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

Approximately 60% of small molecule drugs have N-heterocycles in their structure. 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 cascade method of conjugate addition/cyclization catalyzed by copper (II) for the synthesis of phenylpyrrolo[1,2-a]isoquinolines. These compounds were evaluated against the 3D7 strain (chloroquine-sensitive) of Plasmodium falciparum and showed potential for the development of drugs for the treatment of malaria. Aiming to contribute to these studies, this project proposes the synthesis of new pyrrolo[2,1-a]isoquinolines with diverse set of substituents. Lamellarins are alkaloids containing fused 14-phenyl-6H-[1]benzopyrano[4′,3′:4,5]pyrrolo[2,1-a]isoquinoline or unfused 3,4-diarylpyrrole-2-carboxylate ring systems. Many of them exhibit diverse biological activities, such as inhibition of topoisomerase I and protein kinases and anti-HIV-1. Due to their limited availability from natural marine sources, it is necessary to develop new synthetic methods to obtain lamellarins. Thus, this project will use pyrrolo[2,1-a]isoquinolines for the total synthesis of lamellarins and analogues. We also intend 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 synthesized compounds will be evaluated against P. falciparum at CIBFar of IFSC-USP.

Project details

Drug-based Strategies
Product Development

Nov 2024 — May 2028

Brazil