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Diaryl Pyrazoline, 1,3,4-Oxadizole, and 1,2,4-Triazole Pharmacophore Hybridization: Design, Synthesis, HDAC Inhibition, and Caspase 3/7 Activation Studies

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Abstract

Objective: The study aimed to employ the pharmacophore hybridization technique for the synthesis of novel anticancer compounds by combining the pyrazole moiety with 1,2,4-triazole and 1,3,4-oxadizaole moieties. Methods: Two series of compounds were synthesized, purified, and structurally characterized. The compounds were tested for HDAC inhibitory properties on HDAC4 and HDAC8 isoforms, with a focus on HDAC8 selectivity. Results: Among the synthesized derivatives, an intriguing HDAC8 selectivity was observed. Fourteen compounds were further evaluated for preliminary cytotoxicity across nine solid tumor cell lines. Compound (IXt) demonstrated notable activity against three cell lines. Detailed analysis revealed that caspase activation played a significant role in the cytotoxic effects of (IXt). Cell cycle analysis indicated disruption with decreased cell populations in S and G2/M phases. Discussion: The study underscores the potential of hybridizing diaryl pyrazolines with oxadiazole and triazole 5-membered heterocycles. The observed HDAC8 selectivity and significant cytotoxic effects, particularly with compound (IXt), suggest promising avenues for the development of novel anticancer leads. Conclusions: The hybridization strategy employed in this study, combining diaryl pyrazolines with specific heterocycles, presents a viable approach for the synthesis of anticancer compounds. The identified HDAC8 selectivity and cytotoxicity against multiple cell lines, especially with compound (IXt), warrant further exploration and development of these derivatives as potential anticancer agents.

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DATA AVAILABILITY

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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ACKNOWLEDGMENTS

The authors extend their appreciation to the Deanship of Scientific Research at King Khalid University for funding this work through the large group Research Project under grant number (RGP2/413/44).

Funding

Biological experiments were supported by the State Program of the Ministry of Science and Higher Education of the Russian Federation (no. 075-01551-23-00; FSSF2023-0006).

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Authors and Affiliations

  1. Department of Chemistry, Faculty of Science and Arts, King Khalid University, Mohail, 61421, Assir, Saudi Arabia

    Abdullah Yahya Abdullah Alzahrani

  2. Department of Pharmaceutical Chemistry, Bharati Vidyapeeth’s College of Pharmacy, 400614, Navi Mumbai, India

    Pratibha Gupta, Vijay Patil & C. S. Ramaa

  3. Department of Chemical Engineering and Biotechnology, University of Applied Sciences Darmstadt, 64295, Haardtring 100, Germany

    Franz-Josef Meyer-Almes

  4. Laboratory of Biochemical Fundamentals of Pharmacology and Cancer Models, N.N. Blokhin Cancer Research Center, 115478, Moscow, Russia

    D. V. Sokolova & V. S. Pokrovsky

  5. Department of Biochemistry, Laboratory of Experimental Oncology, Patrice Lumumba People’s Friendship University, 117198, Moscow, Russia

    D. V. Sokolova, D. V. Sokolova & V. S. Pokrovsky

Authors
  1. Abdullah Yahya Abdullah Alzahrani
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  7. C. S. Ramaa
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Contributions

The authors AYAA and PG—synthesized the compounds and done structural characterization. The author VP—contributed in the synthesis, writing and editing. The author F-JM-A—contributed in docking and HDAC activity. The authors DVS and TSS—contributed in the anticancer evaluation. The authord VSP and CSR—xontributed in data analysis and done supervision of the research study.

Corresponding authors

Correspondence to V. S. Pokrovsky or C. S. Ramaa.

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This article does not contain any studies involving patients or animals as test objects.

Informed consent was not required for this article. No conflict of interest was declared by the authors.

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Alzahrani, A.Y.A., Gupta, P., Patil, V. et al. Diaryl Pyrazoline, 1,3,4-Oxadizole, and 1,2,4-Triazole Pharmacophore Hybridization: Design, Synthesis, HDAC Inhibition, and Caspase 3/7 Activation Studies. Russ J Bioorg Chem 50, 375–391 (2024). https://doi.org/10.1134/S1068162024020389

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