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
  • 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: [email protected].
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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