Synthesis, biological evaluation, and molecular modeling of 3,5-substituted-N1-phenyl-N4,N4-di-n-butylsulfanilamides as antikinetoplastid antimicrotubule agents.
Dinitroanilines are of interest as antiprotozoal lead compounds because of their selective activity against the tubulin of these organisms, but concern has been raised due to the potentially mutagenic nitro groups. Analogues of N(1)-phenyl-3,5-dinitro-N(4),N(4)-di-n-butylsulfanilamide (GB-II-150, compound 2b), a selective antimitotic agent against African trypanosomes and Leishmania, have been prepared where the nitro groups are replaced with amino, chloro, cyano, carboxylate, methyl ester, amide, and methyl ketone moieties. Dicyano compound 5 displays IC(50) values that are comparable to 2b against purified leishmanial tubulin assembly (6.6 vs 7.4 microM), Trypanosoma brucei brucei growth in vitro (0.26 vs 0.18 microM), Leishmania donovani axenic amastigote growth in vitro (4.4 vs 2.3 microM), and in vitro toxicity against Vero cells (16 vs 9.7 microM). Computational studies provide a rationale for the antiparasitic order of activity of these analogues and further insight into the role of the substituents at the 3 and 5 positions of the sulfanilamide ring.
George
Tesmol G
TG
Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, 500 West 12th Avenue, Columbus, OH 43210, USA.
Endeshaw
Molla M
MM
Morgan
Rachel E
RE
Mahasenan
Kiran V
KV
Delfín
Dawn A
DA
Mukherjee
Mitali S
MS
Yakovich
Adam J
AJ
Fotie
Jean
J
Li
Chenglong
C
Werbovetz
Karl A
KA
D000818:Animals; D002460:Cell Line; D016830:Kinetoplastida / Q000187:drug effects* / Q000378:metabolism / Q000469:parasitology; D007893:Leishmania donovani / Q000187:drug effects* / Q000378:metabolism / Q000469:parasitology; D008870:Microtubules / Q000187:drug effects* / Q000378:metabolism / Q000469:parasitology; D008956:Models, Chemical; D008958:Models, Molecular; 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*; D014353:Trypanosomiasis, African / Q000188:drug therapy; D050257:Tubulin Modulators / Q000737:chemistry / Q000494:pharmacology
D013424:Sulfanilamides; D014344:Trypanocidal Agents; D050257:Tubulin Modulators