Potent 1,3-disubstituted-9H-pyrido[3,4-b]indoles as new lead compounds in antifilarial chemotherapy

Substituted 9H-pyrido[3,4-b]indoles (beta-carbolines) identified in our lab oratory as potential pharmacophore for designing macrofilaricidal agents, h ave been explored further for identifying the pharmacophore responsible for high order of adulticidal activity. This has led to syntheses and macrofil aricidal evaluations of a number of 1-aryl-9H-pyrido[3,4-b]indole-3-carboxy l derivatives (3-7). The macrofilarical activity was initially evaluated in vivo against Acanthoeilonema viteae. Amongst all the synthesized compounds , only twelve compounds namely 3a, 3c, 3d, 3f, 4c, 4d, 4f, 5a, 6f, 6h, 6i a nd 7h have exhibited either > 90% micro- or macrofilaricidal activity or st erilization of female worms. These compounds have also been screened agains t Litomosoides carinii and of these only 3f and 5a have also been found to be active. Finally these two compounds have been evaluated against Brugia m alayi. The structure activity relationship (SAR) associated with position-1 and 3 substituents in beta-carbolines have been discussed. It has been obs erved that the presence of carbomethoxy at position-3 and an aryl substitue nt at position-1 in beta-carbolines effectively enhance antifilarial activi ty particularly against A. viteae. Amongst the various compounds screened, methyl 1-(4-methylphenyl)-9H-pyrido[3,4-b]indole-3-carboxylate (4c) has sho wn highest adulticidal activity and methyl 1-(4-chlorophenyl)1,2,3,4-tetrah ydro-9H-pyrido[3,4-b]indole-3-carboxylate (3a) has shown highest microfilar icidal action against A. viteae at 50mg/ kgx5 days (ip). Another derivative of this compound namely 1-(4-chlorophenyl)-3-hydroxymethyl-9H-pyrido[3,4-b ]indole (5a) exhibited highest activity against L. carinii at 30 mg/kg x 5 days (ip) and against B. malayi at 50 mg/kg x 5 days (ip) or at 200 mg/ kgx 5 days (po). (C) 1999 Elsevier Science Ltd. All rights reserved.