431065-78-0Relevant academic research and scientific papers
Discovery of potent hepatitis C virus NS5A inhibitors with dimeric structures
Lemm, Julie A.,Leet, John E.,O'Boyle II, Donald R.,Romine, Jeffrey L.,Huang, Xiaohua Stella,Schroeder, Daniel R.,Alberts, Jeffrey,Cantone, Joseph L.,Sun, Jin-Hua,Nower, Peter T.,Martin, Scott W.,Serrano-Wu, Michael H.,Meanwell, Nicholas A.,Snyder, Lawrence B.,Gao, Min
, p. 3795 - 3802 (2011)
The exceptional in vitro potency of the hepatitis C virus (HCV) NS5A inhibitor BMS-790052 has translated into an in vivo effect in proof-of-concept clinical trials. Although the 50% effective concentration (EC50) of the initial lead, the thiazolidinone BMS-824, was ～10 nM in the replicon assay, it underwent transformation to other inhibitory species after incubation in cell culture medium. The biological profile of BMS-824, including the EC 50, the drug concentration required to reduce cell growth by 50% (CC50), and the resistance profile, however, remained unchanged, triggering an investigation to identify the biologically active species. Highperformance liquid chromatography (HPLC) biogram fractionation of a sample of BMS-824 incubated in medium revealed that the most active fractions could readily be separated from the parental compound and retained the biological profile of BMS-824. From mass spectral and nuclear magnetic resonance data, the active species was determined to be a dimer of BMS-824 derived from an intermolecular radical-mediated reaction of the parent compound. Based upon an analysis of the structural elements of the dimer deemed necessary for anti-HCV activity, the stilbene derivative BMS-346 was synthesized. This compound exhibited excellent anti-HCV activity and showed a resistance profile similar to that of BMS-824, with changes in compound sensitivity mapped to the N terminus of NS5A. The N terminus of NS5A has been crystallized as a dimer, complementing the symmetry of BMS-346 and allowing a potential mode of inhibition of NS5A to be discussed. Identification of the stable, active pharmacophore associated with these NS5A inhibitors provided the foundation for the design of more potent inhibitors with broad genotype inhibition. This culminated in the identification of BMS-790052, a compound that preserves the symmetry discovered with BMS-346. Copyright
Synthetic transition from thiourea-based compounds to tetrazole derivatives: Structure and biological evaluation of synthesized new n-(furan-2-ylmethyl)-1h-tetrazol-5-amine derivatives
Bielenica, Anna,Dobrowolski, Micha? A.,Kmiecik, Sebastian,Olejarz, Wioletta,Podsiad, Ma?gorzata,Roszkowski, Piotr,Struga, Marta,Szulczyk, Daniel
, (2021/06/21)
Twelve novel derivatives of N-(furan-2-ylmethyl)-1H-tetrazol-5-amine were synthesized. For obtained compound 8, its corresponding substrate single crystals were isolated and X-ray diffraction experiments were completed. In the initial stage of research, in silico structure-based pharmacological prediction was conducted. All compounds were screened for their antibacterial and antimycobacterial activities using standard and clinical strains. The cytotoxic activity was evaluated against a panel of human cancer cell lines, in contrast to normal (HaCaT) cell lines, by using the MTT method. All examined derivatives were found to be noncytotoxic against normal cell lines. Within the studied group, compound 6 showed the most promising results in antimicrobial studies. It inhibited four hospital S. epidermidis rods’ growth, when applied at the amount of 4 μg/mL. However, the most susceptible to the presence of compound 6 was S. epidermidis T 5501 851/19 clinical strain, for which the MIC value was only 2 μg/mL. Finally, a pharmacophore model was established based on lead compounds from this and our previous work.
Synthesis, Structural Studies and Biological Evaluation of Halogen Derivatives of 1,3-Disubstituted Thiourea
Bielenica, Anna,St?pień, Karolina,Sawczenko, Aleksandra,Lis, Tadeusz,Kozio?, Anna E.,Madeddu, Silvia,Collu, David,Iuliano, Filippo,Ko?mider, Anita,Struga, Marta
, p. 636 - 646 (2017/07/15)
Background: Halogen-substituted thiourea derivatives exert well-documented antimicrobial, antiviral and anticancer properties. Objective: This work evaluates antimicrobial and cytotoxic activities of newly synthesized fluorinated thiourea compounds. Method: Two series of thioureas were obtained by the condensation reaction of 4-amino-1-benzylpiperidine (1a-14a) or furfurylamine (1b-14b) and fluorinated isothiocyanates. The anti HIV-1 activity evaluation was based on inhibition of virus-induced cytopathogenicity in exponentially growing MT-4 cell, determined by the MTT method. Antibacterial potency was examined by the disc-diffusion method under standard conditions using Mueller-Hinton II agar medium according to CLSI guidelines. Antifungal effects were assessed using Mueller-Hinton agar and 2% glucose and 0.5μg/mL Methylene Blue Dye Medium. The viability of HaCaT and A549 cells was assessed by determination of MTT salt conversion by mitochondrial dehydrogenase, whereas release of lactate dehydrogenase from the cytosol to culture medium was a marker of the cell death. Results: The X-ray crystallography studies showed the conformations adopted by the molecules 2a, 7a, 2b and 7b. Compounds 1a and 14a proved cytotoxic against MT-4 cells and different other cell lines derived from human haematological tumors (CC50 10 μM). They influenced on viability, mortality and the growth rate of healthy HaCaT cells. Derivatives 1a, 6a and 2b exhibited moderate activity against Gram-positive bacteria (MIC values 8-128 μg/ml). Conclusio n: The results indicate that new 1,3-disubstituted thioureas exert moderate in vitro antimicrobial and cytotoxic effects.
