title: Aryl aryl methyl thio arenes prevent multidrug-resistant malaria in mouse by promoting oxidative stress in parasites.
abstract: We have synthesized a new series of aryl aryl methyl thio arenes (AAMTAs) and evaluated antimalarial activity in vitro and in vivo against drug-resistant malaria. These compounds interact with free heme, inhibit hemozoin formation, and prevent Plasmodium falciparum growth in vitro in a concentration-dependent manner. These compounds concentration dependently promote oxidative stress in Plasmodium falciparum as evident from the generation of intraparasitic oxidants, protein carbonyls, and lipid peroxidation products. Furthermore, AAMTAs deplete intraparasite GSH levels, which is essential for antioxidant defense and survival during intraerythrocytic stages. These compounds displayed potent antimalarial activity not only in vitro but also in vivo against multidrug-resistant Plasmodium yoelii dose dependently in a mouse model. The mixtures of enantiomers of AAMTAs containing 3-pyridyl rings were found to be more efficient in providing antimalarial activity. Efforts have been made to synthesize achiral AAMTAs 17-23 and among them, compound 18 showed significant antimalarial activity in vivo.
authors.affiliation: Division of Infectious Diseases and Immunology, CSIR-Indian Institute of Chemical Biology, 4, Raja S. C. Mullick Road, Jadavpur, Kolkata 700032, West Bengal, India.
authors.forename: Manish
authors.initials: M
authors.lastname: Goyal
authors.forename: Priyanka
authors.initials: P
authors.lastname: Singh
authors.forename: Athar
authors.initials: A
authors.lastname: Alam
authors.forename: Sajal Kumar
authors.initials: SK
authors.lastname: Das
authors.forename: Mohd Shameel
authors.initials: MS
authors.lastname: Iqbal
authors.forename: Sumanta
authors.initials: S
authors.lastname: Dey
authors.forename: Samik
authors.initials: S
authors.lastname: Bindu
authors.forename: Chinmay
authors.initials: C
authors.lastname: Pal
authors.forename: Sanjit Kumar
authors.initials: SK
authors.lastname: Das
authors.forename: Gautam
authors.initials: G
authors.lastname: Panda
authors.forename: Uday
authors.initials: U
authors.lastname: Bandyopadhyay
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000627:therapeutic use*; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D005978:Glutathione / Q000378:metabolism; D006418:Heme / Q000378:metabolism; D006841:Hydrocarbons, Aromatic / Q000737:chemistry*; D008288:Malaria / Q000469:parasitology / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018384:Oxidative Stress / Q000187:drug effects*; D010963:Plasmodium falciparum / Q000187:drug effects*
chemical_list: D000962:Antimalarials; D006841:Hydrocarbons, Aromatic; D006418:Heme; D005978:Glutathione