Design, synthesis and biological evaluation of novel aminothiazoles as antiviral compounds acting against human rhinovirus

Décor, Anne; Grand‐Maître, Chantal; Hucke, Oliver; O'Meara, Jeff A.; Kuhn, Cyrille; Forget, Léa Constantineau; Brochu, Christian; Malenfant, Éric; Bertrand-Laperle, Mégan; Bordeleau, Josée; Ghiro, Élise; Pesant, Marc; Fazal, Gulrez; Gorys, Vida; Little, Michael J.; Boucher, Colette; Bordeleau, Sylvain; Turcotte, Pascal; Guo, Jingzhong; Garneau, Michel; Spickler, Catherine; Gauthier, Annick

doi:10.1016/j.bmcl.2013.04.077

Cited by 22 publications

(16 citation statements)

References 11 publications

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“…This aminothiazole series was optimized for activity against HRV and had no cytotoxicity as demonstrated by compound 1 with an antiviral potency ranging from 110 to 480 nM against 10 HRV genotypes of species A and B, and the CC 50 was Ͼ64 M (Table 1). Design, synthesis, and chemical optimization of this aminothiazole series is described elsewhere (65). Compounds within this aminothiazole series proved active against subgenomic luciferase reporter HRV-A16Luc and HRV-B14Luc replicons as well as a full-length HRV-C15 W10 LUC reporter replicon (exemplified by compound 2 in Table 2), further demonstrating that this series is acting at the intracellular replication stage of the HRV infectious cycle.…”

Section: Screening Of a Diverse Subset Of The Proprietary Collection mentioning

confidence: 95%

Phosphatidylinositol 4-Kinase III Beta Is Essential for Replication of Human Rhinovirus and Its Inhibition Causes a Lethal Phenotype In Vivo

Spickler

Lippens

Laberge

et al. 2013

Antimicrob Agents Chemother

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Human rhinovirus (HRV) is the predominant cause of the common cold, but more importantly, infection may have serious repercussions in asthmatics and chronic obstructive pulmonary disorder (COPD) patients. A cell-based antiviral screen against HRV was performed with a subset of our proprietary compound collection, and an aminothiazole series with pan-HRV species and enteroviral activity was identified. The series was found to act at the level of replication in the HRV infectious cycle. In vitro selection and sequencing of aminothiazole series-resistant HRV variants revealed a single-nucleotide mutation leading to the amino acid change I42V in the essential HRV 3A protein. This same mutation has been previously implicated in resistance to enviroxime, a former clinical-stage antipicornavirus agent. Enviroxime-like compounds have recently been shown to target the lipid kinase phosphatidylinositol 4-kinase III beta (PI4KIII␤). A good correlation between PI4KIII␤ activity and HRV antiviral potency was found when analyzing the data over 80 compounds of the aminothiazole series, covering a 750-fold potency range. The mechanism of action through PI4KIII␤ inhibition was further demonstrated by small interfering RNA (siRNA) knockdown of PI4KB, which reduced HRV replication and also increased the potency of the PI4KIII␤ inhibitors. Inhibitors from two different structural classes with promising pharmacokinetic profiles and with very good selectivity for PI4KIII␤ were used to dissociate compound-related toxicity from target-related toxicity. Mortality was seen in all dosing groups of mice treated with either compound, therefore suggesting that short-term inhibition of PI4KIII␤ is deleterious.

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Section: Screening Of a Diverse Subset Of The Proprietary Collection mentioning

confidence: 95%

Phosphatidylinositol 4-Kinase III Beta Is Essential for Replication of Human Rhinovirus and Its Inhibition Causes a Lethal Phenotype In Vivo

Spickler

Lippens

Laberge

et al. 2013

Antimicrob Agents Chemother

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“…7 It is also used as a coenzyme TPP (thiamine pyrophosphate) * For correspondence for conversion of pyruvate to acetyl coenzyme A which is one of the steps in carbohydrate metabolism. 8 Aminothiazoles have applications both in human and veterinary medicines 9 and are familiar for anti-viral, 10 anti-bacterial, 11 anti-inflammatory 12 and anti-cancer 13 activities. The study of the influence of amino functional group on the activity of 2-amino histamine derivatives proved the ability of 2-aminothiazole to form proton transfer complexes and hence 2-amino histamine serves as 'molecular model'.…”

Section: Introductionmentioning

confidence: 99%

Identification of robust synthon in the molecular salts of 2-aminothiazole with substituted benzoic acids: A case study

2014

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Six new salts of an API intermediate 2-aminothiazole with different carboxylic acid coformers were synthesized and characterized by IR (Infrared spectroscopy), 1 H-NMR, DSC (Differential scanning calorimetry), XRPD (X-ray powder diffraction) and single crystal XRD. The crystal structure of the salts with benzoic acid, 2,3-, 2,4-, 2,5-, 2,6-dihydroxybenzoic acids and 2,4-dinitrobenzoic acid were determined. The thiazole moiety exhibited solvent (polarity) assisted tautomerism in all reported salts and proton transfer was noticed to the ring N of thiazole due to which two point supramolecular synthon N + −H(thiazole)· · · O − (acid), N−H(amine)· · · O − (acid) was observed. The crystal structures were studied with respect to the positional effect of the competing functional groups like hydroxyl (−OH) and nitro (−NO 2 ) as well as their donor and acceptor abilities for hydrogen bonding. The presence of the non-conventional hydrogen bond (C−H· · · O) has been found to play a critical role in the formation of secondary supramolecular architectures.

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“…2-Aminothiazole derivatives possess the antimycobacterial [2] antiplasmodial [3], antifungal [4], antiplatelet [5], antiviral [6], hypoglycemic [7] and other activities. The anticancer studies of different 2-acylaminothiazole derivatives exhibited their potent inhibitory activity against a wide range of human cancerous cell lines [8][9][10][11][12][13][14].…”

Section: Issn 2308-8303mentioning

confidence: 99%

“…Melting points were uncorrected and were measured in open capillary tubes. The 1 H-NMR spectra were recorded on a Varian Gemini (400 MHz) in DMSO-d 6 , TMS was the internal standard.…”

Section: Experimental Partmentioning

confidence: 99%

The synthesis and anticancer properties of 2-(4-amino-5-methyl-4H-[1,2,4]triazol-3-ylsulfanyl)-N-(5-R-benzylthiazol-2-yl)-acetamides

Ostapiuk¹,

Matiychuk²,

Obushak³

2015

J. org. pharm. chem.

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Design, synthesis and biological evaluation of novel aminothiazoles as antiviral compounds acting against human rhinovirus

Cited by 22 publications

References 11 publications

Phosphatidylinositol 4-Kinase III Beta Is Essential for Replication of Human Rhinovirus and Its Inhibition Causes a Lethal Phenotype In Vivo

Phosphatidylinositol 4-Kinase III Beta Is Essential for Replication of Human Rhinovirus and Its Inhibition Causes a Lethal Phenotype In Vivo

Identification of robust synthon in the molecular salts of 2-aminothiazole with substituted benzoic acids: A case study

The synthesis and anticancer properties of 2-(4-amino-5-methyl-4H-[1,2,4]triazol-3-ylsulfanyl)-N-(5-R-benzylthiazol-2-yl)-acetamides

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