“…Changes in the sugar configuration as well as removal or replacement of substituents of the glucose moiety proved detrimental for the inhibition. Therefore, in 2015 Bokor et al elaborated synthetic methods for D -glucal attached to oxadiazoles by a C–C bond [ 62 ]. For the preparation of the target compounds 226 , two main routes were used; the functionalized glucal 226 was made by the formation of the heterocycle in the final stage (Scheme 36 ) or the 1,2-double bond can be introduced into a preformed C -glucopyranosyl heterocycle 227 (Scheme 37 ).…”
Section: -Glycosides As Antidiabetic Agentsmentioning
confidence: 99%
“…Test compounds 226 were obtained by Zemplen debenzoylation. Unfortunately, none of these showed significant inhibition of rabbit muscle glycogen phosphorylase b, indicating that the binding of the aglycones was not strong enough to override the detrimental effects of the changes in the sugar parts of the molecules [ 62 ]. Scheme 36 First method of compounds 226 synthesis [ 62 ] Scheme 37 Second method of compounds 226 synthesis [ 62 ] …”
Section: -Glycosides As Antidiabetic Agentsmentioning
This review is an effort to summarize recent developments in synthesis of
O
-glycosides and
N
-,
C
-glycosyl molecules with promising antidiabetic potential. Articles published after 2000 are included. First, the
O
-glycosides used in the treatment of diabetes are presented, followed by the
N
-glycosides and finally the
C
-glycosides constituting the largest group of antidiabetic drugs are described. Within each group of glycosides, we presented how the structure of compounds representing potential drugs changes and when discussing chemical compounds of a similar structure, achievements are presented in the chronological order.
C
-Glycosyl compounds mimicking
O
-glycosides structure, exhibit the best features in terms of pharmacodynamics and pharmacokinetics. Therefore, the largest part of the article is concerned with the description of the synthesis and biological studies of various
C
-glycosides. Also
N
-glycosides such as
N
-(β-
d
-glucopyranosyl)-amides,
N
-(β-
d
-glucopyranosyl)-ureas, and 1,2,3-triazolyl derivatives belong to the most potent classes of antidiabetic agents. In order to indicate which of the compounds presented in the given sections have the best inhibitory properties, a list of the best inhibitors is presented at the end of each section. In summary, the best inhibitors were selected from each of the summarizing figures and the results of the ranking were placed. In this way, the reader can learn about the structure of the compounds having the best antidiabetic activity. The compounds, whose synthesis was described in the article but did not appear on the figures presenting the structures of the most active inhibitors, did not show proper activity as inhibitors. Thus, the article also presents studies that have not yielded the desired results and show directions of research that should not be followed. In order to show the directions of the latest research, articles from 2018 to 2019 are described in a separate Sect.
5
. In Sect.
6
, biological mechanisms of action of the glycosides and patents of marketed drugs are described.
“…Changes in the sugar configuration as well as removal or replacement of substituents of the glucose moiety proved detrimental for the inhibition. Therefore, in 2015 Bokor et al elaborated synthetic methods for D -glucal attached to oxadiazoles by a C–C bond [ 62 ]. For the preparation of the target compounds 226 , two main routes were used; the functionalized glucal 226 was made by the formation of the heterocycle in the final stage (Scheme 36 ) or the 1,2-double bond can be introduced into a preformed C -glucopyranosyl heterocycle 227 (Scheme 37 ).…”
Section: -Glycosides As Antidiabetic Agentsmentioning
confidence: 99%
“…Test compounds 226 were obtained by Zemplen debenzoylation. Unfortunately, none of these showed significant inhibition of rabbit muscle glycogen phosphorylase b, indicating that the binding of the aglycones was not strong enough to override the detrimental effects of the changes in the sugar parts of the molecules [ 62 ]. Scheme 36 First method of compounds 226 synthesis [ 62 ] Scheme 37 Second method of compounds 226 synthesis [ 62 ] …”
Section: -Glycosides As Antidiabetic Agentsmentioning
This review is an effort to summarize recent developments in synthesis of
O
-glycosides and
N
-,
C
-glycosyl molecules with promising antidiabetic potential. Articles published after 2000 are included. First, the
O
-glycosides used in the treatment of diabetes are presented, followed by the
N
-glycosides and finally the
C
-glycosides constituting the largest group of antidiabetic drugs are described. Within each group of glycosides, we presented how the structure of compounds representing potential drugs changes and when discussing chemical compounds of a similar structure, achievements are presented in the chronological order.
C
-Glycosyl compounds mimicking
O
-glycosides structure, exhibit the best features in terms of pharmacodynamics and pharmacokinetics. Therefore, the largest part of the article is concerned with the description of the synthesis and biological studies of various
C
-glycosides. Also
N
-glycosides such as
N
-(β-
d
-glucopyranosyl)-amides,
N
-(β-
d
-glucopyranosyl)-ureas, and 1,2,3-triazolyl derivatives belong to the most potent classes of antidiabetic agents. In order to indicate which of the compounds presented in the given sections have the best inhibitory properties, a list of the best inhibitors is presented at the end of each section. In summary, the best inhibitors were selected from each of the summarizing figures and the results of the ranking were placed. In this way, the reader can learn about the structure of the compounds having the best antidiabetic activity. The compounds, whose synthesis was described in the article but did not appear on the figures presenting the structures of the most active inhibitors, did not show proper activity as inhibitors. Thus, the article also presents studies that have not yielded the desired results and show directions of research that should not be followed. In order to show the directions of the latest research, articles from 2018 to 2019 are described in a separate Sect.
5
. In Sect.
6
, biological mechanisms of action of the glycosides and patents of marketed drugs are described.
“…In the cases of 1,2,4-triazoles 57 and imidazoles 58, which aglycons gave the best inhibitors with an attached glucose unit, a weakening of three orders of magnitude could be observed [82]. Introduction of a double bond into the glucopyranose ring as in 59-61, to make the compounds somewhat similar to the glycosyliumion-like transition state of the catalyzed reaction, resulted in inefficient derivatives [84]. However, the exchange of the 2-OH to the isosteric NH 2 group gave highly active compounds 62-64, nevertheless, these lagged behind the parent glucose derivatives by factors of ~22, ~12 and ~6, respectively [85].…”
Section: Inhibition Of Rmgpb By Compounds Modified In the Glucose Unitmentioning
Glycomimetics are compounds that resemble carbohydrate molecules in their chemical structure and/or biological effect. A large variety of compounds can be designed and synthesized to get glycomimetics, however, C-glycosyl derivatives represent one of the most frequently studied subgroup. In the present survey syntheses of a range of five- and six membered C-glycopyranosyl heterocycles, anhydro-aldimine type compounds, exo-glycals, C-glycosyl styrenes, carbon-sulfur bonded oligosaccharide mimics are described. Some of the C-glycopyranosyl azoles, namely 1,2,4-triazoles and imidazoles belong to the most efficient glucose analog inhibitors of glycogen phosphorylase known to date. Biological studies revealed the therapeutical potential of such inhibitors. Other synthetic derivatives offer versatile possibilities to get further glycomimetics.
“…It is used as S1P1 receptor agonists in the treatment of multiple sclerosis, an autoimmune disorder, transplant rejection and it also agonists for cortical muscarinic receptors to treat Alzheimer's disease . It shows antidiabetes, anti‐inflammatory properties, anti‐bacterial agents, anti‐cancer agents and used as an HIV‐integrase inhibitor . 1,2,4‐oxadiazoles is a Nrf2 activator, which has been developed for the treatment of inflammation .…”
An innovative green synthesis of 3,5‐disubstituted 1,2,4‐oxadiazoles from dithioesters using water as a solvent. This approach becomes more interesting because it undergoes nucleophilic substitution–dehydration–intramolecular cyclization in a single step to give 3,5‐disubstituted 1,2,4‐oxadiazoles in good to excellent yields under transition‐metal free conditions and allows wide functional group tolerance. This green protocol leads to synthesis of a drug lead molecule, Ataluren and their analogues.
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