SYNTHESIS, CHARACTERIZATION, AND IN VITRO ANTIMALARIAL ACTIVITY OF DIHYDROXYLATION DERIVATIVES OF TRICLOSAN

Wahyu Fitriana,Ade Arsianti,Kiyomi Kakiuchi,Arry Yanuar,Hiroki Tanimoto

doi:10.22159/ijap.2020.v12s1.ff007

Abstract

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.

Highlights

To date, malaria remains one of the most devastating diseases of tropical and subtropical countries and is caused by the protozoan parasites of the Plasmodium genus
Our results indicate that both of the enantioenriched analogs (+)-1 and (–)-1 of the 2’-chloro- and phenol-modified series exhibited better antimalarial activity profiles than the unsubstituted triclosan
We have synthesized novel triclosan analogs that appear to have potent antiplasmodial activity. The design of these new analogs was initiated with the introduction of chirality, and the analogs were synthesized in five steps to obtain a moderate yield

Summary

Introduction

Malaria remains one of the most devastating diseases of tropical and subtropical countries and is caused by the protozoan parasites of the Plasmodium genus. Malaria causes over 500 million new cases each year, with approximately 3 billion people living under the threat of malaria. Chemoresistance is of increasing concern, primarily for Plasmodium falciparum, the parasite responsible for cerebral malaria, which is the most serious type of malaria infection. This chemoresistance is believed to be a major factor in the worldwide upsurge of malaria [6]; there is an urgent need for new and potent antimalarial treatments [7]

Methods

Results

Conclusion