Antibiotics: The Need for Innovation
Nathan Keighley in Miraculous Medicines and the Chemistry of Drug Design, 2020
A single fluorine atom at position 6 greatly increased activity as well as uptake into the bacterial cell. Addition of a piperazine ring on position 7 is beneficial; improved oral adsorption, tissue distribution, metabolic stability, as well as improving the level and spectrum of activity are among the advantages. Presumably, the ability for the basic substituent to form a zwitterion with the carboxyl group is the reason for these improved drug properties. Further modifications include addition of an isopropyl ring to nitrogen 1, and replacement of pyridine with benzene. This leads to the development of ciprofloxacin, which is regarded as one of the most active broad spectrum antibiotics available. Furthermore, bacteria are slow to develop resistance to it, unlike nalidixic acid.
Microbial Pathways of Lipid A Biosynthesis
Helmut Brade, Steven M. Opal, Stefanie N. Vogel, David C. Morrison in Endotoxin in Health and Disease, 2020
The structure of the lipid A of P. aeruginosa differs from that of E. coli and other gram-negative enteric organisms (13). Accordingly, P aeruginosa lipid A contains N-linked (R)-3-hydroxylaurate at positions 2 and 2′ and O-linked (R)-3-hydroxydecanoate at positions 3 and 3′. In addition, the acyloxyacyl substituents of this P. aeruginosa lipid A are located at the 2- and 2′-positions, and the predominant acyloxy substituent is lauric acid. The sequence of reactions involved in lipid A synthesis in P. aeruginosa also appears to differ from the sequence of reactions demonstrated in E. coli. Thus, the complete fatty acylation of lipid A in P. aeruginosa occurs prior to the incorporation of Kdo residues (108). Indeed, Mohan and Raetz (127) demonstrated the in vitro transfer of laurate from lauroyl-ACP into lipid IVA in extracts of P. aeruginosa, but acylation of (Kdo)2-lipid IVA was also possible. In addition, only one laurate was incorporated, and although the structure of the reaction product was not determined, the laurate was presumed to be incorporated as an acyloxyacyl substituent. In this regard it should be noted that E. coli lipid IVA was used as the acceptor in these studies, and it is possible that incorporation of a second laurate acyloxy substituent would have occurred if the P. aeruginosa equivalent of E. coli lipid IVA had been used as an acceptor.
Primary Biliary Cirrhosis Bench to Bedside
Gianfranco Alpini, Domenico Alvaro, Marco Marzioni, Gene LeSage, Nicholas LaRusso in The Pathophysiology of Biliary Epithelia, 2020
We postulate that people genetically predisposed to PBC have inherited such predisposition based on either the cytochrome p450 pathway or another metabolic process responsible for degrading halogenated compounds. A large number of common pharmaceuticals such as diuretic agents are halogenated structures. In fact, halogens are common substituents in pharmaceuticals that modulate binding, activity and metabolism. In addition, there are large numbers of detergents, commonly used at home and commercially, that are rich in halogenated derivatives. Estrogens have already been shown to modulate the expression of many liver metabolic pathways and may explain the preponderance of women with PBC. Finally, the presence of primarily small bile duct destruction may be reflective of the local mucosal immune response, which is more prominent on epithelial surfaces.136 Indeed, PBC is often referred to as an epithelitis with involvement not only of bile ducts, but also of salivary glands.
Synthesis and structure–activity relationships for some novel diflapolin derivatives with benzimidazole subunit
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2022
Lisa Vieider, Eva Zoeller, Erik Romp, Martin Schoenthaler, Victor Hernández-Olmos, Veronika Temml, Thomas Hasenoehrl, Daniela Schuster, Oliver Werz, Ulrike Garscha, Barbara Matuszczak
For preparation of the compounds with the benzimidazole core, the synthetic strategy developed in our group21,24 was slightly modified (see Figure 3). Starting from 2-chloromethylbenzimidazole (1), the tert-butoxycarbonyl group was introduced by reaction with di-tert-butyl dicarbonate. This N-substituent served on the one hand as a protecting group25 for the nitrogen and on the other hand as a further structural modification. The reaction of the resulting 1‐tert‐butoxycarbonyl‐2-chloromethylbenzimidazole (2) with the methyl substituted or unsubstituted 4-nitrophenol in the presence of base (potassium carbonate) afforded compounds 3a–c. Subsequent reduction of the nitro function with ammonium formate and palladium on charcoal as catalyst in methanol led to the appropriate amines 4a–c. The first target compounds with N-Boc substituent (i.e. 5a–f) became accessible by reaction of the amines with 3,4-dichlorophenylisocyanate or 3,4-dichlorophenylisothiocyanate, respectively. Subsequently, the N-substituent was split off with trifluoroacetic acid, which led to the second type of target compounds 6a–f.
Design, synthesis, in vitro and in vivo evaluation of benzylpiperidine-linked 1,3-dimethylbenzimidazolinones as cholinesterase inhibitors against Alzheimer’s disease
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2020
Jun Mo, Tingkai Chen, Hongyu Yang, Yan Guo, Qi Li, Yuting Qiao, Hongzhi Lin, Feng Feng, Wenyuan Liu, Yao Chen, Zongliang Liu, Haopeng Sun
Finally, we synthesised compounds 15a–15j with various kinds of groups introduced to the benzyl moiety, to explore the impact of the benzyl moiety structural modification on ChEs inhibitory activities. Compared to 9a, 15a showed an eightfold increase in inhibitory activity towards ChEs, indicating sulphonamide group can enhanced inhibitory activity. Firstly, we introduced methyl group to the benzyl moiety. Methyl substitution at ortho- or meta- position of benzyl (15b and 15c, respectively) showed comparable activity to 15a while the para-substituted compound 15d led to reduced inhibitory activity. Next, we evaluated the impact of the methoxy group substituents on ChEs inhibitory activities. Compared to 15a, 15e showed reduced inhibitory activity. Then, compounds with different halogen substituents were also synthesised. When substituted by F (15f), it showed reduced inhibitory activity. When substituted by Cl (15g–15h), the activity on AChE was meta- > para-. When substituted by Br (15i–15j), the activity on AChE was meta- > para-. And 15j with meta substitution were more selective having an enhanced inhibitory activity on BChE than AChE. When substituted by different halogen atoms, the activity on AChE was –Br > –Cl > –F. We speculated that Br and Cl can form halogen bonds with amino acid, but F cannot form halogen bond. Therefore, the compounds with Br and Cl substituents were more potent than F.
Design, synthesis and cholinesterase inhibitory properties of new oxazole benzylamine derivatives
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2020
Ivana Šagud, Nikolina Maček Hrvat, Ana Grgičević, Tena Čadež, Josipa Hodak, Milena Dragojević, Kornelija Lasić, Zrinka Kovarik, Irena Škorić
Generally, although these compounds, with the exception of compound trans-17, systematically differ only by their substituent on the benzyl group and its substituent position (ortho-, meta-, para-), this structural variation cannot be easily related to IC50 values. The most potent inhibitors, compounds trans-12, trans-10 and trans-8 have ortho-methoxy, meta-fluoro and meta-methoxy substituents at the phenyl rings, respectively. Moreover, ortho- (trans-12) and meta- (trans-8) analogues had about a 3 times lower IC50 than their para-methoxy analogue (trans-4). Similarly, the meta-fluoro substituted compound, trans-10, exhibited a 2.5 times lower IC50 than its para-fluoro analogue, trans-6. In case of the methyl substituent, the position of the substituent was not relevant because all three compounds (trans-3, trans-7 and trans-11) had a similar IC50 and were the weakest inhibitors among the tested compounds (Table 1). Nevertheless, the para-substitution and methyl-substitution led to inactive compounds, while the ortho/meta-methoxy and the meta-fluoro were active derivatives. It is not surprising that the activity was noticeably different between the most potent (trans-12) and the weakest inhibitor (trans-11) differed in the methoxy and methyl substituent at position 2, respectively.
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