title: Synthesis and antitubulin activity of N1- and N4-substituted 3,5-dinitro sulfanilamides against African trypanosomes and Leishmania.
abstract: Thirty analogues of N(1)-phenyl-3,5-dinitro-N(4),N(4)-di-n-propylsulfanilamide (GB-II-5, compound 3), a new antikinetoplastid antimitotic agent, have been synthesized and evaluated. The addition of simple functional groups to the N1 aromatic ring generally decreases antiparasitic and antimitotic potency, but placement of a dibutyl substituent at the N4 nitrogen to give N(1)-phenyl-3,5-dinitro-N(4),N(4)-di-n-butylsulfanilamide (compound 35) augments antitrypanosomal and antileishmanial activity. Compound 35 possesses IC(50) values of 0.12 and 2.6 microM against cultured T. brucei and L. donovani amastigote-like forms, surpassing the activity of compound 3 against these parasites by 3.4- and 1.9-fold, respectively. Compound 35 inhibits the assembly of leishmanial tubulin with an IC(50) of 6.9 microM and displays antimitotic effects in cultured T. brucei as assessed by flow cytometry, but shows little effect on purified mammalian tubulin, and displays 100-fold selectivity for trypanosomes over two mammalian cell lines. Although 3 and 35 were not effective in initial in vivo antitrypanosomal assays, the in vitro potency and selectivity of these compounds make N(1)-aryl-3,5-dinitro-N(4),N(4)-dialkylsulfanilamides a promising new class of antikinetoplastid agents that act on parasite tubulin.
authors.affiliation: Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, 500 West 12th Avenue, Columbus, Ohio 43210, USA.
authors.forename: Gautam
authors.initials: G
authors.lastname: Bhattacharya
authors.forename: Johnathan
authors.initials: J
authors.lastname: Herman
authors.forename: Dawn
authors.initials: D
authors.lastname: Delfín
authors.forename: Manar M
authors.initials: MM
authors.lastname: Salem
authors.forename: Todd
authors.initials: T
authors.lastname: Barszcz
authors.forename: Mike
authors.initials: M
authors.lastname: Mollet
authors.forename: Guy
authors.initials: G
authors.lastname: Riccio
authors.forename: Reto
authors.initials: R
authors.lastname: Brun
authors.forename: Karl A
authors.initials: KA
authors.lastname: Werbovetz
mesh_terms: D000818:Animals; D002460:Cell Line; D007893:Leishmania donovani / Q000187:drug effects*; D013329:Structure-Activity Relationship; D013424:Sulfanilamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014344:Trypanocidal Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014346:Trypanosoma brucei brucei / Q000187:drug effects*; D014404:Tubulin / Q000737:chemistry; D050257:Tubulin Modulators
chemical_list: D013424:Sulfanilamides; D014344:Trypanocidal Agents; D014404:Tubulin; D050257:Tubulin Modulators