Synthesis, Structure-Activity Relationships, and Parasitological Profiling of Brussonol Derivatives as New Plasmodium falciparum Inhibitors

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Barbosa, Camila S. ; Ahmad, Anees ; Maluf, Sarah El Chamy ; Moura, Igor M. R. ; Souza, Guilherme E. ; Guerra, Giovanna A. H. ; Barros, Roberto R. Moraes ; Gazarini, Marcos L. ; Aguiar, Anna C. C. ; Burtoloso, Antonio C. B. ; Guido, Rafael V. C.

• Document type: Journal article
• Source: PHARMACEUTICALS; v. 15, n. 7, p. 21-pg., 2022-07-01.

Abstract

Malaria is a parasitic disease caused by protozoan parasites from the genus Plasmodium. Plasmodium falciparum is the most prevalent species worldwide and the causative agent of severe malaria. The spread of resistance to the currently available antimalarial therapy is a major concern. Therefore, it is imperative to discover and develop new antimalarial drugs, which not only treat the disease but also control the emerging resistance. Brussonol is an icetexane derivative and a member of a family of diterpenoids that have been isolated from several terrestrial plants. Here, the synthesis and antiplasmodial profiling of a series of brussonol derivatives are reported. The compounds showed inhibitory activities in the low micromolar range against a panel of sensitive and resistant P. falciparum strains (IC(50)s = 5-16 mu M). Moreover, brussonol showed fast-acting in vitro inhibition and an additive inhibitory behavior when combined with the antimalarial artesunate (FICindex similar to 1). The mode of action investigation indicated that brussonol increased the cytosolic calcium levels within the parasite. Hence, the discovery of brussonol as a new scaffold endowed with antiplasmodial activity will enable us to design derivatives with improved properties to deliver new lead candidates for malaria. (AU)

• FAPESP's process: 13/07600-3 - CIBFar - Center for Innovation in Biodiversity and Drug Discovery
• Grantee: Glaucius Oliva
• Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC
• FAPESP's process: 21/03977-1 - Discovery of inhibitors from Brazilian Savana plants as lead compound candidates for Malaria
• Grantee: Igor Mota Rodrigues de Moura
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 20/14429-2 - Discovery of plasmodium inhibitors as clinical candidates to treat Malaria
• Grantee: Sarah El Chamy Maluf
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 19/17721-9 - The role of Chemistry in holobiont adaptation
• Grantee: Roberto Gomes de Souza Berlinck
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 19/19708-0 - Identification of new antimalarial compounds: a multidisciplinary strategy aimed to search for potent chemical classes against new molecular targets and different stages of life of Plasmodium spp
• Grantee: Anna Caroline Campos Aguiar
• Support Opportunities: Research Grants - Young Investigators Grants
• FAPESP's process: 20/12904-5 - Discovery of Plasmodium falciparum inhibitors from Cerrado plants as lead compounds candidates for malaria: integrated studies of ultra-efficient chromatography, spectroscopy, and biological assays
• Grantee: Rafael Victorio Carvalho Guido
• Support Opportunities: BIOTA-FAPESP Program - Regular Research Grants
• FAPESP's process: 18/06219-8 - Use of Plasmodium knowlesi as a model for malaria research in vitro
• Grantee: Roberto Rudge de Moraes Barros
• Support Opportunities: Research Grants - Young Investigators Grants
• FAPESP's process: 15/20084-0 - Total Synthesis of (-)-Brussonol, (+)-Komaroviquinona and its analogs targeting potential candidates with trypanocidal activity
• Grantee: Anees Ahmad
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 18/07287-7 - Discovery of Acridine and Marinoquinoline Derivatives as Plasmodium falciparum Inhibitors
• Grantee: Guilherme Eduardo de Souza
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 13/18009-4 - Molecular design, synthesis and trypanocidal activity of cruzain reversible covalent inhibitors
• Grantee: Carlos Alberto Montanari
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 21/14319-5 - Antimalarial activity evaluation of new compounds using Plasmodium knowlesi and P. falciparum in vitro
• Grantee: Giovanna Abreu Holanda Guerra
• Support Opportunities: Scholarships in Brazil - Scientific Initiation