Original article Synthesis, anti-tuberculosis activity and 3D-QSAR study of amino acid conjugates of 4-(adamantan-1-yl) group containing quinolines Amit Nayyar a,1 , Sanjay R. Patel a , Mushtaque Shaikh b , Evans Coutinho b, * , Rahul Jain a, ** a Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research, Sector 67, S.A.S. Nagar, Punjab 160 062, India b Department of Pharmaceutical Chemistry, Bombay College of Pharmacy, Kalina, Santacruz (E), Mumbai 400 098, India article info Article history: Received 8 April 2008 Received in revised form 19 September 2008 Accepted 2 October 2008 Available online 11 October 2008 Keywords: Tuberculosis Ring-substituted quinolines CoMFA Amino acid conjugates Anti-tuberculosis abstract The synthesis, antimycobacterial activity and 3D-QSAR study of two series of 4-(adamantan-1-yl) group containing quinolines conjugated to amino acids are described. The most potent analogs displayed in vitro antimycobacterial activity ranging between 1.00 and 3.125 mg/mL. To understand the relationship between structure and activity, a 3D-QSAR analysis has been carried out by Comparative Molecular Field Analysis (CoMFA). The activities of molecules in the test sets were nicely predicted by the CoMFA model generated with field alignment. The best model was obtained using atom-fit alignment. Based on the molecular fields the relationships between structure and activity were easily rationalized. Ó 2008 Elsevier Masson SAS. All rights reserved. 1. Introduction In 1993, the World Health Organization (WHO) declared tuberculosis (TB) a global public health emergency. The disease has advanced, and currently causes approximately 2 million deaths annually [1]. Several interlinked factors contribute to this progression: (a) development of strains resistant to most commonly used drugs such as isoniazid and rifampicin; (b) the spread of the HIV/AIDS pandemic (one third of the approximately 40 million HIV cases worldwide are coinfected with Mycobacterium tuberculosis, and for these individuals, the risk of developing clinical TB is about 10% per year); (c) the difficulty of TB detection in infected individuals (less than 40% of TB cases are detected); and finally; (d) the rising incidence of multidrug-resistant (MDR) TB. To overcome shortcomings of existing regimens of anti-TB drugs, new structural classes of drugs acting via novel biochemical pathways are required [2–4]. Ideally, the new classes of anti-TB drugs must be of low molecular weight, inexpensive for easy availability to poor patients, and possess activity against drug-resistant strains of commonly used anti-TB drugs. Previously, we had reported the discovery of ring-substituted quinolines as a new structural class of anti-TB compounds [5]. The lead compound 2,8-dicyclopentyl-4-methylquinoline (DCMQ) synthesized in one-step is a promising inhibitor and exhibited encouraging activities against drug-sensitive and several single drug-resistant strains (SDR) of M. tuberculosis. The promising activity against SDR strains of several of the currently used anti-TB agents suggests that ring-substituted quinolines exemplified by DCMQ possibly act by new and yet unknown biochemical path- way(s). In attempts to modify the structure of the lead compound DCMQ, we have synthesized several new series of ring-substituted quinolines [6–10]. In one such study, we have reported the synthesis and promising anti-tuberculosis activity of a series of ring-substituted quinolinecarbohydrazides/carboxamides [7]. The most active compounds 4-(adamantan-1-yl)-2-quinolinecarbohy- drazide and 4-(adamantan-1-yl)-2-quinolinecarboxamide (Fig. 1) have displayed 99% and 98% inhibition at 6.25 mg/mL, respectively against drug-sensitive M. tuberculosis H37Rv strain. Both compounds were synthesized using a facile three-step synthetic process in high yields. Therefore, both compounds were considered ideally suited for further structural optimization. In continuation of our anti-tuberculosis drug discovery program and structural diversification of ring-substituted quinolines, herein we report synthesis of various amino acid derivatives (series 1–2, Fig. 2) of 4- * Corresponding author. Tel.: þ91 22 26670905; fax: þ91 22 26670816. ** Corresponding author. Tel.: þ91 172 2214682; fax: þ91 172 2214692. E-mail addresses: evans@bcpindia.org (E. Coutinho), rahuljain@niper.ac.in (R. Jain). 1 Present address: Laboratory of Clinical Infectious Diseases, NIAID, National Institutes of Health, Bethesda, MD 20852, USA. Contents lists available at ScienceDirect European Journal of Medicinal Chemistry journal homepage: http://www.elsevier.com/locate/ejmech 0223-5234/$ – see front matter Ó 2008 Elsevier Masson SAS. All rights reserved. doi:10.1016/j.ejmech.2008.10.004 European Journal of Medicinal Chemistry 44 (2009) 2017–2029