Design, Synthesis, and Biological Activity of Novel 5-((Arylfuran/1<i>H</i>-pyrrol-2-yl)methylene)-2-thioxo-3-(3-(trifluoromethyl)phenyl)thiazolidin-4-ones as HIV-1 Fusion Inhibitors Targeting gp41

“…arylfurans include numerous compounds exhibiting interesting biological and pharmacological activities. [13] For instance, the 2-arylfuran derivative 1 (dantrolene) ( Figure 1) is a muscle relaxant commonly used for the treatment of life-threatening complications during anesthesia; [14] compound 2 ( Figure 1) effectively inhibits infection by both laboratory-adapted and primary HIV-1 strains and blocks HIV-1 mediated cell-cell fusion and gp41 six-helix bundle formation; [15] azofuran 3 ( Figure 1) possesses significant activity against cancer cells without affecting the lymphocyte proliferation in human peripheral blood mononuclear cells; [16] the 3-substituted (5-arylfuran-2-ylcarbonyl)-guanidine 4 ( Figure 1) exhibits high Na + /H + exchange isoform-1 inhibitory activity; [17] and bioymifi (5) (Figure 1) is a compound that binds to the extracellular domain of the DR 5 receptors and induces their aggregation. [18] In 2009, Doucet and co-workers reported that 2-butyl-5-arylfurans could be selectively prepared by the reaction of 2 equiv.…”

Section: A C H T U N G T R E N N U N G (Hetero)arylation Of Furan Andmentioning

confidence: 99%

Cross‐Coupling of Heteroarenes by CH Functionalization: Recent Progress towards Direct Arylation and Heteroarylation Reactions Involving Heteroarenes Containing One Heteroatom

et al. 2014

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In recent years, transition metal-catalyzed direct (hetero)arylation reactions of heteroarenes with (hetero)aryl halides and pseudohalides have received significant attention as eco-friendly and economic alternatives to classical methods for the construction of heteroaryl-(hetero)aryl C À C bonds by transition metal-catalyzed cross-couplings involving the use of stoichiometric amounts of organometallic reagents. This critical review with 430 references covers the results obtained in the period January 2009 to February 2013 in the area of the transition metal-catalyzed direct inter-and intramolecular (hetero)arylation reactions of heteroarenes containing one heteroatom. Particular attention has been given to illustrate chemo-and site selectivity aspects of these reactions as well applications of these C À C bond forming reactions in the synthesis of pharmaceutically relevant compounds, natural products and their analogues and precursors. The most recent advancements into the mechanism(s) of these reactions have also been briefly reported.

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“…Further drug-like inhibitors explorations, including the primary identification of NB-2 and NB-64 micromolar leads [325] and docking-guided optimization to derivatives of 2-aryl 5-(4-oxo-3-phenethyl-2-thioxothiazolidinylidenemethyl) furan (Fig. 3c), have been carried out recently by the same group [326,327]. The most potent inhibitors synthesized so far acquired 14nM IC 50 against the formation of gp41.…”

Section: Towards Potent Ppi Inhibitorsmentioning

confidence: 99%

From Laptop to Benchtop to Bedside: Structure-based Drug Design on Protein Targets

Chen¹,

Morrow²,

Tran³

et al. 2012

curr drug metab

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As an important aspect of computer-aided drug design, structure-based drug design brought a new horizon to pharmaceutical development. This in silico method permeates all aspects of drug discovery today, including lead identification, lead optimization, ADMET prediction and drug repurposing. Structure-based drug design has resulted in fruitful successes drug discovery targeting protein-ligand and protein-protein interactions. Meanwhile, challenges, noted by low accuracy and combinatoric issues, may also cause failures. In this review, state-of-the-art techniques for protein modeling (e.g. structure prediction, modeling protein flexibility, etc.), hit identification/optimization (e.g. molecular docking, focused library design, fragment-based design, molecular dynamic, etc.), and polypharmacology design will be discussed. We will explore how structure-based techniques can facilitate the drug discovery process and interplay with other experimental approaches. KeywordsStructure-based drug design; protein modeling; focused library design; pharmacophore; flexible docking; high-throughput virtual screening; de novo design; protein-protein interaction; polypharmacology Modern computational-aided drug design established a novel platform by which researchers perform in-depth in silico simulation prior to labor-extensive wet-lab validation [1]. It comprises of two major parts corresponding to the information of molecular source it utilizes: structure-based (or receptor-based) drug design and ligand-based drug design. Structure-based drug design, which relies on the knowledge of biological target structures, aims to discover small molecules/peptides leads with desired chemistry properties, and orchestrate the following experimental validation and lead optimization. Structure-based approach provides mechanism-based basis, where potential ligands are excavated using receptor-dependent parameters, while ligand-based approaches bypass the consideration of complex biomolecular "black box" in a living cell. This in silico method permeates all aspects of drug discovery today [2], and we expect it will draw more attentions with the unprecedented advances of computational power and modeling accuracy in this decade.* Corresponding author: Shuxing Zhang, Ph.D., The University of Texas M. D. Anderson Cancer Center, Department of Experimental Therapeutics, Unit 1950, 1901 East Rd., Houston, TX 77054, Telephone: (713)-745-2958 794-5577, shuzhang@mdanderson.org. Conflict of interestThe authors declare that they do not have competing interests. NIH Public Access Author ManuscriptCurr Pharm Des. Author manuscript; available in PMC 2013 November 07.Published in final edited form as:Curr Pharm Des. 2012 ; 18(9): 1217-1239. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptIn this review, we will overview the state-of-the-art structure-based drug discovery techniques ranging from receptor modeling to lead identification and optimization. In each topic, we will also highlight the fruitful successes as well as ch...

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Design, Synthesis, and Biological Activity of Novel 5-((Arylfuran/1H-pyrrol-2-yl)methylene)-2-thioxo-3-(3-(trifluoromethyl)phenyl)thiazolidin-4-ones as HIV-1 Fusion Inhibitors Targeting gp41

Cited by 80 publications

References 36 publications

New thiopyrano[2,3-d][1,3]thiazole derivatives as potential antiviral agents

New thiopyrano[2,3-d][1,3]thiazole derivatives as potential antiviral agents

Cross‐Coupling of Heteroarenes by CH Functionalization: Recent Progress towards Direct Arylation and Heteroarylation Reactions Involving Heteroarenes Containing One Heteroatom

From Laptop to Benchtop to Bedside: Structure-based Drug Design on Protein Targets

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