Synthesis and evaluation of the antiplasmodial activity of pyrrolo[2,1-a]isoquinolines and pyrrolo[2,3-b]indoles

• Grant number: 24/15526-2
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• Start date: November 01, 2024
• End date: May 31, 2028
• Field of knowledge: Physical Sciences and Mathematics - Chemistry - Organic Chemistry
• Principal Investigator: Arlene Gonçalves Corrêa
• Grantee: Ana Claudia Bergler Bernardes
• Host Institution: Centro de Ciências Exatas e de Tecnologia (CCET). Universidade Federal de São Carlos (UFSCAR). São Carlos , SP, Brazil
• Associated research grant: 21/12394-0 - Sustainable synthetic methods employing catalysis, benign solvents, safer reagents, and bio-renewable feedstock, AP.TEM

Abstract

Approximately 60% of small-molecule drugs contain nitrogen heterocycles in their molecular frameworks. Among the N-heterocycles, pyrrolo[2,1-a]isoquinolines and 2-pyrrolo[2,3-b]indoles stand out. Recently, our group reported a one-pot copper(II)-catalyzed conjugate addition/cyclization cascade method for the synthesis of phenylpyrrolo[1,2-a]isoquinolines. These compounds were evaluated against the 3D7 strain (sensitive to chloroquine) of Plasmodium falciparum and demonstrated potential for the development of new drugs for the treatment of malaria. Aiming to contribute with these studies, in this project we propose the synthesis of new pyrrolo[2,1-a]isoquinolines with a diverse set of substituents. Lamellarins are alkaloids containing fused 14-phenyl-6H-[1]benzopyrano[4',3':4.5]pyrrolo[2,1-a]isoquinoline or non-fused 3,4-diarylpyrrole-2-carboxylate ring systems. Many of them exhibit diverse biological activity, such as inhibition of topoisomerase I and protein kinases and anti-HIV-1. Due to the limited availability of this class of compounds from natural marine sources, it is necessary to develop new synthetic methods to obtain lamellarins. Therefore, in this project we will use pyrrolo[2,1-a]isoquinolines for the total synthesis of lamellarins and analogues. It is also intended to develop a new method for the synthesis of 2-pyrrolo[2,3-b]indoles using ¿-azidoketones and 3-formylindoles, via photochemistry, under blue LED irradiation. All synthetic compounds will be evaluated against P. falciparum in CIBFar at IFSC-USP.