2. Academic Validation
  3. Design, synthesis, and structure-activity relationships of five-membered heterocyclic incorporated aryl(alkyl)azoles: From antiproliferative thiazoles to safer anticonvulsant oxadiazoles

Design, synthesis, and structure-activity relationships of five-membered heterocyclic incorporated aryl(alkyl)azoles: From antiproliferative thiazoles to safer anticonvulsant oxadiazoles

  • Bioorg Chem. 2025 Feb:155:108117. doi: 10.1016/j.bioorg.2024.108117.
Mehdi Valipour 1,  Majid Ghasemian 2,  Saeed Karima 3,  Zahra Zakeri Khatir 4,  Helia Aghamiri 5,  Fatemeh Shaki 6,  Sholeh Akbari 6,  Fereshteh Talebpour Amiri 7,  Asieh Hosseini 1,  Majid Jafari-Sabet 8,  Hamid Irannejad 9,  Saeed Emami 10
Affiliations

Affiliations

  • 1 Razi Drug Research Center, Iran University of Medical Sciences, Tehran, Iran.
  • 2 Department of Clinical Biochemistry, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.
  • 3 Department of Clinical Biochemistry, School of Medicine, Shahid Beheshti University of Medical Sciences (SBMU), Tehran, Iran.
  • 4 Department of Medicinal Chemistry, Faculty of Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran.
  • 5 Department of Pharmacology and Toxicology, School of Pharmacy, Iran University of Medical sciences, Tehran, Iran.
  • 6 Department of Toxicology and Pharmacology, Faculty of Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran.
  • 7 Department of Anatomy, Faculty of Medicine, Molecular and Cell Biology Research Center, Mazandaran University of Medical Sciences, Sari, Iran.
  • 8 Razi Drug Research Center, Iran University of Medical Sciences, Tehran, Iran; Department of Pharmacology, School of Medicine, Iran University of Medical Sciences (IUMS), Tehran, Iran.
  • 9 Department of Medicinal Chemistry, Faculty of Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran. Electronic address: irannejadhamid@gmail.com.
  • 10 Department of Medicinal Chemistry, Faculty of Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran. Electronic address: semami@mazums.ac.ir.
PMID: 39778269 DOI: 10.1016/j.bioorg.2024.108117
Abstract

In the current study, a novel series of 1,2,4-oxadiazoles were designed, synthesized, and evaluated for their biological activities. A cell-based antiproliferative screening was accomplished on the newly synthesized 1,2,4-oxadiazoles along with our previously reported aryl(alkyl)azoles (AAAs) containing middle heterocyclic cores thiazole and oxazole. Among the tested compounds, naphthyl- thiazoles demonstrated higher antiproliferative activity and B3 was identified as the most potent compound with IC50 values in the range of 2.03-3.6 µM against SH-SY5Y neuroblastoma, HT-29 colorectal adenocarcinoma, and fibroblast cells (ten folds more potent than 5-FU and irinotecan). Further investigation revealed that B3 strongly inhibits tubulin polymerization with an IC50 of 0.79 µM, outperforming the reference drug colchicine (IC50 = 1.46 µM). In addition, evaluation of B3 on the expression level of Bax, BCL2, and CYCLIN D1 genes indicated the suppression of the cell cycle in the genome level. Interestingly, the 1,2,4-oxadiazole congeners displayed optimal anticonvulsant activity with significantly reduced cytotoxicity. Among the oxadiazole series, compound D4 featuring a 1,2,4-triazole head group demonstrated the highest activity in the maximal electroshock (MES) and pentylenetetrazol (PTZ) tests, with ED50 values of 2.23 and 24.60 mg/kg, respectively. In vivo evaluations suggested that D4 exerts its anticonvulsant effects by enhancing GABAA currents. In conclusion, our findings indicated that B3 in the thiazole congeners is a promising drug candidate for Cancer treatment with a well-defined mechanism of action. Moreover, D4 and its congeners containing oxadiazole core are much safer anti-seizures which have potential for preclinical considerations as novel anticonvulsants.

Keywords

Apoptosis; Convulsion; Oxadiazole; Oxazole; Thiazole; Tubulin polymerization.

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