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. 2025 Oct:165:108941.
doi: 10.1016/j.bioorg.2025.108941. Epub 2025 Sep 5.

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

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

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

Abosede Salami et al. Bioorg Chem. 2025 Oct.

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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Conflict of interest statement

Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: TTT is a co-founder of Hysplex, Inc., with interests in PARP inhibitor development. A.A. is a co-founder of Azkarra Therapeutics, Kytarro, Ovibio Corporation, Tango Therapeutics, Tiller Tx, a member of the board of Cambridge Science Corporation, Cytomx, a member of the scientific advisory board of Ambagon, Bluestar/Clearnote Health, Circle, Genentech, GLAdiator, HAP10, Earli, ORIC, Phoenix Molecular Designs, Trial Library, Yingli/280Bio; a consultant for Next RNA, Novartis and ProLynx; and holds patents on the use of PARP inhibitors held jointly with AstraZeneca from which he has benefited financially (and may do so in the future). The other authors declare no competing financial interest.

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