Design and Synthesis of Novel Heterocyclic Agents As Plasmodium Falciparum Dihydroorotate Dehydrogenase (Pfdhodh) Inhibitors and Anti-Malarial Agents

Abstract

Asymptomatic falciparum and non-falciparum malaria infections are significant challenges to malaria control interventions, as they remain a source of continual infection in the community. That becomes even more important as the debate moves towards elimination and eradication. This study sought to quantify the burden of Plasmodium malaria infection in seven districts in the Eastern Region of Ghana. Malaria severely occurs by Plasmodium falciparum is the deadliest of all types, accounting for 45 percent of all cases. Increasing resistance to various kinds of anti-malarial medicines is a significant issue. As a result, there is an essential clinical demand for novel, effective, and safe medications. PfDHODH inhibitors are seen to be successful in the prevention of malaria. The identification of PfDHODH inhibitors from the ZINC database was performed using pharmacophore Modeling. For structure-based modeling, we started with the confirmation of co-crystal structures of PfDHODH (PDB). PDB ID 6i55 was considered best for structure-based pharmacophore Modeling study after a PROCHECK examination utilizing the Ramachandran plot. The best verified co-crystal structure of PfDHODH used to construct the protein in the PHASE module of the Schrödinger program (trial version). Structure and ligand-based pharmacophore models were created using the PHASE module. The best-verified crystal structure of PfDHODH was used to construct the protein in the PHASE module of the Schrödinger programmed. The PHASE module was used to create structure- and ligand-based pharmacophore models. Validated pharmacophore models were used as 3D search queries to search the ZINC database. Many compounds (ZINC00386658, ZINC08439293, and ZINC09089086) were found in databases with a high fitness score and molecular docking studies in HTVS, SP, and XP. Novel anti- malarial compounds were created based on pharmacophoric characteristics. Visualized amino-acid interactions responsible for PfDHODH activity and performed pharmacophore mapping and molecular studies of designed quinolizines analogs. Synthesis of designed molecules was carried out and analyzed through TLC and mass spectral characterization. ADME prediction and drug-likeness and toxicity testing were performed on the generated compounds. The findings of the pharmacophore modeling and docking experiments will aid in the creation of novel inhibitors with increased PfDHODH inhibitoryeffectiveness. Keywords: PfDHODH inhibitors, structure-based and ligand-based pharmacophore Modeling, Malaria