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Synthetic Approaches to Inhibitors of Isoprenoid Biosynthesis
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Pedro Merino, Loredana Maiuolo, Ignacio Delso, Vincenzo Algieri, Antonio De Nino, Tomas Tejero
A series of spiro[indole-pyrrolizine], spiro[indole-indolizine], and spiro[indole-pyrrolidine] gem-bisphosphonates (67) were synthesized through multicomponent reactions between substituted isatins (65), amino acids (66) and (64) in the presence of montmorillonite (Scheme 2.19) (Li et al., 2015). It is important to note that this synthetic procedure provided a very useful one-pot strategy for the construction of spiro-gem-bisphosphonates. Reagents and conditions: (i) montmorillonite, MeCN, 0.5–2 h, 80°C. (ii) TMSBr, 18 h, rt; then water, 4 h, rt.
Recent Advances in Repositioning Non-Antibiotics against Tuberculosis and other Neglected Tropical Diseases
Published in Venkatesan Jayaprakash, Daniele Castagnolo, Yusuf Özkay, Medicinal Chemistry of Neglected and Tropical Diseases, 2019
Molecular hybridization of pharmacophoric subunits of phenothiazines and other known antibacterial structural motifs is another approach that has been employed to enhance antitubercular effects of phenothiazine drugs. A study by Sharma et al. identified 2-azetidinone promazine hybrids (37 and 38) that displayed an MIC of 2.5 μg/mL against Mtb H37Rv (Figure 3). Moreover, active compounds exhibited notable antifungal activity and activity against other bacteria such as Escherichia coli and Staphylococcus aureus (Sharma et al. 2012). Others reported hybrids of trifluoperazine and antitubercular clinical candidate I-A09 that were achieved using click chemistry. Three hybrids 39–41 showed significant activity (MIC 6.25 μg/mL) against Mtb H37Rv with selectivity index greater than 10 (Figure 3) (Addla et al. 2014). Ramprasad et al. reported antitubercular 1,3,4-thiadiazole phenothiazine hybrids which were nontoxic to a normal Vero cell line, the most active hybrid 42 displayed an MIC of 0.8 μg/mL (Figure 3). Moreover, delineation of structure-activity relationship revealed that the presence of alkyl or substituted phenyl moieties on the 1,3,4-thiadiazole ring enhanced antimycobacterial effects. Also, docking studies demonstrated strong π-π stacking interactions of active chemical entities with InhA and CYP121 (Ramprasad et al. 2015). Another study adapted a Biginelli multicomponent reaction to generate a series of pyrimidine derivatives bearing a phenothiazine nucleus, their evaluation against Mtb H37Rv led to the identification of a derivative 43 with pronounced in vitro activity (MIC 0.02 μg/mL), more potent than isoniazid (MIC 0.03 μg/mL) (Figure 3) (Siddiqui et al. 2014). In other reports, hybridization of thioridazine with a carbazole scaffold resulted in hybrid 44 with poor antimycobacterial activity (MIC 128 μg/mL) against Mtb H37Rv (Figure 3). However, the carbazole hybrid displayed a higher inhibitory activity of ethidium bromide (EtBr) efflux and less cytotoxicity in comparison to thioridazine, a known efflux pump inhibitor. Synergistic effects with isoniazid, rifampicin, amikacin and ofloxacin were also observed (Pieroni et al. 2015).
Crosslinking hyaluronic acid soft-tissue fillers: current status and perspectives from an industrial point of view
Published in Expert Review of Medical Devices, 2021
Jimmy Faivre, Amos I. Pigweh, Julien Iehl, Pauline Maffert, Peter Goekjian, François Bourdon
In order to design new crosslinkers for native HA, based on what is currently marketed by manufacturers, two directions are possible: changing the crosslinker functional groups to use new chemical routes (Figure 2(a)) or changing the crosslinker spacer to modify the physico-chemical properties of the molecule as well as its functionality. As observed in Table 2, a limited number of condensation reactions have been reported in the literature as an alternative to etherification by epoxide opening. Beyond the very classical crosslinking with glutaraldehyde, which toxicity and non-specificity make it inappropriate for skin filler applications, crosslinking of the alcohol groups with a maleic anhydride copolymer was reported by Larrañeta et al. [64]. Alternatively, Huin-Amargier et al. reported the nucleophilic esterification of the HA carboxylate groups with tetraethyleneglycol bis toluenesulfonate [65]. Finally, de Nooy et al. reported an elegant crosslinking process by in situ Ugi multicomponent reaction [66]. Nonetheless, there is still considerable room for innovation, even though innovative crosslinkers are rarely commercially available.
The chemical diversity and structure-based discovery of allosteric modulators for the PIF-pocket of protein kinase PDK1
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2019
Xinyuan Xu, Yingyi Chen, Qiang Fu, Duan Ni, Jian Zhang, Xiaolong Li, Shaoyong Lu
ANCHOR.QUERY is a method that efficiently allows to obtain active molecules from the known molecule by combination of computation and synthesis99. The molecules acquired through this approach can be synthesised in one step by multicomponent reaction (MCR) chemistry. Based on above advantages, Kroon et al. applied ANCHOR.QUERY approach for the new scaffolds that bind to the allosteric PIF-pocket of PDK1100. The starting point of their investigation was based on the cocrystal structure of PDK1-2 complex. Through virtual screening and following SAR research, the racemic compound 7 was synthesised. The ability of the racemic to disrupt the PDK1-PIFtide interaction was different, with IC50 values of 7.0 μΜ for enantiomer 7 A (18, Figure 8) and 15 μM for enantiomer 7B (19, Figure 8), respectively. In both molecules, the 2-chlorophenyl substituent that acts as an anchor is located in the deep PIF-pocket, but shows a different orientation (Figure 14(A) and Figure 14(B)). In the structure of 18-bound PDK1, the 2-chlorophenyl substituent forms a short contact with the residue Phe149, while in the structure of 19-bound PDK1 it turns about 180°, with no contacts with Phe149. In addition, the extra interactions formed by the carboxylic acid group and the amide group of 18 can explain the higher affinity of 18 than 19.
Thioredoxin reductase inhibitors: updated patent review (2017-present)
Published in Expert Opinion on Therapeutic Patents, 2021
Evgeny Chupakhin, Mikhail Krasavin
Thioredoxin protein is the substrate for TrxR and, therefore, designing TrxR inhibitors based on peptidomimetic scaffold mimicking the protein substrate’s backbone is a viable strategy. Our team has developed a series of compounds which were assembled using the Ugi multicomponent reaction (Figure 10). These compounds (dubbed ‘Ugi-type Michael acceptor’ or UMA), represented by compound DVD445 (42) [113,114], incorporate a Michael acceptor-oxocrotonate moiety and a flexible peptoid scaffold. This compound was shown to perturb the thioredoxin system via TrxR inhibition (IC50 0.6 μM) and showed potential for glioma treatment by suppressing the invasion and sensitizing glioma cells to chemotherapy [115].