2. Academic Validation
  3. Exploiting the Tolerant Region I of the Non-Nucleoside Reverse Transcriptase Inhibitor (NNRTI) Binding Pocket: Discovery of Potent Diarylpyrimidine-Typed HIV-1 NNRTIs against Wild-Type and E138K Mutant Virus with Significantly Improved Water Solubility and Favorable Safety Profiles

Exploiting the Tolerant Region I of the Non-Nucleoside Reverse Transcriptase Inhibitor (NNRTI) Binding Pocket: Discovery of Potent Diarylpyrimidine-Typed HIV-1 NNRTIs against Wild-Type and E138K Mutant Virus with Significantly Improved Water Solubility and Favorable Safety Profiles

  • J Med Chem. 2019 Feb 28;62(4):2083-2098. doi: 10.1021/acs.jmedchem.8b01729.
Boshi Huang 1,  Wenmin Chen 1,  Tong Zhao 1,  Zhenyu Li 2,  Xiangyi Jiang 1,  Tiziana Ginex 3,  David Vílchez 3,  Francisco Javier Luque 3,  Dongwei Kang 1,  Ping Gao 1,  Jian Zhang 1,  Ye Tian 1,  Dirk Daelemans 4,  Erik De Clercq 4,  Christophe Pannecouque 4,  Peng Zhan 1,  Xinyong Liu 1
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences , Shandong University , 44 West Culture Road , 250012 Jinan , Shandong , PR China.
  • 2 Department of Pharmacy , Shandong Provincial Hospital Affiliated to Shandong University , Jinan 250021 Shandong , China.
  • 3 Department of Nutrition, Food Science and Gastronomy, Faculty of Pharmacy, Campus Torribera, Institute of Biomedicine (IBUB) and Institute of Theoretical and Computational Chemistry (IQTCUB) , University of Barcelona , 08921 Santa Coloma de Gramenet , Spain.
  • 4 Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy , K.U. Leuven , Herestraat 49 Postbus 1043 (09.A097) , B-3000 Leuven , Belgium.
PMID: 30721060 DOI: 10.1021/acs.jmedchem.8b01729
Abstract

Diarylpyrimidine derivatives (DAPYs) exhibit robust anti-HIV-1 potency, although they have been compromised by E138K variant and severe side-effects and been suffering from poor water solubility. In the present work, hydrophilic morpholine or methylsulfonyl and sulfamide-substituted piperazine/piperidines were introduced into the right wing of DAPYs targeting the solvent-exposed tolerant region I. The anti-HIV-1 activities of 11c (EC50(WT) = 0.0035 μM, EC50(E138K) = 0.0075 μM) were the same as and 2-fold better than that of the lead etravirine against the wild-type and E138K mutant HIV-1, respectively, with a relative low cytotoxicity (CC50 ≥ 173 μM). Further test showed a significant improvement in the water solubility of 11c. Besides, 11c displayed no significant inhibition on main Cytochrome P450 enzymes and exhibited no acute/subacute toxicities at doses of 2000 mg·kg-1/50 mg·kg-1 in mice. Taken together, we consider that 11c is a promising lead for further structural optimization.

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