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Article

N-Benzyl-6-Chloro-4-Hydroxy-2-Quinolone-3-Carboxamides: Synthesis, Computational Studies, and Biological Investigation as Anticancer Agents

by
Sara Jamal Meknas
1,
Eveen Al-Shalabi
1,
Rima Hajjo
1,2,3,
Sanaa K. Bardaweel
4,
Ghassan Abushaikha
5,
Kamal Sweidan
6,
Swapnaa Balaji
7,
Amit K. Tiwari
7,
Haizhen A. Zhong
8 and
Dima A. Sabbah
1,*
1
Department of Pharmacy, Faculty of Pharmacy, Al-Zaytoonah University of Jordan, Amman 11733, Jordan
2
Laboratory for Molecular Modeling, Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
3
National Center for Epidemics and Communicable Disease Control (JCDC), Amman 11183, Jordan
4
Department of Pharmaceutical Sciences, School of Pharmacy, University of Jordan, Amman 11942, Jordan
5
Department of Medicinal and Biological Chemistry, College of Pharmacy and Pharmaceutical Sciences, University of Toledo, Toledo, OH 43606, USA
6
Department of Chemistry, The University of Jordan, Amman 11942, Jordan
7
Department of Pharmacology and Experimental Therapeutics, College of Pharmacy and Pharmaceutical Sciences, University of Toledo, Toledo, OH 43614, USA
8
DSC 309, Department of Chemistry, The University of Nebraska at Omaha, Omaha, NE 68182, USA
*
Author to whom correspondence should be addressed.
Molecules 2026, 31(4), 655; https://doi.org/10.3390/molecules31040655
Submission received: 29 December 2025 / Revised: 9 February 2026 / Accepted: 10 February 2026 / Published: 13 February 2026
(This article belongs to the Special Issue Novel Heterocyclic Compounds: Synthesis and Applications)
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Abstract

Cancer remains the second leading cause of death worldwide, highlighting the urgent need for novel therapeutic agents. In this work, twenty derivatives of N-benzyl-6-chloro-4-hydroxy-2-quinolone-3-carboxamides were synthesized and spectroscopically analyzed using FT-IR, NMR (1H and 13C), and elemental analysis. Substitution of benzyl moiety with o-CH3 (8), p-OCH3 (10), m-CH3 (18), p-CH3 (19), and p-CF3 (21) demonstrated three-fold distinct cytotoxicity against human colon cancer (HCT-116) cells with IC50s of 72.0, 100.0–112.0 µM. The cheminformatics calculations disclosed that the analogues possess diverse physicochemical properties and invariable predictions across six drug-likeness scoring models, supporting their potential cytotoxicity profile against colorectal cancer cell lines (Caco-2 and HCT-116). The docking studies against both wild-type and mutant PI3Kα clarified binding interactions, implying that particular functionalities improve efficacy and selectivity. This study provides further evidence for the therapeutic promise of quinolones in targeting cancer-specific pathways and expedites the process for developing potent anticancer agents.
Keywords: anticancer agents; cheminformatics; HCT-116; PC-3; pathway analysis; N-benzyl-6-chloro-4-hydroxy-2-quinolone-3-carboxamide anticancer agents; cheminformatics; HCT-116; PC-3; pathway analysis; N-benzyl-6-chloro-4-hydroxy-2-quinolone-3-carboxamide
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MDPI and ACS Style

Meknas, S.J.; Al-Shalabi, E.; Hajjo, R.; Bardaweel, S.K.; Abushaikha, G.; Sweidan, K.; Balaji, S.; Tiwari, A.K.; Zhong, H.A.; Sabbah, D.A. N-Benzyl-6-Chloro-4-Hydroxy-2-Quinolone-3-Carboxamides: Synthesis, Computational Studies, and Biological Investigation as Anticancer Agents. Molecules 2026, 31, 655. https://doi.org/10.3390/molecules31040655

AMA Style

Meknas SJ, Al-Shalabi E, Hajjo R, Bardaweel SK, Abushaikha G, Sweidan K, Balaji S, Tiwari AK, Zhong HA, Sabbah DA. N-Benzyl-6-Chloro-4-Hydroxy-2-Quinolone-3-Carboxamides: Synthesis, Computational Studies, and Biological Investigation as Anticancer Agents. Molecules. 2026; 31(4):655. https://doi.org/10.3390/molecules31040655

Chicago/Turabian Style

Meknas, Sara Jamal, Eveen Al-Shalabi, Rima Hajjo, Sanaa K. Bardaweel, Ghassan Abushaikha, Kamal Sweidan, Swapnaa Balaji, Amit K. Tiwari, Haizhen A. Zhong, and Dima A. Sabbah. 2026. "N-Benzyl-6-Chloro-4-Hydroxy-2-Quinolone-3-Carboxamides: Synthesis, Computational Studies, and Biological Investigation as Anticancer Agents" Molecules 31, no. 4: 655. https://doi.org/10.3390/molecules31040655

APA Style

Meknas, S. J., Al-Shalabi, E., Hajjo, R., Bardaweel, S. K., Abushaikha, G., Sweidan, K., Balaji, S., Tiwari, A. K., Zhong, H. A., & Sabbah, D. A. (2026). N-Benzyl-6-Chloro-4-Hydroxy-2-Quinolone-3-Carboxamides: Synthesis, Computational Studies, and Biological Investigation as Anticancer Agents. Molecules, 31(4), 655. https://doi.org/10.3390/molecules31040655

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