Discovery of novel pyridazinylthioacetamides as potent HIV-1 NNRTIs using a structure-based bioisosterism approach

Yu’ning Song; Peng Zhan; Dongwei Kang; Xiao Li; Ye Tian; Zhenyu Li; Xuwang Chen; Wenmin Chen; Christophe Pannecouque; Erik De Clercq; Xinyong Liu

doi:10.1039/C3MD00028A

Discovery of novel pyridazinylthioacetamides as potent HIV-1 NNRTIs using a structure-based bioisosterism approach

Yu’ning Song,†^a Peng Zhan,†*^a Dongwei Kang,†^a Xiao Li,†^a Ye Tian,†^a Zhenyu Li,†^a Xuwang Chen,†^a Wenmin Chen,†^a Christophe Pannecouque,^b Erik De Clercq^b and Xinyong Liu †*^a

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* Corresponding authors

^a Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44, West Culture Road, Jinan, Shandong, P.R.China
E-mail: zhanpeng@sdu.edu.cn, xinyongl@sdu.edu.cn
Fax: +86 531 88382731
Tel: +86 531 88382005

^b Rega Institute for Medical Research, KU Leuven, Minderbroedersstraat 10, B-3000 Leuven, Belgium

Abstract

In continuation of our endeavors to develop new, potent, selective, and less toxic anti-HIV agents, we describe our structure-based bioisosterism design, synthetic strategy, and structure–activity relationship (SAR) studies that led to the identification of pyridazinylthioacetamides, a novel class of NNRTIs, isosteres of arylazolylthioacetanilide derivatives. Nearly all of the tested compounds inhibited HIV-1 strain IIIB replication in the lower micromolar concentration range (EC₅₀: 0.046–5.46 μM). Notably, the most promising compound 8k exhibited extremely potent inhibitory activity against HIV-1 replication with an EC₅₀ value of 0.046 μM, CC₅₀ of 99.9 μM and the viral selectivity index amounted to 2149. These values were much better than those of NVP (EC₅₀ = 0.09 μM) and DDC (EC₅₀ = 1.04 μM). Compound 8k also exhibited moderate inhibition of enzymatic activity with an IC₅₀ value of 4.06 μM, which was of the same order of magnitude as that of NVP (2.74 μM). Docking calculations were also performed to investigate the binding mode of compound 8k into the non-nucleoside binding site of HIV-1 RT and to rationalize some SARs.

MedChemComm

Discovery of novel pyridazinylthioacetamides as potent HIV-1 NNRTIs using a structure-based bioisosterism approach

Abstract

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Discovery of novel pyridazinylthioacetamides as potent HIV-1 NNRTIs using a structure-based bioisosterism approach

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