Novel 1H-pyrrolo[2,3-b]pyridine sulfonamide analogues: Design, synthesis, in-vitro anticancer and molecular docking studies

• Published in: Journal of molecular structure 2025-02, Vol.1322, p.140319, Article 140319
• Main Authors: Mothe, Thirupathi, Konkala, Veera Swamy, Gopala, Sridhar Goud, Lingala, Arun Kumar, Murahari, Kiran Kumar, Desireddi, Janardana Reddi, Manchal, Ravinder
• Format: Article
• Language: English
• Subjects: 1-(arylsulfonyl)-4-(4-methylpiperazin-1-yl)- 1H-pyrrolo[2,3-b]pyridine; 1-(arylsulfonyl)-4-morpholino-1H-pyrrolo[2,3-b]pyridine; 1H-pyrrolo[2,3-b]pyridine; Anticancer activity; Breast cancer; Lung cancer; Molecular docking; Sulfonamides
• ISSN: 0022-2860
• DOI: 10.1016/j.molstruc.2024.140319

•We have designed and synthesized a novel pyrrolo[2,3-b] pyridine derivatives.•The synthesized compounds were tested against MCF-7 breast cancer cell lines and A549 lung cancer cell lines.•The synthesized compounds were shown good to moderate activity against the MCF-7 & A-549 cell lines.•The IC50 values of tested compounds against the MCF-7 & A-549 cell lines ranged from 22.3 ± 0.1 to 141.2 ± 0.5 µg/mL and 24.4 ± 0.2 to >200 µg/mL.•6 g and 7f exhibited significant in vitro cytotoxic effects with IC50 values of 22.3 ± 0.1 µg/mL, 31.4 ± 0.5 µg/mL against MCF-7 breast cancer cell lines and 24.4 ± 0.2 µg/mL and 36.3 ± 0.1 µg/mL against A549 lung cancer cell lines respectively. In this current article, we have been reported a novel series of 1-(arylsulfonyl)-4-morpholino-1H-pyrrolo[2,3-b]pyridine (6 a-h) and 1-(arylsulfonyl)-4-(4-methylpiperazin-1-yl)-1H-pyrrolo[2,3-b]pyridine (7 a-g). The synthesized compounds were characterized by their 1H NMR, 13C NMR, LCMS and HRMS spectral data. These compounds were screened for their in-vitro biological studies against two types of cancer cell lines namely, MCF-7 breast cancer cell lines and A549 lung cancer cell line. All the synthesized compounds showed good to moderate cytotoxicity. The activity ranged from the IC50 22.3 ± 0.1 μg/mL to 141.2 ± 0.5 against the breast cancer cell line MCF-7 whereas, the IC50 values ranged 24.4 ± 0.2 μg/mL to >200±0.1 μg/mL with lung cancer cell line A549. Broadly, morpholine-substituted compounds such as 6a-h showed better activity than N-methyl piperazine compounds 7 a-g. The data revealed that compounds 6 g and 7f exhibited significant in vitro cytotoxic effects with IC50 values of 22.3 ± 0.1 µg/mL, 31.4 ± 0.5 µg/mL against breast cancer MCF-7 cell line and 24.4 ± 0.2 µg/mL & 36.3±µg/mL against A549 cancer cell line. Furthermore, computational studies were conducted for 6 g and 7f using EGFR (PDB ID-4HJO), and compound 6 g possessing the high binding energy (-10.83 kcal/mol) due to the establishment of two hydrogen bonds with LYS721 and PHE832 residues. Whereas compound 7f exhibited a good binding energy of -8.60 kcal/mol due to the formation of one hydrogen bond with TYR867. Finally, the molecular properties of the designed compounds were calculated using Swiss ADME software. Many of them obey the rule of 5 with good properties. [Display omitted]