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Design, synthesis and biological evaluation of Novel 1H-benzo[d]imidazole derivatives as Fatty Acid Synthase (FASN) inhibitors for cancer treatment
* 1 , 2 , 1 , 3 , 2 , 1
1  Department of Pharmacy, Indira Gandhi National Tribal University, Lalpur, Amarkantak (MP)-484887, India
2  School of Biotechnology, KIIT University, Campus-11, Patia, Bhubaneswar, Orissa-751024, India
3  LAQV, REQUIMTE, Departamento de Química e Bioquímica, Faculdade de Ciências, Universidade do Porto, Rua do Campo Alegre s/n, 4169-007 Porto, Portugal
Academic Editor: Alfredo Berzal-Herranz


FASN a metabolic oncoprotein overexpressed in multiple cancer and regulates the fatty acid requirement for proliferated cells. Thus, FASN has been proposed as a promising novel target for anticancer drug discovery. Herein we report the de-novo design and synthesis of small molecule FASN inhibitors (CTL) targeting breast and colorectal cancer. The structure-activity relationship studies led to identify CTL-1 and CTL-7 as potent, selective FASN inhibitors had an IC50 2.5 and 3.0 µM. The CTL-1 and CTL-7 inhibits proliferation of colon cell (with IC50 range of 3-5 µM) in HCT-116, CaCO2 and breast cells MCF-7, MDA-MB-231. However, in non-cancerous cell line HEK-293 the IC50 of CTL-1 and CTL-7 was above 30 µM. Further cell cycle analysis and apoptosis assay of CTL-1 and CTL-7 in HCT-116 cells represents S-phase arrest along with prolong apoptotic effect. The western blot analysis of CTL-1 and CTL-7 establish the FASN pathway participation in causing cell apoptosis. The molecular dynamics simulation studies indicate the high affinity of CTL-1 and CTL-7 against the FASN enzyme.

Keywords: Fatty acid synthase inhibitor, cancer, apoptosis, cell cycle, enzyme inhibition, MD simulation