Dey, Sujit KumarBeraud-Dufour, SophieRiechers, Dean EdwardLandau, Olivia Augusta...
17页
查看更多>>摘要：Alpha-linolenic acid (ALA), an essential omega-3 polyunsaturated fatty acid found in plants, exerts neuroprotection and anti-inflammatory effects in chronic and acute CNS disease models. However, the underlying mechanisms are not yet understood. Since ALA is not incorporated into the brain, the observed health benefits may result from some of its metabolites. The putative formation of dihydroxylated ALA derivatives (called linotrins) was recently shown in vitro in the presence of lipoxygenases. However, the in vitro biosynthesis of linotrins was neither stereoselective nor quantitatively efficient for studying their physiological roles as enantiomeric pure forms. Herein, we report the first stereo-controlled synthesis that features regio- and stereoselective hydrometalations of alkynes for assembling the sensitive E,Z,E-conjugated trienes, as well as LC-MS investigations that provide evidence of linotrins occurrence in plants. Moreover, strong anti-inflammatory effects on microglia highlight the potential physiological importance of linotrins and open new perspectives in search of CNS therapeutics. (C) 2022 Elsevier Masson SAS. All rights reserved.
查看更多>>摘要：Voriconazole (VCZ) was the first approved triazole antifungal drug with 1-(1H-1,2,4-triazol-1-yl)butan-2-ol substructure. This drug showed a broad spectrum of activity, especially against yeasts and molds, and opened a new avenue toward the novel class of systemic antifungal agents. Modification of 2-fluoropyrimidine in the side chain of VCZ resulted in a newer generation of triazolylbutanols including efinaconazole, albaconazole, ravuconazole, and isavuconazole with the favorable antifungal spectrum, enhanced pharmacokinetic properties, and tolerable toxicity profiles. Due to the importance of triazolylbutanols in the discovery and development of new antifungal agents, in this review we have focused on the synthetic approaches and structural diversity of triazolylbutanols derived from vor-iconazole. This comprehensive review provides highlighting scope for medicinal chemists for the design, synthesis and development of novel potential antifungal drugs having better activity, pharmacokinetic property and toxicity profile.(c) 2022 Elsevier Masson SAS. All rights reserved.
查看更多>>摘要：P2X receptors are potential therapeutic targets for the treatment of various neurodegenerative disorders, pain, inflammation, hypertension, and cancer. Adamantane ring has been reported to exhibit significant inhibitory potential towards P2X receptors, especially for P2X7R. We have utilized uniqueness of adamantane moiety in our synthesized compounds and introduced various substitutions that enhanced the potency as well as selectivity for P2XR subtypes. Among synthesized derivatives, 4n and 5b were found to be most potent and selective inhibitors for h-P2X4R and h-P2X7R, respectively. 4n was found to be highly selective for h-P2X4R with IC50 & PLUSMN; SEM = 0.04 & PLUSMN; 0.01 mu M, that is 22 times more potent than BX-430, a standard selective inhibitor of h-P2X4R. 5b has IC50 & PLUSMN; SEM of 0.073 & PLUSMN; 0.04 mu M, which is comparable with the known antagonists of h-P2X7R. 4n and 5b were studied for mode of inhibition of P2XRs and both were found to be negative allosteric modulators. In silico studies were also conducted to find the type of interactions as well as mode of inhibition.& nbsp;(c) 2022 Elsevier Masson SAS. All rights reserved.
de Oliveira, Gabriel MeloKaralic, IzetHulpia, FabianSoeiro, Maria de Nazare C....
15页
查看更多>>摘要：Chagas disease and leishmaniasis are two poverty-related neglected tropical diseases that cause high mortality and morbidity. Current treatments suffer from severe limitations and novel, safer and more effective drugs are urgently needed. Both Trypanosoma cruzi and Leishmania are auxotrophic for purines and absolutely depend on uptake and assimilation of host purines. This led us to successfully explore purine nucleoside analogues as chemotherapeutic agents against these and other kinetoplastid in-fections. This study extensively explored the modification of the 6-amino group of tubercidin, a natural product with trypanocidal activity but unacceptable toxicity for clinical use. We found that mono-substitution of the amine with short alkyls elicits potent and selective antitrypanosomal and anti-leishmanial activity. The methyl analogue 15 displayed the best in vitro activity against both T. cruzi and L. infantum and high selectivity versus host cells. Oral administration for five consecutive days in an acute Chagas disease mouse model resulted in significantly reduced peak parasitemia levels (75, 89 and 96% with 12.5, 25 and 50 mg/kg/day, respectively). as well as increased animal survival rates with the lower doses (83 and 67% for 12.5 and 25 mg/kg/day, respectively). (c) 2022 Elsevier Masson SAS. All rights reserved.
查看更多>>摘要：Intrinsically disordered proteins (IDPs) play important roles in disease pathologies; however, their lack of defined stable 3D structures make traditional drug design strategies typically less effective against these targets. Based on promising results of targeted covalent inhibitors (TCIs) on challenging targets, we have developed a covalent design strategy targeting IDPs. As a model system we chose tau, an endogenous IDP of the central nervous system that is associated with severe neurodegenerative diseases via its aggregation. First, we mapped the tractability of available cysteines in tau and prioritized suitable warheads. Next, we introduced the selected vinylsulfone warhead to the non-covalent scaffolds of potential tau aggregation inhibitors. The designed covalent tau binders were synthesized and tested in aggregation models, and inhibited tau aggregation effectively. Our results revealed the usefulness of the covalent design strategy against therapeutically relevant IDP targets and provided promising candidates for the treatment of tauopathies.(c) 2022 The Author(s). Published by Elsevier Masson SAS. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
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