title: Synthesis, biological evaluation, and structure-activity relationships of N-benzoyl-2-hydroxybenzamides as agents active against P. falciparum (K1 strain), Trypanosomes, and Leishmania.
abstract: In our efforts to identify novel chemical scaffolds for the development of new antiprotozoal drugs, a compound library was screened against Toxoplasma gondii tachyzoites with activity discovered for N-(4-ethylbenzoyl)-2-hydroxybenzamide 1a against T. gondii as described elsewhere. Synthesis of a compound set was guided by T. gondii SAR with 1r found to be superior for T. gondii , also active against Thai and Sierra Leone strains of Plasmodium falciparum , and with superior ADMET properties as described elsewhere. Herein, synthesis methods and details of the chemical analysis of the compounds in this series are described. Further, this series of N-benzoyl-2-hydroxybenzamides was repurposed for testing against four other protozoan parasites: Trypanosoma brucei rhodesiense , Trypanosoma cruzi , Leishmania donovani , and P. falciparum (K1 isolate). Structure-activity analyses led to the identification of compounds in this set with excellent antileishmanial activity (compound 1d). Overall, compound 1r was the best and had activity 21-fold superior to that of the standard antimalarial drug chloroquine against the K1 P. falciparum isolate.
authors.affiliation: Drug Discovery Program, Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, 833 South Wood Street, Chicago, Illinois 60612, USA.
authors.forename: Jozef
authors.initials: J
authors.lastname: Stec
authors.forename: Qingqing
authors.initials: Q
authors.lastname: Huang
authors.forename: Marco
authors.initials: M
authors.lastname: Pieroni
authors.forename: Marcel
authors.initials: M
authors.lastname: Kaiser
authors.forename: Alina
authors.initials: A
authors.lastname: Fomovska
authors.forename: Ernest
authors.initials: E
authors.lastname: Mui
authors.forename: William H
authors.initials: WH
authors.lastname: Witola
authors.forename: Samuel
authors.initials: S
authors.lastname: Bettis
authors.forename: Rima
authors.initials: R
authors.lastname: McLeod
authors.forename: Reto
authors.initials: R
authors.lastname: Brun
authors.forename: Alan P
authors.initials: AP
authors.lastname: Kozikowski
mesh_terms: D000962:Antimalarials / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001549:Benzamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007094:Imides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007893:Leishmania donovani / Q000187:drug effects*; D021261:Parasitic Sensitivity Tests; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000302:isolation & purification; D013329:Structure-Activity Relationship; D014344:Trypanocidal Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014345:Trypanosoma / Q000187:drug effects*; D016833:Trypanosoma brucei rhodesiense / Q000187:drug effects; D014349:Trypanosoma cruzi / Q000187:drug effects
chemical_list: D000962:Antimalarials; D001549:Benzamides; D007094:Imides; C574635:N-(4-(diethylamino)benzoyl)-2-hydroxybenzamide; D014344:Trypanocidal Agents