Potent 1,3-Disubstituted-9H-pyrido[3,4-b]indoles as New Lead Compounds in Anti®larial Chemotherapy y Sanjay K. Srivastava, a Alka Agarwal, a Prem M.S. Chauhan, a, * Shiv K. Agarwal, { Amiya P. Bhaduri, a Som N. Singh, x Nigar Fatima b and Ranjit K. Chatterjee b a Division of Medicinal Chemistry, Central Drug Research Institute, Lucknow 226001, India b Division of Parasitology, Central Drug Research Institute, Lucknow 226001, India Received 10 November 1998; accepted 29 January 1999 AbstractÐSubstituted 9H-pyrido[3,4-b]indoles (b-carbolines) identi®ed in our laboratory as potential pharmacophore for designing macro®laricidal agents, have been explored further for identifying the pharmacophore responsible for high order of adulticidal activity. This has led to syntheses and macro®laricidal evaluations of a number of 1-aryl-9H-pyrido[3,4-b]indole-3-carboxylate derivatives (3±7). The macro®larical activity was initially evaluated in vivo against Acanthoeilonema viteae. Amongst all the syn- thesized compounds, only twelve compounds namely 3a, 3c, 3d, 3f, 4c, 4d, 4f, 5a, 6f, 6h, 6i and 7h have exhibited either >90% micro- or macro®laricidal activity or sterilization of female worms. These compounds have also been screened against 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 malayi. The structure activity relationship (SAR) associated with position-1 and 3 substituents in b-carbolines have been discussed. It has been observed that the presence of carbomethoxy at position-3 and an aryl substituent at position-1 in b-carbolines eectively enhance anti®larial activity particularly against A. viteae. Amongst the various compounds screened, methyl 1-(4- methylphenyl)-9H-pyrido[3,4-b]indole-3-carboxylate (4c) has shown highest adulticidal activity and methyl 1-(4-chlorophenyl)- 1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole-3-carboxylate (3a) has shown highest micro®laricidal action against A. viteae at 50 mg/ kg5 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5 days (ip) and against B. malayi at 50 mg/kg5 days (ip) or at 200 mg/ kg5 days (po). # 1999 Elsevier Science Ltd. All rights reserved. Introduction The successful treatment of ®lariasis, a disease of many tropical and subtropical areas, is not possible because of the nonavailability of macro®laricidal drugs. 1±3 The age old drug diethyl carbamazine (DEC) continues to be the mainstay of clinical practice despite its well known de®ciencies. 4,5 Ivermectin, a semisynthetic macrocyclic lactone antibiotic, may take an impact as micro®laricide for onchocerciasis but it did not irreversibly damage the adult ®larial worms. 6 Although organic arsenical com- pounds have long been known as good macro- ®laricides, 7 their potential toxicity to the host has prevented their development as useful anti®larial drugs. Besides these anti®larials, a number of phenoxy- cyclohexane derivatives, 8 2,4,6-substituted triazines, 9 5-amino and 5,8-diaminoisoquinolines, 10 aplysinoposin derivatives 11 and 1,1 0 -dicyano-2-substituted ethylenes 12 were identi®ed as potential ®laricides but most of the compounds exhibited very poor adulticidal response. Benzimidazole group of anthelmintics exhibit high order of activity against intestinal helminths but have not found application for the treatment of tissue dwell- ing helminths. 13,14 Therefore the need arose to identify structural prototypes associated with macro®laricidal activity. In earlier communications, 15±24 the macro®laricidal activities of 1-substituted and 1,5-/1,6-/1,7- and 1,8-dis- ubstituted-9H-pyrido[3,4-b]indoles, (III-VII, Fig. 2) and representatives of pyrido[3,4- b]imidazo[1,2- c 0 ]quin- azolo[4,5-e] and [4,5-g]indoles (Fig. 1) were reported. These research activities did not reveal the optimal structural requirements to evoke very high order of macro®laricidal activity. In continuation of this work, it was considered essential to evaluate 1,3-disubstituted- 9H-pyrido[3,4-b]indoles (Fig. 3) because of the reasons stated later. Centrally acting agents known to interact with benzo- diazepine and g-aminobutyric acid (GABA) receptors 0968-0896/99/$ - see front matter # 1999 Elsevier Science Ltd. All rights reserved. PII: S0968-0896(99)00050-4 Bioorganic & Medicinal Chemistry 7 (1999) 1223±1236 Key words: b-Carboline; macro®laricidal; sterilization. *Corresponding author. y CDRI Communication No. 5795. { Present address: Wochkaradt Research Centre, D-4, MIDC, Chi- kalthana Aurangabad, India. x Present address: Department of Physiology, DIPAS, Timarpur, Delhi-54, India.