Design, development, synthesis, and docking analysis of 2′‐substituted triclosan analogs as inhibitors for <i>Plasmodium falciparum</i> Enoyl‐ACP reductase

Objective: The emergence of malaria as a global health problem over the past few decades, accompanied by the rise of chemoresistant strains ofPlasmodium falciparum, has emphasized the need for the discovery of new therapeutic drugs against this disease. In this study, enantiomericallyenriched (enantioenriched) analogs of triclosan were synthesized and evaluated for antimalarial activity against P. falciparum cultures.Methods: Enantioselective dihydroxylation of the olefin in amide seven was performed efficiently using chiral quinine ligand (DHQ)2PHAL to yieldenantioenriched dihydroxy propionamide derivative (+)-1 in moderate yields. In a similar way, the chiral quinidine ligand (DHQD)2PHAL was used asstereoselectivity agent yielded the desired enantioenriched (−)-1. The enantioenriched products were used for further in vitro assay, and accordingly thepercent enantiomeric excess (% ee) was not determined. The structures of compounds were proven by spectral data (1H NMR, 13C NMR, and mass spectra).Results: The phenol moiety at the C1 position of triclosan was chemically substituted with a methoxy group, in conjunction with an introducedstereocenter in a 2,3-dihydroxy-propionamide group at C2’ position. Unmodified triclosan inhibited the P. falciparum cultures with an IC50 value of27.2 μM. By contrast, the triclosan analogs, compounds (+)-1 and (−)-1, inhibited the P. falciparum cultures with IC50 values of 0.034 and 0.028 μM,respectively.Conclusion: Collectively, our preliminary in vitro results suggest that these triclosan analogs have potent antimalarial activity and represent apromising new treatment strategy on further development.

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“…Compound 6 was prepared by three chemical reactions in accordance with a previously reported procedure [18] (Fig. 2).…”

Section: Resultsmentioning

confidence: 99%

“…Continuing the work of earlier studies attempting to identify new and potent antimalarial treatments [14][15][16][17][18][19][20], in this study, we synthesized modified structures of triclosan and evaluated their antimalarial activities.…”

Section: Introductionmentioning

confidence: 99%

Synthesis, Characterization, and in Vitro Antimalarial Activity of Dihydroxylation Derivatives of Triclosan

Fitriana

Yanuar²,

Arsianti³

et al. 2020

Int J App Pharm

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“…Triclosan substituted at 2′ position (The Cl at position 2′ in ring B of triclosan was chemically substituted with NH (2), NO (2) functional groups) was used to inhibit Pf ENR as studied by Kapoor et al. (55). A number of compounds are screened, synthesized, and evaluated for their potencies to inhibit (Table 1).…”

Section: Compounds Against Enoyl‐acp Reductase Of Plasmodium Falciparmentioning

confidence: 99%

Antimalarial Drugs and Drug Targets Specific to Fatty Acid Metabolic Pathway of Plasmodium falciparum

Qidwai

Khan²

2012

Chem Biol Drug Des

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Plasmodium falciparum, a causitive agent of malaria, is the third most prevalent factor for mortility in the world. Falciparum malaria is an example of evolutionary and balancing selection. Because of mutation and natural selection, the parasite has developed resistance to most of the existing drugs. Under such circumstances, there is a growing need to develop new molecular targets in P. falciparum. A four membrane bound organelles called apicoplast, very much similar to that of chloroplast of plants, have been found in parasite. Therefore, the proteins involved in metabolic pathways of apicoplasts are important drug targets. Among the pathways in apicoplast, fatty acid biosynthetic pathway is the most important metabolic pathway in P. falciparum. Several studies have explored the role of different proteins involved in this pathway and antimalarial compounds against this target. In this review, we have studied the role of different proteins in fatty acid metabolism and designing, synthesis and evaluation of compounds against the targets identified in fatty acid metabolic pathway. Malaria is the global health problem and causes worldwide morbidity and mortality. Approximately, 300-500 million clinical cases and one million deaths caused per year worldwide due to malaria (1). Four Plasmodium species (P. vivax, P. ovale, P. malariae, and P. falciparum) are responsible for human malaria. Out of these, P. falciparum species causes most fatal form of malaria. This parasite has a plastid like organelle called as apicoplast. Resistance to known antimalarial and the lack of an effective vaccine have created an urgent need to discover new biologically active compounds. A four-membrane plastid organelle, the apicoplast is present in many apicomplexan parasites including P. falciparum, and apicoplast is believed to have arisen through endosymbiosis of an algal cell that had previously incorporated a cyanobacterium (2). The sequencing of the P. falciparum genome coupled with a detailed analysis of the proteins of known function, which were targeted to the apicoplast, allowed the construction of an apicoplast specific metabolic map (3). Several metabolic pathways exist in apicoplast, differing significantly from those found in the human host, based on its prokaryotic origin and has been considered as potential drug target for new therapeutics (4). Fatty acid biosynthetic pathway is the most important pathway in apicoplast. Most eukaryotes have type I fatty acid synthase (FAS) enzymes, which are large multifunctional enzymes composed of one or two polypeptides. Malaria parasites of the genus Plasmodium do not contain FAS and rely instead on a type II fatty acid synthase (FAS II) for the de novo production of fatty acids. Seven proteins found in the P. falciparum genome comprise a dissociated FAS II (5). The FAS II of P. falciparum is composed of six discrete enzymes, and the acyl carrier protein (ACP) serves to shuttle the nascent fatty acid among the enzymes of pathway. The apicoplast of parasite is the site for FAS II biosyn...

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“…P. falciparum enoyl-acyl carrier protein reductase (PfENR) reduces the trans-2-enoyl bond of enoyl-acyl carrier protein (ACP) substrate to saturated acyl-ACPs and it plays a vital role in completing the successive rounds of fatty acid elongation process. PfENR is an emerging new important target for the development of anti-microbial and anti-parasitic molecules [5] . In the present study, a selected 19 compounds namely alginic acid, atropine, chlorogenic acid, chrotacumine A & B, 1 coenzyme Q 1 , 4-coumaric acid, curcumin, ellagic acid, embelin, 5-O-methyl embelin, eugenyl glucoside, glabridin, hyoscyamine, nordihydroguaiaretic acid, rohitukine, scopolamine, tlatlancuayin and ursolic acid.…”

Section: Introductionmentioning

confidence: 99%

Natural Compounds as Inhibitors of Plasmodium Falciparum Enoyl-acyl Carrier Protein Reductase (PfENR): An In silico Study

Narayanaswamy¹,

Lam²,

Ismail³

2017

Journal of the Chosun Natural Science

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Demand for a new anti-malarial drug has been dramatically increasing in the recent years. Plasmodium falciparum enoyl-acyl carrier protein reductase (PfENR) plays a vital role in fatty acid elongation process, which now emerged as a new important target for the development of anti-microbial and anti-parasitic molecules. In the present study, 19 compounds namely alginic acid, atropine, chlorogenic acid, chrotacumine A & B, coenzyme Q 1 , 4-coumaric acid, curcumin, ellagic acid, embelin, 5-O-methyl embelin, eugenyl glucoside, glabridin, hyoscyamine, nordihydroguaiaretic acid, rohitukine, scopolamine, tlatlancuayin and ursolic acid were evaluated on their docking behaviour on P. falciparum enoyl-acyl carrier protein reductase (PfENR) using Auto dock 4.2. The docking studies and binding free energy calculations exhibited that glabridin gave the highest binding energy (-8.07 kcal/mol) and 4-coumaric acid in contrast showed the least binding energy (-4.83 kcal/mol). All ligands except alginic acid, ellagic acid, hyoscyamine and glabridin interacted with Gln409 amino acid residue. Interestingly four ligands namely coenzyme Q 1 , 4-coumaric acid, embelin and 5-O-methyl embelin interacted with Gln409 amino acid residue present in both chains (A & B) of PfENR protein. Thus, the results of this present study exhibited the potential of these 19 ligands as P. falciparum enoyl-acyl carrier protein reductase (PfENR) inhibitory agents and also as anti-malarial agents.

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Design, development, synthesis, and docking analysis of 2′‐substituted triclosan analogs as inhibitors for Plasmodium falciparum Enoyl‐ACP reductase

Cited by 10 publications

References 30 publications

Synthesis, Characterization, and in Vitro Antimalarial Activity of Dihydroxylation Derivatives of Triclosan

Synthesis, Characterization, and in Vitro Antimalarial Activity of Dihydroxylation Derivatives of Triclosan

Antimalarial Drugs and Drug Targets Specific to Fatty Acid Metabolic Pathway of Plasmodium falciparum

Natural Compounds as Inhibitors of Plasmodium Falciparum Enoyl-acyl Carrier Protein Reductase (PfENR): An In silico Study

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