Synthesis and biological activity of certain alkyl 5-(alkoxycarbonyl)-1H-benzimidazole-2-carbamates and related derivatives: a new class of potential antineoplastic and antifilarial agents.
A series of methyl and ethyl 5-(alkoxycarbonyl)-1H-benzimidazole-2-carbamates (7-19) and methyl 5-carbamoyl-1H-benzimidazole-2-carbamates (24-34) have been synthesized via the reaction of an appropriate alcohol or amine with the acid chloride derivatives 6a or 6b at room temperature. Reaction of an alcohol with acid chloride 6a at reflux temperature afforded transesterified products 20-23 in good yield. Treatment of methyl 5-amino-1H-benzimidazole-2-carbamate with substituted benzoyl chlorides furnished the methyl 5-benzamido-1H-benzimidazole-2-carbamates (36-38). Compounds 9, 16, 20, and 22 demonstrated significant growth inhibition in L1210 cells with IC50's less than 1 microM. Growth inhibition by this series of compounds appears to be associated with mitotic spindle poisoning. All the compounds tested, 9, 10, 19, 20, 22, and 23, caused significant accumulation of L1210 cells in mitosis. Compounds 7, 9, 19, 25, 26, 27, and 36 showed significant in vivo antifilarial activity against adult worms of Brugia pahangi, Litomosoides carinii, and Acanthocheilonema viteae in experimentally infected jirds.
Ram
S
S
Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor 48109-1065.
Wise
D S
DS
Wotring
L L
LL
McCall
J W
JW
Townsend
L B
LB
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001562:Benzimidazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D002219:Carbamates / Q000138:chemical synthesis* / Q000494:pharmacology; D005369:Filaricides / Q000138:chemical synthesis* / Q000494:pharmacology; D051379:Mice; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000970:Antineoplastic Agents; D001562:Benzimidazoles; D002219:Carbamates; D005369:Filaricides