ORIGINAL RESEARCH Design, synthesis and evaluation of aminobenzophenone derivatives containing nitrogen mustard moiety as potential central nervous system antitumor agent Rajesh K. Singh • D. N. Prasad • T. R. Bhardwaj Received: 4 December 2012 / Accepted: 13 March 2013 Ó Springer Science+Business Media New York 2013 Abstract A series of novel substituted aminobenzophe- none derivatives containing nitrogen mustard moiety (5a–f) were synthesized and characterized on the basis of their IR, 1 H NMR, 13 C NMR, CHN, and mass spectral data. All the compounds when evaluated for chemical 4-(4- nitrobenzyl) pyridine alkylating activity proved to be active alkylating agents. All the synthesized compounds were subjected to physicochemical parameters determination required for central nervous system (CNS) activity through computational, online software, and QikProp 3.2. The log P values and other in silico ADME physicochemical descriptors analyzed lay between the ranges those are required for good BBB penetration. The in vitro antipro- liferative activity against human cancer cell lines viz. A 549 (lung), COLO 205 (colon), U 87 (glioblastoma), and IMR-32 (neuroblastoma) was investigated. Most of the test compounds showed potent antitumor activity, especially compound (5f) which displayed the highest activity against CNS cancer cell line comparable to that of chlorambucil and docetaxel. The preliminary structure–activity rela- tionship (SAR) revealed that 5-chloroaminobenzophenone- mustard series (5a–c) exhibited better antitumor activity than 5-nitroaminobenzophenone-mustard series (5d–f). Keywords 2-Aminobenzophenone  Nitrogen mustard  Blood–brain barrier  Physicochemical ADME descriptors  NBP assay  In vitro cytotoxicity Introduction Cancer is considered as the most serious health problem all over the world. Of all the cancer, Brain cancers are the sec- ond leading cause of cancer-related deaths in males while the fifth leading cause of cancer-related deaths in women. It accounts for 85–90 % of all primary central nervous system (CNS) tumors. Approximately, 42 % of all brain and CNS tumors occurred in males and 58 % in females (Dolecek et al., 2012). Nitrogen mustard classes of drug such as chlorambucil and mechlorethamine, bifunctional alkylators are still used extensively in the treatment of leukemia and solid tumors. The main demerits of mustard drug are their high reactivity so toxic to normal peripheral tissue and hydrophilicity which does not allow the molecule to cross blood–brain barrier (BBB) and, therefore, make these drugs not of much clinical significance to patients suffering from brain tumor (Francisco et al., 2008). Various attempts have been made to overcome the limited access of nitrogen mustard into the brain such as synthesizing their lipophilic analogs (Genka et al. 1993) or by linking the active anticancer moiety to lipophilic carrier (Peng et al., 1975; Hirata and Driscoll, 1976; Bartzatt, 2004) and chemical drug delivery system (Bodor et al., 1989; El-Sherbeny et al., 2003). Moreover, recent study revealed that targeting N-mustard moiety by linking to various carriers having optimized physico- chemical properties resulted in more potency and less peripheral cytotoxicity than the corresponding untargeted mustard (Mourelatos et al., 2012; Marvania et al., 2011; Design, synthesis and evaluation of aminobenzophenone derivatives containing nitrogen mustard moiety as potential central nervous system antitumor agent. R. K. Singh (&)  D. N. Prasad Pharmaceutical Chemistry Division, Shivalik College of Pharmacy, Nangal, Rupnagar 140126, Punjab, India e-mail: rksingh244@gmail.com T. R. Bhardwaj Indo-Soviet Friendship (ISF) College of Pharmacy, Moga 142001, Punjab, India 123 Med Chem Res DOI 10.1007/s00044-013-0582-8 MEDICINAL CHEMISTR Y RESEARCH