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      Imidazole: Synthesis, Functionalization and Physicochemical Properties of a Privileged Structure in Medicinal Chemistry

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      Molecules
      MDPI AG

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          Abstract

          Imidazole was first synthesized by Heinrich Debus in 1858 and was obtained by the reaction of glyoxal and formaldehyde in ammonia, initially called glyoxaline. The current literature provides much information about the synthesis, functionalization, physicochemical characteristics and biological role of imidazole. Imidazole is a structure that, despite being small, has a unique chemical complexity. It is a nucleus that is very practical and versatile in its construction/functionalization and can be considered a rich source of chemical diversity. Imidazole acts in extremely important processes for the maintenance of living organisms, such as catalysis in enzymatic processes. Imidazole-based compounds with antibacterial, anti-inflammatory, antidiabetic, antiparasitic, antituberculosis, antifungal, antioxidant, antitumor, antimalarial, anticancer, antidepressant and many others make up the therapeutic arsenal and new bioactive compounds proposed in the most diverse works. The interest and importance of imidazole-containing analogs in the field of medicinal chemistry is remarkable, and the understanding from the development of the first blockbuster drug cimetidine explores all the chemical and biological concepts of imidazole in the context of research and development of new drugs.

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          Microbially Produced Imidazole Propionate Impairs Insulin Signaling through mTORC1

          Interactions between the gut microbiota, diet, and the host potentially contribute to the development of metabolic diseases. Here, we identify imidazole propionate as a microbially produced histidine-derived metabolite that is present at higher concentrations in subjects with versus without type 2 diabetes. We show that imidazole propionate is produced from histidine in a gut simulator at higher concentrations when using fecal microbiota from subjects with versus without type 2 diabetes and that it impairs glucose tolerance when administered to mice. We further show that imidazole propionate impairs insulin signaling at the level of insulin receptor substrate through the activation of p38γ MAPK, which promotes p62 phosphorylation and, subsequently, activation of mechanistic target of rapamycin complex 1 (mTORC1). We also demonstrate increased activation of p62 and mTORC1 in liver from subjects with type 2 diabetes. Our findings indicate that the microbial metabolite imidazole propionate may contribute to the pathogenesis of type 2 diabetes.
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            Development and use of quantum mechanical molecular models. 76. AM1: a new general purpose quantum mechanical molecular model

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              The depth of chemical time and the power of enzymes as catalysts.

              The fastest known reactions include reactions catalyzed by enzymes, but the rate enhancements that enzymes produce had not been fully appreciated until recently. In the absence of enzymes, these same reactions are among the slowest that have ever been measured, some with half-times approaching the age of the Earth. This difference provides a measure of the proficiencies of enzymes as catalysts and their relative susceptibilities to inhibition by transition-state analogue inhibitors. Thermodynamic comparisons between spontaneous and enzyme-catalyzed reactions, coupled with structural information, suggest that in addition to electrostatic and H-bonding interactions, the liberation of water molecules from an enzyme's active site into bulk solvent sometimes plays a prominent role in determining the relative binding affinities of the altered substrate in the ground state and transition state. These comparisons also indicate a high level of synergism in the action of binding determinants of both the substrate and the enzyme, that are not directly involved in the chemical transformation of the substrate but contribute to the rate of its transformation at an enzyme's active site.
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                Author and article information

                Contributors
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                Journal
                MOLEFW
                Molecules
                Molecules
                MDPI AG
                1420-3049
                January 2023
                January 13 2023
                : 28
                : 2
                : 838
                Article
                10.3390/molecules28020838
                36677894
                d0bf5625-bdcf-4778-9780-b43f9ff320f3
                © 2023

                https://creativecommons.org/licenses/by/4.0/

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