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New Strategies to Discover Non-Ribosomal Peptides as a Source of Antibiotics Molecules
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Mario Alberto Martínez-Núñez, Zuemy Rodríguez-Escamilla, Víctor López y López
From β-lactams synthesized by linear NRPSs type A semisynthetic derivatives have been obtained that recover antimicrobial activity against strains that have acquired resistance to antibiotics. For example, Yokoo et al. (2016) carried out chemical modifications of the side chains at the C-3 or at the C-7 position of cephalosporins; all of the compounds that they synthesized have an aminothiazole alkoxyimino group at the C-7 position with a cyanamide group at the pyridinium ring at the C-3 leading to novel 7β-[2-(2-aminothiazole-4-yl)-2-(Z)-(alkoxyimino)acetamido]- cephalosporins and presenting potent antibacterial activity against Gram-positive and Gram-negative bacteria including β-lactamase non-producing penicillin-resistant Haemophilus influenzae (BLNAR), penicillin-resistant S. pneumoniae (PRSP) and S. aureus (Yokoo et al., 2016). On the other hand, Yamawaki et al. (2007) conducted chemical modification and optimization of the cephalosporin in the aminothiazole and alkoxyimino moieties at the C-7 side chain demonstrating that novel cephalosporins having both a 1-carboxyalkoxyimino moiety and a chloroaminothiazole moiety at the C-7 exhibit potent antibacterial activity. Among the modified cephalosporins, 7beta-[2-(2-amino-5-chlorothiazol- 4yl)-2(Z)-((S)-1-carboxyethoxyimino)acetamido] cephalosporins showed the most potent antibacterial activity against Gram-negative and Gram-positive bacteria (Yamawaki et al., 2007).
Aztreonam and Aztreonam-Avibactam
Published in M. Lindsay Grayson, Sara E. Cosgrove, Suzanne M. Crowe, M. Lindsay Grayson, William Hope, James S. McCarthy, John Mills, Johan W. Mouton, David L. Paterson, Kucers’ The Use of Antibiotics, 2017
Few interactions occur between aztreonam and other drugs. Co-administration of metronidazole parenteral solutions and the injectable aztreonam may lead to the development of pink color in their intravenous admixtures (Thakur et al., 1991). Nitrite ions may be produced in metronidazole solutions at the time of preparation or during storage by the effects of temperature and light. Under acidic pH conditions, the aminothiazole moiety of aztreonam can be diazotized by the nitrite ion contributed by metronidazole solutions. The diazotized molecule, in turn, reacts with another aztreonam molecule by diazo coupling. The result is a pink-colored product (Thakur et al., 1991). An interaction between aztreonam and nafcillin sodium in 0.9% sodium chloride injection or 5% dextrose injection stored in glass or plastic containers has been reported (Riley and Lipford, 1986). Admixtures of aztreonam and nafcillin sodium may become cloudy and show evidence of a fine precipitate.
The Metabolism of Alcohol and Its Implications for the Pathogenesis of Disease
Published in Victor R. Preedy, Ronald R. Watson, Alcohol and the Gastrointestinal Tract, 2017
The catalase contribution might be enhanced if significant amounts of H2O2 become available through β-oxidation of fatty acids such as octanoate, palmitate, and oleate in peroxisomes.137 However, the peroxisomal enzymes do not oxidize short chain fatty acids such as octanoate and this phenomenon was observed only in the absence of ADH activity. Otherwise the rate of alcohol metabolism is reduced by adding fatty acids,138 and β-oxidation of fatty acids is inhibited by NADH produced from alcohol metabolism via ADH.138 Similarly, generation of reducing equivalents from alcohol by ADH in the cytosol inhibits H2O2 generation leading to significantly diminished rates of peroxidation of alcohols via catalase.139 Various other results have indicated that peroxisomal fatty acid oxidation does not play a major role in alcohol metabolism.140 Furthermore, when Handler and Thurman137 used fatty acids to stimulate alcohol oxidation, this effect was very sensitive to inhibition by aminotriazole — a catalase inhibitor. Therefore, if this mechanism plays an important role in vivo, one would expect a significant inhibition of alcohol metabolism after aminothiazole administration in vivo, when physiologic amounts of fatty acids and other substrates for H2O2 generation are present. A number of studies, however, have shown that aminotriazole treatment has little, if any, effect on alcohol oxidation in vivo, as reviewed by Takagi et al.141 and Kato et al.,142,143 who have confirmed this effect, while also verifying its inhibitory effect on catalase mediated alcohol peroxidation in vitro. Despite the considerable controversy that originally surrounded this issue, it is now agreed by the principal contenders involved that catalase cannot account for microsomal ethanol oxidation.144,145 However, catalase could contribute to fatty acid oxidation. Indeed, long-term ethanol consumption is associated with increases in the content of a specific cytochrome (P-450 4A1) which promotes microsomal GO-hydroxylation of fatty acids. Products of co-oxidation increase liver cytosolic fatty acid-binding protein (L-FABPc) content and peroxisomal β-oxidation,146 an alternate pathway for fatty acid disposition. ω-Oxidation may compensate at least in part for the deficit in fatty acid oxidation due to the ethanol-induced injury of the mitochondria.53
Monocyclic beta–lactams for therapeutic uses: a patent overview (2010–2020)
Published in Expert Opinion on Therapeutic Patents, 2021
Katarina Grabrijan, Nika Strašek, Stanislav Gobec
Synthetic methods toward monocyclic beta-lactam core are well elaborated in both academic and patent literature (for examples see Figure 18). Most recent published patents focus on modifications of the aminothiazole oxime side chain to improve the potency and spectrum of antibacterial activity. Due to cefiderocol, a cephalosporin linked to a siderophore that is active against all three critical pathogens from the WHO list, some are trying to use iron transport to improve uptake also for monocyclic beta-lactams. Others focus on improving serine beta-lactamase stability by altering the substituents at C-4 and developing compounds with cis configuration. Unfortunately, the patented monobactams have a narrow spectrum of antibacterial activity and focus on either one of the P. aeruginosa or Enterobacteriaceae species.
Design, synthesis and cytotoxic evaluation of novel bis-thiazole derivatives as preferential Pim1 kinase inhibitors with in vivo and in silico study
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2023
Mohammad M. Al-Sanea, Tamer M. Nasr, Samir Bondock, Aya Y. Gawish, Nada M. Mohamed
Structurally, the aliphatic substituted phenyl aminothiazole derivatives 3a–c showed remarkable decrease of their cytotoxic activity if unsubstituted or substituted with an ester group at 3a and 3c, respectively. Meanwhile, adding a methyl ketone at 3b resulted in more than 50% growth inhibition of several cancerous cell lines at the tested concentration (Table S1). On the other hand, the un/substituted azophenyl derivatives 5a–b showed lower cytotoxicity than their aliphatic congeners where the unsubstituted 5a had noticeable cytotoxicity towards renal CAKI-1, SN12C and UO-31 cell lines comparing to its ether analogue 5b. Removing the azo-linker and directly attach the phenyl moiety to the thiazole ring at 6a–c favoured their cytotoxicity with the unsubstituted and para-fluoro substitution offered inhibitory activity of several cell line growth comparing to their chloride congener. In the same context; replacing the azo-linker with an imine at 8a–c increased the cytotoxicity towards MCF-7 in the presence of another para-fluoro phenyl. Replacing the third phenyl group of the imine containing derivatives 8a–c with aliphatic moieties 9 decreased its cytotoxic activity exhibited only 59% inhibition of the lung cancer HOP-92 cell line. Moreover, it was noticed that substituting the phenyl ring with a fluoride group had the privilege over the unsubstituted and chloride substituted analogues in 6a–c and 8a–c. This might due to the large size of the chloride moiety comparing to the hydrogen or fluoride that hindered the cellular uptake.
Synthesis and biological evaluation of thiazole derivatives as LbSOD inhibitors
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2019
Camila C. Bitencourt Brito, Hélder Vinicius Carneiro da Silva, Daci José Brondani, Antonio Rodolfo de Faria, Rafael Matos Ximenes, Ivanildo Mangueira da Silva, Julianna F. C. de Albuquerque, Marcelo Santos Castilho
The 2-aminothiazole derivatives were obtained from the mixture of equimolar amounts 0.175 g (2.3 × 10−3 mol) of thiourea dissolved in 15 ml of methanol followed by the addition of 0.513 g (2.3 × 10−3 mol) of substituted acetophenone halide dissolved in 20 ml methanol, to form a white suspension. The reaction was left for 15 min at room temperature under magnetic stirring. After that, the mixture was dissolved in 0.6 ml of HCl (dropwise). The reaction was heated to 90 °C in an oil bath, the pH adjusted between 4 and 5. The reaction time was 2 h. The reaction was monitored by thin layer chromatography. The product was ice-cooled and filtered. The compound was purified by crystallization from methanol.