2. Academic Validation
  3. Structure-activity relationship studies on 2-thienylidene substituted 3-oxo-2,3-dihydrobenzofuran-7-carboxamides as poly (ADP-ribose) polymerase inhibitors

Structure-activity relationship studies on 2-thienylidene substituted 3-oxo-2,3-dihydrobenzofuran-7-carboxamides as poly (ADP-ribose) polymerase inhibitors

  • Bioorg Chem. 2025 Sep 5:165:108941. doi: 10.1016/j.bioorg.2025.108941.
Abosede Salami 1,  Ugochi Adiele 1,  Griffin Coate 1,  Morgan Diolaiti 2,  Huadong Chen 2,  Junhao Lu 2,  Alan Ashworth 3,  Manisha Patil 1,  Joshua S Fleishman 1,  Andhavaram Ramaraju 1,  Akanksha Patel 1,  Himaxi Patel 1,  Ketankumar Patel 1,  Megumi Murakami 4,  Suresh V Ambudkar 4,  Tanaji T Talele 5
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, New York 11439, United States.
  • 2 UCSF Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, California 94158, United States.
  • 3 UCSF Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, California 94158, United States; Department of Medicine, University of California, San Francisco, California 94158, United States.
  • 4 Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, MD 20892, United States.
  • 5 Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, New York 11439, United States. Electronic address: talelet@stjohns.edu.
PMID: 40945025 DOI: 10.1016/j.bioorg.2025.108941
Abstract

A series of 2-thienylidene substituted 3-oxo-2,3-dihydrobenzofuran-7-carboxamide derivatives was synthesized and evaluated to investigate structure-activity relationship for inhibiting PARP1 enzyme activity. These efforts led to the identification of a new isosteric lead compound 2, (Z)-5-((7-carbamoyl-3-oxobenzofuran-2(3H)-ylidene)methyl) thiophene-2-carboxylic acid (PARP1 IC50 = 20 nM). Subsequently, the pendant carboxyl group of 2 was coupled with several amines to access adenine binding pocket (ABP) of PARP1 active site. Among the resulting analogs, several derivatives with a structural diversity in PARP1 ABP binding motifs showed PARP1 IC50 values in the range of 17 nM - 640 nM. These derivatives also showed improved cellular inhibition of PARylation compared to lead 2. Collectively, PARP1 ABP binding moieties such as (R)-3-aminoquinuclidine in 9, 1-methylspiro[indoline-3,3'-piperidin]-2-one in 11 and benzimidazole in 13 and 15 were favorable and thus these derivatives will serve as refined leads for future SAR optimization.

Keywords

3-oxo-2,3-dihydrobenzofuran-7-carboxamide; ABC transporters; Docking; In vitro ADME; Knoevenagel condensation; PARP1; PARylation; Thienylidene.

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