Design and Synthesis of Novel HIV-1 NNRTIs with Bicyclic Cores and with Improved Physicochemical Properties

0568174 - ÚOCHB 2024 RIV US eng J - Journal Article
Prener, Ladislav - Baszczyňski, Ondřej - Kaiser, Martin Maxmilian - Dračínský, Martin - Stepan, G. - Lee, Y. J. - Brumshtein, B. - Yu, H. - Jansa, P. - Lansdon, E. B. - Janeba, Zlatko
Design and Synthesis of Novel HIV-1 NNRTIs with Bicyclic Cores and with Improved Physicochemical Properties.
Journal of Medicinal Chemistry. Roč. 66, č. 3 (2023), s. 1761-1777. ISSN 0022-2623. E-ISSN 1520-4804
Institutional support: RVO:61388963
Keywords : reverse transcriptase inhibitors * wild type * optimization
OECD category: Organic chemistry
Impact factor: 7.3, year: 2022
Method of publishing: Open access
https://doi.org/10.1021/acs.jmedchem.2c01574

Non-nucleoside reverse transcriptase inhibitors (NNRTIs) represent cornerstones of current regimens for treatment of human immunodeficiency virus type 1 (HIV-1) infections. However, NNRTIs usually suffer from low aqueous solubility and the emergence of resistant viral strains. In the present work, novel bicyclic NNRTIs derived from etravirine (ETV) and rilpivirine (RPV), bearing modified purine, tetrahydropteridine, and pyrimidodiazepine cores, were designed and prepared. Compounds 2, 4, and 6 carrying the acrylonitrile moiety displayed single-digit nanomolar activities against the wild-type (WT) virus (EC50 = 2.5, 2.7, and 3.0 nM, respectively), where the low nanomolar activity was retained against HXB2 (EC50 = 2.2-2.8 nM) and the K103N and Y181C mutated strains (fold change, 1.2-6.7×). Most importantly, compound 2 exhibited significantly improved phosphate-buffered saline solubility (10.4 μM) compared to ETV and RPV (≪1 μM). Additionally, the binding modes of compounds 2, 4, and 6 to the reverse transcriptase were studied by X-ray crystallography.
Permanent Link: https://hdl.handle.net/11104/0339509


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