Imidazo[1,2-a]pyridines linked with thiazoles/thiophene motif through keto spacer as potential cytotoxic agents and NF-jB inhibitors Kamala K. Vasu a,⇑,d , Chander Singh Digwal b,d,e,1 , Amit N. Pandya a,d , Dhaivat H. Pandya a , Jayesh A. Sharma a , Sneha Patel a , Milee Agarwal c,d a Department of Medicinal Chemistry, B. V. Patel Pharmaceutical Education and Research Development (PERD) Centre, Sarkhej-Gandhinagar Highway, Thaltej, Ahmedabad 380054, Gujarat, India b Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER)-Ahmedabad, Ahmedabad 380 058, Gujarat, India c Department of Pharmacology and Toxicology, B. V. Patel Pharmaceutical Education and Research Development (PERD) Centre, Sarkhej-Gandhinagar Highway, Thaltej, Ahmedabad 380054, Gujarat, India article info Article history: Received 4 August 2017 Revised 5 October 2017 Accepted 25 October 2017 Available online xxxx Keywords: Imidazo[1,2-a]pyridine Thiazole Thiophene Cytotoxicity NF-jB inhibitors abstract A series of new imidazo[1,2-a]pyridine linked with thiazole/thiophene motif through a keto spacer were synthesized and tested for their cytotoxic potential against three human cancer cell lines including A549, HeLa and U87-MG using MTT assay. Compounds A2, A3, A4, C1 and C2 showed cytotoxicity against all the three cell lines. The selectivity index for compound A4 for A549 and HeLa cells was comparable to that of doxorubicin. Among the synthesized compounds, B5 showed the maximum inhibition of NF-jB activity as ascertained by NF-jB reporter assay (IC 50 = 6.5 ± 0.6 mM). Treatment of NCI-H23 cells (EGFR overex- pressed, KRAS G12V mutant) with erlotinib and gefitinib along with compounds A4 and B5 indicated syn- ergistic and additive potential of combination therapy. Ó 2017 Elsevier Ltd. All rights reserved. Cancer is a life threatening global health risk caused by abnor- mal functioning of multiple intracellular regulatory systems that occur in normal cells and characterized by aberrant cellular prolif- eration. 1,2 The disease is induced by a series of genetic and epige- netic changes, which can be triggered by both external (tobacco, alcohol, chemicals, infectious agents, and radiation) 3–5 and internal factors involving hormones, inherited mutations, cytokines and chemokines. 6–8 Among internal factors, NF-jB is an inducible tran- scription factor involved in the regulation of large number of nor- mal cellular processes, such as immune and inflammatory responses, cellular growth and apoptosis. 9,10 NF-jB proteins are a family of eukaryotic transcription factors. In unstimulated cells, NF-jB is present in the cytoplasm bound to its inhibitory subunit IjB. When these cells are stimulated by external stimuli or cellular signaling, active NF-jB is released from its cytoplasmic complex, translocates to nucleus and binds to DNA. 11,12 NF-jB binding to DNA regulates cellular signaling pertaining to cell survival, cell differentiation and cell growth. Uncoupling of NF-jB proteins from their regulators leads to their constitutive activation. Constitutively activated NF-jB is involved in various aspects of carcinogenesis such as proliferation of cancer cell, evading apoptosis and increased metastatic potential. 13,14 Hence, inhibition of NF-jB transcriptional activation is considered as an important target for developing anticancer agents. A large number of structurally diverse molecules from natural products as well as from synthetic origin have been synthesized and evaluated for their NF-jB inhibitory activity (Fig. 1). For instance, curcumin, a major component of turmeric, and resvera- trol, present in red grapes, have been reported to suppress the acti- vation of NF-jB through inhibition of IKK activity. 15,16 Rugulactone and its derivatives exerted strong anti-proliferative effects in MDA- MB-231 cells through the inhibition of NF-jB. 17 1,3,5-Triazine, 18 indoline, 19 benzoxathiole, 20 and coumarin 21 as core nucleus have been well documented as inhibitors of NF-jB. In addition, Choi et al., synthesized benzofuran and 2,3-dihydrobenzofuran-2-car- boxamide derivatives and tested their NF-jB inhibitory activity in LPS-stimulated RAW 264.7 macrophage cells. 22 However, only benzofuran-2-carboxylic acid N-(4 0 -hydroxy)phenylamide was found to possess potent anti-proliferative as well as NF-jB inhibi- tory activity. https://doi.org/10.1016/j.bmcl.2017.10.060 0960-894X/Ó 2017 Elsevier Ltd. All rights reserved. ⇑ Corresponding author. E-mail address: kamalav@perdcentre.com (K.K. Vasu). d Equal first authors. e Presently Department of Medicinal Chemistry, National Institute of Pharmaceu- tical Education and Research (NIPER)-Balanagar, Hyderabad 500037, India. 1 # Communication number: PERD 8550617 Bioorganic & Medicinal Chemistry Letters xxx (2017) xxx–xxx Contents lists available at ScienceDirect Bioorganic & Medicinal Chemistry Letters journal homepage: www.elsevier.com/locate/bmcl Please cite this article in press as: Vasu K.K., et al. Bioorg. Med. Chem. Lett. (2017), https://doi.org/10.1016/j.bmcl.2017.10.060