Design, Synthesis, and Structure−Activity Relationship of a Novel Series of 2-Aryl 5-(4-Oxo-3-phenethyl-2-thioxothiazolidinylidenemethyl)furans as HIV-1 Entry Inhibitors

Abstract

We previously identified two small molecules targeting the HIV-1 gp41, N-(4-carboxy-3-hydroxy) phenyl-2,5-dimethylpyrrole 12 (NB-2) and N-(3-carboxy-4-chloro) phenylpyrrole 13 (NB-64) that inhibit HIV-1 infection at low μM level. Based on molecular docking analysis, we designed a series of 2-aryl 5-(4-oxo-3-phenethyl-2-thioxothiazolidinylidenemethyl)furans. Compared with 12 and 13, these compounds have bigger molecular size (437-515 Da) and could occupy more space in the deep hydrophobic pocket on the gp41 NHR-trimer. Fifteen 2-aryl 5-(4-oxo-3-phenethyl-2-thioxothiazolidinylidenemethyl)furans (11a-o) were synthesized by Suzuki-Miyaura cross coupling, followed by a Knoevenagel condensation and tested for their anti-HIV-1activity and cytotoxicity on MT-2 cells. We found that all 15 compounds had improved anti-HIV-1 activity and 3 of them (11a, 11b, and 11d) exhibited inhibitory activity against replication of HIV-1 IIIB and 94UG103 at <100 nM range, more than 20-fold more potent than 12 and 13, suggesting that these compounds can serve as leads for development of novel small molecule HIV fusion inhibitors.

High-Throughput HIV–Cell Fusion Assay for Discovery of Virus Entry Inhibitors

“…In the final 6-helix bundle structure (6HB), three HR1 and three HR2 coalesce forming a highly stable antiparallel helical bundle. A number of small-molecule inhibitors of HIV-1 fusion that interfere with CD4-induced conformational changes in gp120, 8,9 coreceptor binding, [10][11][12] and the gp41 6HB formation [13][14][15][16][17][18][19][20][21][22][23][24] have been identified by high-throughput screening (HTS). Currently, only two HIV-1 fusion inhibitors (enfuvirtide and maraviroc) have been approved for clinical use.…”

“…In vitro screening has identified competitive inhibitors of assembly of the gp41 HR1-and HR2-derived peptides into the 6HB. [13][14][15][16][17][18][19][20][21][22][23][24] HTS for smallmolecule inhibitors competing with the chemokine (RANTES) binding to CCR5 has led to the identification of identified coreceptor antagonists that effectively blocked fusion of CCR5-tropic viruses: maraviroc, Sch-C, and TAK-779. [10][11][12] These narrowly focused readouts provide a powerful means to identify specific inhibitors of a given step of the virus entry, but exclude all other targets for inhibition of HIV-1 fusion.…”

Introduction

“…1.2). 2-Thioxo-1,3-thiazolidine derivative 1 shows potent inhibition of HIV-1 replication at the nanomolar level [14,15], which is directed at the deep hydrophobic pocket in the N-terminal heptad repeat trimer of the viral gp41. Compound 1 blocks HIV-1-mediated cell-cell fusion and the formation of gp41 six-helix bundles, as does enfuvirtide [15].…”

Discovery and SAR of Thiazolidine-2,4-dione Analogues as Insulin-like Growth Factor-1 Receptor (IGF-1R) Inhibitors via Hierarchical Virtual Screening

“…10 Most recently, several TZD derivates have been reported as potent inhibitors of PI3Kγ, 11 Pim kinase family, 12 and HIV-1 entry protein gp41, 13 highlighting their versatile roles in multiple indications spanning from inflammatory diseases to cancers. However, to our knowledge, there are no public reports that identified TZDs as bearing potent inhibitory activity against IGF-1R except that some in vivo assays uncovered TZDs were involved in the process of IGF-1R pathway suppression.…”