New N-(isoxazol-3-yl)-4-(1,3,4-thiadiazol-3(2H)-yl)benzenesulfonamide derivatives as potent Aurora kinases inhibitors: Design, synthesis and anti-proliferative activity
- Bioorg Chem. 2026 Sep 5:179:110027. doi: 10.1016/j.bioorg.2026.110027.
- 1. Department of Pharmaceutical Sciences, College of Pharmacy, Princess Nourah bint Abdulrahman University, P.O. Box 84428, Riyadh 11671, Saudi Arabia.
- 2. Pharmaceutical Medicinal Chemistry & Drug Design Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo 11884, Egypt. Electronic address: [email protected].
- 3. Department of Chemistry, Faculty of Science, Al-Azhar University, Nasr City, Cairo, Egypt.
- 4. Faculty of Pharmacy, Al-Azhar University, Cairo 11884, Egypt.
- 5. Pharmaceutical Medicinal Chemistry & Drug Design Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo 11884, Egypt.
- 6. Chemistry Department, Faculty of Science, New Valley University, El-Kharja 72511, Egypt.
- 7. Physics Department, Faculty of Science, Alexandria University, Alexandria, Egypt.
- 8. Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo 11884, Egypt. Electronic address: [email protected].
- 9. Pharmacognosy and Medicinal Plants Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo 11884, Egypt. Electronic address: [email protected].
A new series of seven N-(isoxazol-3-yl)-4-(1,3,4-thiadiazol-3(2H)-yl)benzenesulfonamide derivatives (22-28) was designed, synthesized, and biologically evaluated as potential dual Aurora Kinase A/B inhibitors. Cytotoxicity screening against MCF-7, PC-3, HepG-2, and HCT-116 cell lines revealed variable activities, with compound 25 emerging as the most potent derivative (IC50 = 7.72-9.51 μM) and exhibiting selective toxicity toward Cancer cells over normal WI-38 fibroblasts. Mechanistic studies demonstrated that compound 25 significantly reduced intracellular levels of Aurora A and Aurora B kinases in MCF-7 cells, decreasing Aurora A from 53.96 to 42.21 pg/mg protein and Aurora B from 63.84 to 36.48 pg/mg protein, with a more pronounced inhibition of Aurora B. Flow cytometric analysis revealed marked induction of G2/M phase arrest (46.10% vs 26.46% in control), indicating disruption of mitotic progression. In addition, compound 25 induced significant Apoptosis, increasing early and late apoptotic populations to 7.99% and 25.39%, respectively, accompanied by a substantial reduction in viable cells. This effect was further supported by activation of the intrinsic apoptotic pathway, as evidenced by a 7.6-fold increase in Caspase-3 expression, upregulation of Bax, and downregulation of Bcl-2.Computational analyses were performed to rationalize the observed biological behavior. DFT calculations confirmed the structural and electronic stability of compound 25. Molecular docking revealed that compound 25 binds strongly to Aurora A and B through key hydrogen-bonding and hydrophobic interactions within the ATP-binding site. Subsequent 100 ns MD simulations, MM-GBSA analyses, Pro-LIF profiling, and PCA of trajectories collectively confirmed the dynamic stability, thermodynamic favorability, and persistence of key interactions in the complexes. In silico ADME and toxicity assessments further indicated favorable pharmacokinetic properties and low predicted toxicity for compound 25. Collectively, the experimental and computational findings establish compound 25 as a promising dual Aurora Kinase A/B inhibitor, integrating potent antiproliferative activity with a mechanistically supported and computationally validated interaction profile, warranting further optimization and in vivo evaluation.
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Cat. No.Product NameDescriptionTargetResearch Area
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Research Areas: Cancer