Marinoquinoline as a new class of antiplasmodial compounds: structure-activity relationship and investigation of the mechanism of action

Author(s)

Patrícia Santos Barbosa

• Document type: Doctoral Thesis
• Press: Campinas, SP.
• Institution: Universidade Estadual de Campinas (UNICAMP). Instituto de Química
• Defense date: 2022-05-23

Examining board members

Carlos Roque Duarte Correia; Júlio Cezar Pastre; Ronaldo Aloise Pilli; Daniela Barretto Barbosa Trivella; Anna Caroline Campos Aguiar

• Advisor: Carlos Roque Duarte Correia

Abstract

Malaria, a parasitic disease caused by species of the genus Plasmodium, was responsible, in 2020, for approximately 627 thousand deaths and 240 million cases worldwide. Venezuela, Bolivia and Brazil account for 77% of cases in South America. Due to cases of resistance to the main antimalarial drugs, including artemisinin derivatives, malaria therapy is currently a challenge. A strategy used to solve this problem is the discovery of new drugs with therapeutic targets not involved in the resistance mechanisms already developed by Plasmodium species. In this regard, marinoquinolines, alkaloids containing the 3H-pyrrolo[2,3-]quinoline nucleus, emerge as an alternative in the discovery of new antimalarial drugs. The application of ligand-based drug design resulted in the discovery of a new lead compound, the MQ-30, with high potency and selectivity. The presence of carbamate in the structure of MQ-30 was associated with the potency at the nanomolar scale. Continuing this study, this doctoral thesis demonstrates the potential of marinoquinolines as a new class of antiplasmodial compounds, through qualitative structure-activity relationship studies and investigations of the mechanism of action. Initially, a study was carried out on the importance of carbamate in the structure of MQ-30 through the synthesis of new derivatives, using the classical techniques of medicinal chemistry of alkyl substituent variation, chain elongation and bioisosterism. New marinoquinoline derivatives containing the carbamate group with different alkyl substituent or urea group were synthetically obtained, presenting from the absence of inhibitory activity to high potency. Thus, insights into the importance of tert-butyl carbamate for potency of the hit compound MQ-30 were gained, resulting in the discovery of four new promising derivatives presenting promising antiplasmodial activity. In sequence, new marinoquinoline derivatives were obtained in order to use the autofluorescence of this class of compounds in the investigation of the mechanism of action. Using bioisosterism between carbamates and amides, new derivatives were obtained by coupling the marinoquinoline nucleus with amino acids. This séries provided ten new derivatives with submicromolar inhibitory activity, from which one of those derivatives was chosen as a probe compound for imaging and biochemical studies. The chosen compound showed adequate pharmacological characteristics, as well as structural similarity with MQ-30. As a result of this study, it was possible to obtain insights that the class of marinoquinolines may be acting as antiplasmodial agents through the inhibition of cysteine proteases, in a secondary mechanism of action. The tool employed in the investigation of the therapeutic target was the reverse molecular docking in an artificial intelligence model. The in silico studies carried out internally by the company Selvita S.A. indicated the PfPKG protein may be an important therapeutic target for the marinoquinoline class. Thus, biochemical studies should be performed to investigate this target. All the biological part described in this thesis was carried out in collaboration with the research group of Prof. Rafael Guido (IFSC/USP) and his collaborators. The collaboration of Prof. Carlos Correia with Prof. Rafael Guido is part of a project involved in the CEPID-CIBFar (FAPESP grant number 2013/07600-3) (AU)

• FAPESP's process: 18/03143-0 - DEVELOPMENT OF NEW MARINOQUINOLINES AS ANTIMALARIAL AGENTS: DESIGN, SYNTHESIS AND BIOLOGICAL EVALUATION
• Grantee: Patricia Santos Barbosa
• Support Opportunities: Scholarships in Brazil - Doctorate