title: Antimalarial Activity of Small-Molecule Benzothiazole Hydrazones.
abstract: We synthesized a new series of conjugated hydrazones that were found to be active against malaria parasite in vitro, as well as in vivo in a murine model. These hydrazones concentration-dependently chelated free iron and offered antimalarial activity. Upon screening of the synthesized hydrazones, compound 5f was found to be the most active iron chelator, as well as antiplasmodial. Compound 5f also interacted with free heme (KD [equilibrium dissociation constant] = 1.17 ± 0.8 μM), an iron-containing tetrapyrrole released after hemoglobin digestion by the parasite, and inhibited heme polymerization by parasite lysate. Structure-activity relationship studies indicated that a nitrogen- and sulfur-substituted five-membered aromatic ring present within the benzothiazole hydrazones might be responsible for their antimalarial activity. The dose-dependent antimalarial and heme polymerization inhibitory activities of the lead compound 5f were further validated by following [(3)H]hypoxanthine incorporation and hemozoin formation in parasite, respectively. It is worth mentioning that compound 5f exhibited antiplasmodial activity in vitro against a chloroquine/pyrimethamine-resistant strain of Plasmodium falciparum (K1). We also evaluated in vivo antimalarial activity of compound 5f in a murine model where a lethal multiple-drug-resistant strain of Plasmodium yoelii was used to infect Swiss albino mice. Compound 5f significantly suppressed the growth of parasite, and the infected mice experienced longer life spans upon treatment with this compound. During in vitro and in vivo toxicity assays, compound 5f showed minimal alteration in biochemical and hematological parameters compared to control. In conclusion, we identified a new class of hydrazone with therapeutic potential against malaria.
authors.affiliation: Division of Infectious Diseases and Immunology, CSIR-Indian Institute of Chemical Biology, Jadavpur, Kolkata, West Bengal, India.
authors.forename: Souvik
authors.initials: S
authors.lastname: Sarkar
authors.affiliation: Division of Infectious Diseases and Immunology, CSIR-Indian Institute of Chemical Biology, Jadavpur, Kolkata, West Bengal, India.
authors.forename: Asim A
authors.initials: AA
authors.lastname: Siddiqui
authors.affiliation: Division of Infectious Diseases and Immunology, CSIR-Indian Institute of Chemical Biology, Jadavpur, Kolkata, West Bengal, India.
authors.forename: Shubhra J
authors.initials: SJ
authors.lastname: Saha
authors.affiliation: Division of Infectious Diseases and Immunology, CSIR-Indian Institute of Chemical Biology, Jadavpur, Kolkata, West Bengal, India.
authors.forename: Rudranil
authors.initials: R
authors.lastname: De
authors.affiliation: Division of Infectious Diseases and Immunology, CSIR-Indian Institute of Chemical Biology, Jadavpur, Kolkata, West Bengal, India.
authors.forename: Somnath
authors.initials: S
authors.lastname: Mazumder
authors.affiliation: Division of Infectious Diseases and Immunology, CSIR-Indian Institute of Chemical Biology, Jadavpur, Kolkata, West Bengal, India.
authors.forename: Chinmoy
authors.initials: C
authors.lastname: Banerjee
authors.affiliation: Division of Infectious Diseases and Immunology, CSIR-Indian Institute of Chemical Biology, Jadavpur, Kolkata, West Bengal, India.
authors.forename: Mohd S
authors.initials: MS
authors.lastname: Iqbal
authors.affiliation: Division of Infectious Diseases and Immunology, CSIR-Indian Institute of Chemical Biology, Jadavpur, Kolkata, West Bengal, India.
authors.forename: Shiladitya
authors.initials: S
authors.lastname: Nag
authors.affiliation: Department of Chemistry, University of Calcutta, Kolkata, West Bengal, India.
authors.forename: Susanta
authors.initials: S
authors.lastname: Adhikari
authors.affiliation: Division of Infectious Diseases and Immunology, CSIR-Indian Institute of Chemical Biology, Jadavpur, Kolkata, West Bengal, India ubandyo_1964@yahoo.com.
authors.forename: Uday
authors.initials: U
authors.lastname: Bandyopadhyay
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D052160:Benzothiazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002738:Chloroquine / Q000737:chemistry / Q000494:pharmacology; D018432:Drug Resistance, Multiple; D006835:Hydrazones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D007501:Iron / Q000737:chemistry; D008297:Male; D051379:Mice; D010963:Plasmodium falciparum / Q000187:drug effects; D010967:Plasmodium yoelii / Q000187:drug effects; D011739:Pyrimethamine / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000962:Antimalarials; D052160:Benzothiazoles; D006835:Hydrazones; D002738:Chloroquine; D007501:Iron; C005465:benzothiazole; D011739:Pyrimethamine