Novel series of 1,2,4-trioxane derivatives as antimalarial agents

Abstract

Among three series of 1,2,4-trioxane derivatives, five compounds showed good in vitro antimalarial activity, three compounds of which exhibited better activity against P. falciparum resistant (RKL9) strain than the sensitive (3D7) one. Two best compounds were one from aryl series and the other from heteroaryl series with IC50 values of 1.24 µM and 1.24 µM and 1.06 µM and 1.17 µM, against sensitive and resistant strains, respectively. Further, trioxane derivatives exhibited good binding affinity for the P. falciparum cysteine protease falcipain 2 receptor (PDB id: 3BPF) with well defined drug-like and pharmacokinetic properties based on Lipinski’s rule of five with additional physicochemical and ADMET parameters. In view of having antimalarial potential, 1,2,4-trioxane derivative(s) reported herein may be useful as novel antimalarial lead(s) in the discovery and development of future antimalarial drug candidates as P. falciparum falcipain 2 inhibitors against resistant malaria.

In vitro and in vivo models used for antimalarial activity: A brief review

“…Comparison between parasitemia in the controls (considered as 100% growth) and that in test cultures allow evaluating the percent inhibition of parasite growth followed by determination of the inhibitory concentration of 50% of the parasite growth (IC ) for test compounds. This is a 50 simple measurement which is classically known as the Minimum Inhibitory Concentration (MIC) method , Rudrapal et al, 2017aRudrapal et al, 2017b). Alternatively, instead of counting all parasites in the blood smears, the number of schizonts is counted against the total number of parasites (after 24 h of incubation) in thick films prepared from the cellular layer of the cultured samples (Gogoi et al, 2016;Kashyap et al, 2016).…”

Molecular Docking, Drug-Likeness Studies and ADMET Prediction of Quinoline Imines for Antimalarial Activity

“…After energy minimization, the Chain A of falcipain 2 protein was defined as a receptor and the binding site sphere was selected based on the ligand binding location of E-64. A receptor grid was thereby generated around the binding cavity (active sites) of protein by specifying the key amino acid residues (Cys 42, Gly 83 and His 174) 1,7 . In DS, binding site sphere was set with a radius of 20 Å and x, y, z dimensions of -52.25, -4.46, -19.25, respectively.…”

“…Malaria continues to be a growing infectious disease burden around the world. According to WHO, about 200-300 million people are afflicted by malaria with approximately 430,000 deaths per year globally 1 . Plasmodium falciparum causes dreadful malaria infections such as cerebral malaria in children as well as in adults.…”

Spiroverknüpfte und ringanellierte 1,2,4‐Trioxepan‐, 1,2,4‐Trioxocan‐ und 1,2,4‐Trioxonan‐Cyclohexadienone: cyclische Peroxide mit ungewöhnlicher Ringkonformationsdynamik

“…[12] Außerdem wurden Dyaden (zusätzlich zu Hybriden oder dimeren Strukturen) [13] aus natürlichen Artemisininderivaten und synthetischen Trioxanen hergestellt. [18] Dieses Verfahren nutzt als Reagens Oxone ,das Dreifachsalz aus 2KHSO 5 ,K HSO 4 und K 2 SO 4 ,e in sehr starkes Oxidationsmittel mit dem Kaliumsalz der Caroschen Säure (Caroat) als reaktive Komponente. B.…”

“…[16] Ein weiterer Wegz uA llylhydroperoxiden ist die Caroat-Oxidation von Phenolen, die an C-4 substituiert sind [17] -eine Methode,die auch fürdie Synthese neuer spiroverknüpfter 1,2,4-Trioxane verwendet wurde. [18] Dieses Verfahren nutzt als Reagens Oxone ,das Dreifachsalz aus 2KHSO 5 ,K HSO 4 und K 2 SO 4 ,e in sehr starkes Oxidationsmittel mit dem Kaliumsalz der Caroschen Säure (Caroat) als reaktive Komponente. [19] Die Caroatreaktion von Phenolen erfolgt unter moderat basischen Bedingungen (pH 8) im wässrigen Medium.…”