing non-proliferating parasites in a quiescent state. Competing Interests: The authors declare no conflict of interest.
Databáze:	MEDLINE
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