Synthesis and Evaluation of Bifunctional Aminothiazoles as Antiretrovirals Targeting the HIV-1 Nucleocapsid Protein

被引：9

作者：

Mori, Mattia ^{[1
]}

Lang, Maria Chiara Dasso ^{[1
]}

Saladini, Francesco ^{[2
]}

Palombi, Nastasja ^{[1
]}

Kovalenko, Lesia ^{[3
]}

De Forni, Davide ^{[4
]}

Poddesu, Barbara ^{[4
]}

Friggeri, Laura ^{[1
]}

Giannini, Alessia ^{[2
]}

Malancona, Savina ^{[5
]}

Summa, Vincenzo ^{[5
]}

Zazzi, Maurizio ^{[2
]}

Mely, Yves ^{[3
]}

Botta, Maurizio ^{[1
,6
,7
]}

机构：

[1] Univ Siena, Dept Excellence 2018 2022, Dept Biotechnol Chem & Pharm, Via Aldo Moro 2, I-53100 Siena, Italy

[2] Univ Siena, Dept Med Biotechnol, Viale Mario Bracci 16, I-53100 Siena, Italy

[3] Univ Strasbourg, CNRS, Fac Pharm, Lab Bioimagerie & Pathol,UMR 7021, 74 Route Rhin, F-67401 Illkirch Graffenstaden, France

[4] ViroStat Srl, Viale Umberto I 46, I-07100 Sassari, Italy

[5] IRBM Sci Pk SpA, Via Pontina Km 30-600, I-00071 Pomezia, RM, Italy

[6] Temple Univ, Coll Sci & Technol, Ctr Biotechnol, Sbarro Inst Canc Res & Mol Med, BioLife Sci Bldg,Suite 333,1900 N 12th St, Philadelphia, PA 19122 USA

[7] Lead Discovery Siena Srl, Vittorio Alfieri 31, I-53019 Castelnuovo, Berardenga, Italy

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2019年 / 10卷 / 04期

关键词：

Nucleocapsid protein; HIV; NC inhibitors; aminothiazole; drug resistance; antiretroviral; STRUCTURAL-CHARACTERIZATION; PROVIRAL DNA; IDENTIFICATION; INHIBITION; BINDING; RECOGNITION; COMPLEX; TAR;

D O I：

10.1021/acsmedchemlett.8b00506

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Small molecule inhibitors of the HIV-1 nucleocapsid protein (NC) are considered as promising agents in the treatment of HIV/AIDS. In an effort to exploit the privileged 2-amino-4-phenylthiazole moiety in NC inhibition, here we conceived, synthesized, and tested in vitro 18 NC inhibitors (NCIs) bearing a double functionalization. In these NCIs, one part of the molecule is deputed to interact noncovalently with the NC hydrophobic pocket, while the second portion is designed to interact with the N-terminal domain of NC. This binding hypothesis was verified by molecular dynamics simulations, while the linkage between these two pharmacophores was found to enhance antiretroviral activity both on the wild-type virus and on HIV-1 strains with resistance to currently licensed drugs. The two most interesting compounds 6 and 13 showed no cytotoxicity, thus becoming valuable leads for further investigations.

引用

页码：463 / 468

页数：11

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