Design and Synthesis of Novel Bis-Imidazolyl Phenyl Butadiyne Derivatives as HCV NS5A Inhibitors

Hamdy, Jehad; Emadeldin, Nouran; Hamed, Mostafa M.; Frakolaki, Efseveia; Katsamakas, Sotirios; Vassilaki, Niki; Zoidis, Grigoris; Hirsch, Anna K. H.; Abdel-Halim, Mohammad; Abadi, Ashraf H.

doi:10.3390/ph15050632

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Design and Synthesis of Novel Bis-Imidazolyl Phenyl Butadiyne Derivatives as HCV NS5A Inhibitors

Jehad Hamdy

^1,†,

Nouran Emadeldin

^1,†,

Mostafa M. Hamed

², Efseveia Frakolaki^3,‡,

⁴

^4,*

^2,5

^1,*

and

Ashraf H. Abadi

^1,*

Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo 11835, Egypt

Drug Design and Optimization, Helmholtz Institute for Pharmaceutical Research Saarland (HIPS)—Helmholtz Centre for Infection Research (HZI), Campus E8.1, 66123 Saarbrücken, Germany

Molecular Virology Laboratory, Department of Microbiology, Hellenic Pasteur Institute, Vas. Sofias Avenue, 11521 Athens, Greece

⁴

Division of Pharmaceutical Chemistry, Department of Pharmacy, School of Health Sciences, National and Kapodistrian University of Athens, Panepistimiopolis-Zografou, 15771 Athens, Greece

⁵

Department of Pharmacy, Saarland University, Campus E8.1, 66123 Saarbrücken, Germany

Authors to whom correspondence should be addressed.

^†

These authors contributed equally to this work.

^‡

This manuscript is dedicated to the memory of our dear colleague and co-author Efseveia Frakolaki, who passed away while the manuscript was in preparation.

Academic Editor: Serena Massari

Pharmaceuticals 2022, 15(5), 632; https://doi.org/10.3390/ph15050632

Received: 28 February 2022 / Revised: 8 May 2022 / Accepted: 12 May 2022 / Published: 20 May 2022

(This article belongs to the Special Issue Antiviral Drugs 2021)

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Abstract

In today’s global plan to completely eradicate hepatitis C virus (HCV), the essential list of medications used for HCV treatment are direct-acting antivirals (DAAs), as interferon-sparing regimens have become the standard-of-care (SOC) treatment. HCV nonstructural protein 5A (NS5A) inhibitors are a very common component of these regimens. Food and Drug Administration (FDA)-approved NS5A inhibitors, although very potent, do not have the same potency against all eight genotypes of HCV. Therefore, this study aims to synthesize NS5A inhibitor analogues with high potency pan-genotypic activity and high metabolic stability. Starting from an NS5A inhibitor scaffold previously identified by our research group, we made several modifications. Two series of compounds were created to test the effect of changing the length and spatial conformation (para-para vs. meta-meta-positioned bis-imidazole-proline-carbamate), replacing amide groups in the linker with imidazole groups, as well as different end-cap compositions and sizes. The frontrunner inhibits genotype 1b (Con1) replicon, with an EC₅₀ value in the picomolar range, and showed high genotypic coverage with nanomolar range EC₅₀ values against four more genotypes. This together with its high metabolic stability (t½ > 120 min) makes it a potential preclinical candidate. View Full-Text

Keywords: direct-acting antivirals; NS5A inhibitors; HCV antivirals; pan-genotypic activity; Gt1b molecular docking; diphenyldiyne core

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MDPI and ACS Style

Hamdy, J.; Emadeldin, N.; Hamed, M.M.; Frakolaki, E.; Katsamakas, S.; Vassilaki, N.; Zoidis, G.; Hirsch, A.K.H.; Abdel-Halim, M.; Abadi, A.H. Design and Synthesis of Novel Bis-Imidazolyl Phenyl Butadiyne Derivatives as HCV NS5A Inhibitors. Pharmaceuticals 2022, 15, 632. https://doi.org/10.3390/ph15050632

AMA Style

Hamdy J, Emadeldin N, Hamed MM, Frakolaki E, Katsamakas S, Vassilaki N, Zoidis G, Hirsch AKH, Abdel-Halim M, Abadi AH. Design and Synthesis of Novel Bis-Imidazolyl Phenyl Butadiyne Derivatives as HCV NS5A Inhibitors. Pharmaceuticals. 2022; 15(5):632. https://doi.org/10.3390/ph15050632

Chicago/Turabian Style

Hamdy, Jehad, Nouran Emadeldin, Mostafa M. Hamed, Efseveia Frakolaki, Sotirios Katsamakas, Niki Vassilaki, Grigoris Zoidis, Anna K.H. Hirsch, Mohammad Abdel-Halim, and Ashraf H. Abadi. 2022. "Design and Synthesis of Novel Bis-Imidazolyl Phenyl Butadiyne Derivatives as HCV NS5A Inhibitors" Pharmaceuticals 15, no. 5: 632. https://doi.org/10.3390/ph15050632

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Design and Synthesis of Novel Bis-Imidazolyl Phenyl Butadiyne Derivatives as HCV NS5A Inhibitors

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