ORIGINAL RESEARCH 2-Aminobenzimidazole conjugates of NSAIDS: novel compounds with immunomodulatory, anti-inflammatory and antioxidant actions Yogita Bansal • Om Silakari Received: 6 October 2013 / Accepted: 20 July 2014 Ó Springer Science+Business Media New York 2014 Abstract 2-Aminobenzimidazole (ABZ) and guanidine have immunomodulatory activity, whereas NSAIDs have anti-inflammatory activity. We, therefore, developed sev- eral novel ABZ-NSAID conjugate compounds and tested their anti-inflammatory and immunomodulatory activities. We also measured their antioxidant and ulcerogenic prop- erties. We found that all compounds had not only anti- inflammatory activity but they also had immunomodula- tory and antioxidant activities. While compound 2 had immunostimulatory activity (humoral antibody titre, HAT 7.2 ± 0.20 and carbon clearance index, K 0.030 ± 0.001), compound 9 had immunosuppressive activity (HAT 3.4 ± 0.24 and K 0.012 ± 0.002). These two compounds did not produce ulcers and hence were safe to the gastric mucosa. In addition, we used Lipinski’s parameters and found that all compounds had drug-like properties. Thus, we have provided new evidences to use compounds 2 and 9 for the treatment of inflammatory and immunomodulatory disorders like rheumatoid arthritis, ulcerative colitis, mul- tiple sclerosis, osteoarthritis and cancer. Keywords 2-Aminobenzimidazole  NSAIDs  Immunomodulatory  Anti-inflammatory  Antioxidant  Lipinski  Ulcerogenic Introduction 2-Aminobenzimidazole (ABZ), is a rigid form of guanidine pharmacophore (Greenhill and Lue, 1993). Guanidine is an immunomodulator as it alters the inducible form of nitric oxide synthetase in immune cells. The guanidine deriva- tives stimulate dilation of blood vessels and activate leu- cocytes to attack tumour cells, fungi and bacteria (Hamley and Tinker, 1995). In addition, the ABZ-substituted com- pounds have antiviral (Li et al., 2007), anthelmintics, antiproliferative (Mavrova et al., 2013; Nawrocka et al., 2004), antihypertensive (Settimo et al., 1991), H 3 antago- nistic (Mor et al., 2004), human glucagon receptor antag- onistic (Kim et al., 2008), male contraceptive (Chen et al., 2013) and anti-infective (Zhang et al., 2012) activities. These compounds also inhibit chemokine receptor (CXCR3) (Hayes et al., 2008), interleukin 2-inducible T cell kinase (ITK) (Lo et al., 2008) and lymphocyte tyrosine kinase (Lck) (Zhang et al., 2009), and thereby, alter the immune system. The structure–activity relationship (SAR) study of interleukin-2-inducible T cell kinase (ITK) inhibitors suggests that an acyl/aroyl moiety at amino group of ABZ is important for binding interactions in kinase specificity pocket of ITK receptor (Cook et al., 2009). Moreover, the clinical use of levamisole, mizori- bine, methotrexate, 6-mercaptopurine, and azathioprine (Fig. 1) for various immunomodulatory diseases such as leukaemia and other carcinomas, rheumatoid arthritis, organ transplants (Krensky et al., 2006) further supports that the ABZs are important immunomodulators. The NSAIDs (diclofenac, ibuprofen, salicylic acid, mefenamic acid, indomethacin, flurbiprofen, naproxen, ketoprofen, mesalamine, felbinac and salicylic acid) are widely used to treat inflammatory disorders. These are often prescribed with immunomodulators to treat complex Y. Bansal  O. Silakari (&) Molecular Modelling Lab (MML), Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala 147002, India e-mail: omsilakari@rediffmail.com 123 Med Chem Res DOI 10.1007/s00044-014-1198-3 MEDICINAL CHEMISTR Y RESEARCH