Synthesis, Characterization and Biological Evaluation of Benzimidazole - Dihydroartemisinin Hybrids as Potential Dual Acting Antimalarial Agents

Abstract

<jats:p>Malaria is a parasitic disease caused by various species of the Plasmodium parasite. In 2016, there were about 216 million cases resulting in 445,000 deaths, with sub-saharan Africa bearing the heaviest burden of the disease. The currently recommended treatment for malaria are combination therapies containing Artemisinin (ACT’s). However, the effectiveness of the Artemisinins is being compromised by the emergence of resistance to the drug and this amplifies the need for new antimalarial drugs. The Benzimidazole scaffold is one of the privileged structures in medicinal chemistry and is associated with a number of biological activities including antimalarial activity which may be through inhibition of the Plasmodial plasmepsin II enzyme. The present study utilizes the concept of molecular hybridization to synthesize hybrid compounds that contain two pharmacophores, acting through two distinct mechanisms. The aim is to improve efficacy and possibly prevent or slow down the emergence of parasite resistance. To confirm their structures, the conjugates were purified by chromatography and characterized using Nuclear Magnetic Resonance (NMR), Mass spectrometry and Infra-red spectroscopy. Antimalarial activities of the hybrids were evaluated in-vitro against the 3D7 strain of Plasmodium falciparum using the parasite Lactate dehydrogenase assay. The hybrids were successfully synthesized with yields ranging from 63.48 percent to 67.60 percent and were all active against the parasite. The Mebendazole conjugate of dihydroartemisinin showed the highest activity with IC50 of 6.861 nM and 6.967 nM for the 5-Benzimidazolecarboxylic acid conjugate of dihydroartemisinin. All the compounds showed statistically significant (p &lt; 0.05) increase in activity as compared to Dihydroartemisinin and Chloroquine alone. These hybrid compounds with improved physicochemical and pharmacological properties may serve as templates for the development of a new class of anitmalarial drugs, which possess advantages over existing drugs in terms of effectiveness and also the ability to overcome the problem of resistance during malaria chemotherapy.</jats:p>

Recent Trends in the Development of Benzimidazole Hybrid Derivatives and Their Antimalarial Activities

“…[14][15][16][17][18] Substituted benzimidazole derivatives possess potent and pertinent activity by inhibiting intraerythrocytic asexual blood stages and the transmissible gametocyte stages of P. falciparum as well as potent plasmodium plasmepsin enzyme inhibitors. 19,20 The quantitative structure-activity relationship (QSAR) model calculates binding affinity and interaction using multiple linear regression analysis (MLRA), topological and geometric descriptors, total energy, and the highest occupied molecular orbital associated with pharmacological deeds or assets of benzimidazole scaffolds. [21][22][23] The novelty of the present work is the summarization of a recent study to elaborate the antimalarial activity of benzimidazole hybrid derivatives against antimalarial drug-resistant developed by the P. falciparum strain along with their structural-activity relationships.…”

In pursuit of new anti-malarial candidates: novel synthesized and characterized pyrano-benzodioxepin analogues attenuated Plasmodium berghei replication in malaria-infected mice

“…In addition, Plasmodium falciparum, Plasmodium berghei, and Plasmodium vivax, the major causative organisms of severe infection in humans and animals, have exhibited increased resistance against the recommended mainstream artemisinin combination therapies (ACTs). The emerging resistance, particularly in southeast Asia and some tropical African regions, calls for urgent development and deployment of potent alternatives (Ajima et al, 2019;Esmark et al, 2004;WHO, 2020). Following previous reports, pyrano-benzodioxepin scaffolds are generally known as potential enzyme inhibitors capable of finding utilization in malaria remedies (Ajima et al, 2019;Banerjee et al, 2002;Jaudzems et al, 2014;N€ oteberg et al, 2003;Muthas et al, 2005).…”

“…The emerging resistance, particularly in southeast Asia and some tropical African regions, calls for urgent development and deployment of potent alternatives (Ajima et al, 2019;Esmark et al, 2004;WHO, 2020). Following previous reports, pyrano-benzodioxepin scaffolds are generally known as potential enzyme inhibitors capable of finding utilization in malaria remedies (Ajima et al, 2019;Banerjee et al, 2002;Jaudzems et al, 2014;N€ oteberg et al, 2003;Muthas et al, 2005).…”