Design, synthesis and biological evaluation of novel 5-fluoro-1H-benzimidazole-4-carboxamide derivatives as potent PARP-1 inhibitors

Junwei Wang; Xuyan Wang; Hui Li; Dezhong Ji; Yuyan Li; Yungen Xu; Qihua Zhu

doi:10.1016/j.bmcl.2016.06.045

Design, synthesis and biological evaluation of novel 5-fluoro-1H-benzimidazole-4-carboxamide derivatives as potent PARP-1 inhibitors

Bioorg Med Chem Lett. 2016 Aug 15;26(16):4127-32. doi: 10.1016/j.bmcl.2016.06.045. Epub 2016 Jun 16.

Authors

Junwei Wang¹, Xuyan Wang², Hui Li³, Dezhong Ji³, Yuyan Li², Yungen Xu¹, Qihua Zhu¹

Affiliations

¹ Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China; Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, China.
² Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, China.
³ Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China.

PMID: 27353531
DOI: 10.1016/j.bmcl.2016.06.045

Abstract

A series of novel 5-fluorine-benzimidazole-4-carboxamide analogs were designed and synthesized. All target compounds were evaluated for their PARP-1 inhibitory activity. Compounds possessed high intrinsic PARP-1 inhibitory potency have been evaluated in vitro cellular assays to measure the potentiation effect of cytotoxic agents against cancer cell line. These efforts led to the identification of compound 10f, which displayed strong inhibition against the PARP-1 enzyme with an IC50 of 43.7nM, excellent cell inhibitory activity in HCT116 cells (IC50=7.4μM) and potentiation of temozolomide cytotoxicity in cancer cell line A549 (PF50=1.6).

Keywords: Antitumor; Benzimidazole; Fluorine atom; Inhibitors; PARP-1.

MeSH terms

A549 Cells
Amides / chemical synthesis
Amides / chemistry*
Amides / toxicity
Antineoplastic Agents / chemical synthesis*
Antineoplastic Agents / chemistry
Antineoplastic Agents / toxicity
Benzimidazoles / chemical synthesis*
Benzimidazoles / chemistry*
Benzimidazoles / toxicity
Binding Sites
Cell Survival / drug effects
Dacarbazine / analogs & derivatives
Dacarbazine / toxicity
Drug Design*
Enzyme Inhibitors / chemical synthesis*
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / toxicity
HCT116 Cells
Humans
Molecular Docking Simulation
Poly (ADP-Ribose) Polymerase-1 / antagonists & inhibitors*
Poly (ADP-Ribose) Polymerase-1 / metabolism
Protein Binding
Protein Structure, Tertiary
Structure-Activity Relationship
Temozolomide

Substances

5-fluoro-1H-benzimidazole-4-carboxamide
Amides
Antineoplastic Agents
Benzimidazoles
Enzyme Inhibitors
Dacarbazine
benzimidazole
Poly (ADP-Ribose) Polymerase-1
Temozolomide