Dihydroorotate (DHODH) is an essential enzyme of de novo pyrimidine biosynthesis, catalysing the ubiquinone- mediated oxidation of dihydroorotate to orotate. DHODH is considered a druggable target. Recently, academics and industry researchers have been directing efforts in investigating DHODH inhibition to manage autoimmune diseases, cancer, malaria, and other diseases. Our group initiated this research project with the aim to study the molecular mechanism of PfDHODH inhibition using MD simulation in order to design novel inhibitors. A program named, HeroMDAnalysis was developed to assist in the analysis of MD simulation. Importantly, this GUI tool can be very helpful to biochemists, synthetic chemists, and pharmacologists involved in the area of MD simulation. Progressively, in the context of identifying novel inhibitors to target PfDHODH, various computer- aided drug design approaches were utilized. The pursuit resulted in 3 different series of imidazo-fused heterocycles namely: 1) Aminomethylated-imidazo[1,2-a]pyridines, 2) N-arylated-imidazo[2,1- b][1,3,4]thiadiazoles, and 3) 1H-benzo[d]imidazole-alkyl-acetamides. Progressively, the imidazo-fused heterocycles were synthesized using novel chemical methodologies. The advantages of methodologies used in this project includes atom economy, operational simplicity, reduced waste, and moderate to good yields. A total of 38 compounds were synthesized, and structure elucidation was carried out using advanced spectroscopic techniques including 1H and 13C NMR, ESI-MS, FT-IR, CHNS elemental analysis. Finally, the synthesized compounds were investigated for in vitro anti-malarial activities against Plasmodium falciparum 3D7 (Drug sensitive), Dd2 (Chloroquine-resistant), and INDO (Chloroquine-resistant), and anti-cancer activities against MCF-7 (human breast adenocarcinoma) and A549 (NSC lung cancer) cell lines. The present study resulted in identification of 3 compounds which have showed inhibitory potential of IC50 Pf3D7 cell line. The compounds were also active against drug resistant cell lines of Plasmodium parasite (PfDd2 and PfINDO). Further, the molecules could serve as lead for further optimization of potency and preclinical development.