Abstract
Among all the malaria parasites, P. falciparum is the most predominant species which has developed drug resistance against most of the commercial anti-malarial drugs. Thus, finding a new molecule for the inhibition of enzymes of P. falciparum is the pharmacological challenge in present era. Herein, ten novel molecules have been designed with an amalgamation of cinchonidine, carbohydrate moiety and triazole ring by utilizing copper-catalyzed click reaction of cinchonidine-derived azide and clickable glycosyl alkynes. The molecular docking of developed molecules showed promising results for plasmepsin inhibition in the form of effective binding with target proteins.
Highlights
Malaria has been a medical challenge for centuries mostly in tropical and subtropical countries of the world
O-Propargyl ether derivatives of orthogonally protected carbohydrates 2a–j were chosen as the appropriate glycosyl alkynes because of their easy synthesis and almost intact sugar architecture in their structure
The synthesis of sugar O-propargyl ethers 2a–c was commenced with the orthogonal acetonide protection of D-glucose according to the standard procedures described in literature29. 3-O-Propargylation of acetonide protected glucose using propargyl bromide in THF in presence of NaH at room temperature for 10 hours afforded respective 3-O-propargyl ether derivative 2a according to the procedure described in literature (Fig. 3)[30]
Summary
Malaria has been a medical challenge for centuries mostly in tropical and subtropical countries of the world. Plasmepsin I and II are known to play crucial role in hemoglobin catabolism by cleaving the hemoglobin alpha chain between Phe[33] and Leu[34] which are located in hinge region which results into dislocation and partial unfolding of globin subunits which further causes more protease sites within the globin polypeptide chains At this stage, further degradation of large globin fragments takes place by action of plasmepsins and falcipains. Plasmepsins, which play a key role in the survival of P. falciparum in the host, have emerged as the new effective targets for development of antimalarial drugs with plasmepsin inhibition mode of action Because of their key functioning in malaria symptoms and consequences, these enzymes are the main target of the anti-malarial drugs[3,4]. In continuation of our previous experience on click chemistry in glycoscience,[15,16,17,18,19,20,21,22,23,24,25,26,27] this reaction was chosen for cycloaddition reaction of cinchonidine-derived azide and sugar-derived terminal alkynes to achieve our designed target molecules (Fig. 1)
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