Zharylkasyn A. Abilov

Synthesis of 2-arylated thiadiazolopyrimidones by Suzuki–Miyaura cross-coupling: a new class of nucleotide pyrophosphatase (NPPs) inhibitors

Over expression of nucleotide pyrophosphatase (NPPs) activity is associated with chondrocalcinosis, osteoarthritis, type 2 diabetes, neurodegenerative diseases, allergies and cancer metastasis. The potential of NPPs inhibitors as therapeutic agents, and the scarceness of their structure–activity relationship, encouraged us to develop new NPP inhibitors. Specifically, 2-bromo-7-methyl-5-oxo-5H-1,3,4-thiadiazolopyrimidine and its corresponding 6-fluoro derivatives were synthesized via a Suzuki–Miyaura reaction. The cross-coupling reaction with different arylboronic acids gave desired coupling products in good to excellent yields and showed wide functional group tolerance. Furthermore, all compounds were investigated for their potential to inhibit two families of ecto-nucleotidases, i.e. nucleoside triphosphate diphosphohydrolases (NTPDase) and NPPs. Interestingly, our compounds were identified as selective inhibitors of NPPs. Among derivatives 5a–5i, compound 5i (IC50 ± SEM = 0.39 ± 0.01 μM) was found to be the most potent inhibitor of h-NPP1 and compound 5h (IC50 ± SEM = 1.02 ± 0.05 μM) was found to be the most potent inhibitor of h-NPP3. Similarly, for fluorinated thiadiazolopyrimidones, derivative 6e (IC50 ± SEM = 0.31 ± 0.01 μM) exhibited the best inhibition of NPP1 and it was found that this compound exhibited ≈28 fold improvement in inhibitory potential as compared with the reference control i.e. Suramin (IC50 ± SEM = 8.67 ± 1.3 μM). Moreover, homology modelling and molecular docking studies of both inhibitors were carried out to suggest the putative binding mode of inhibitors with the respective enzyme i.e. h-NPP1 and h-NPP3.

2-Substituted 7-trifluoromethyl-thiadiazolopyrimidones as alkaline phosphatase inhibitors. Synthesis, structure activity relationship and molecular docking study

Alkaline Phosphatases (APs) play a key role in maintaining a ratio of phosphate to inorganic pyrophosphate (Pi/PPi) and thus regulate extracellular matrix calcification during bone formation and growth. Among different isozymes of AP, aberrant increase in the level of tissue non-specific alkaline phosphatase (TNAP) is strongly associated with vascular calcification and end-stage renal diseases. In this context, we synthesized a novel series of fluorinated pyrimidone derivatives, i.e., 2-bromo-7-trifluoromethyl-5-oxo-5H-1,3,4-thiadiazolepyrimidones. The bromine functionality was further used for derivatisation by nucleophilic aromatic substitution using amines as nucleophiles as well as by Palladium catalysed Suzuki-Miyaura reactions. The synthesized derivatives were found potent but non-selective inhibitors of both isozymes of AP. Arylated thiadiazolopyrimidones exhibited stronger inhibitory activities than 2-amino-thiadiazolopyrimidones. The binding modes and possible interactions of the most active inhibitor within the active site of the enzyme were observed by molecular docking studies.

Synthesis of Functionalized Acetophenones by Formal [3+3] Cyclocondensations of 1,3-Bis(silyloxy)-1,3-butadienes with 3-Alkoxyand 3-Silyloxy-2-acetyl-2-en-1-ones

The TiCl4-mediated cyclization of 1,3-bis(silyloxy)-1,3-butadienes with 2-acetyl-1-silyloxybut-1- en-3-one and 3-acetyl-4-silyloxypent-3-en-2-one, readily available from 3-(formyl)acetylacetone and 3-(acetyl)acetylacetone (triacetylmethane), afforded a variety of functionalized acetophenones Graphical Abstract Synthesis of Functionalized Acetophenones by Formal [3+3] Cyclocondensations of 1,3-Bis(silyloxy)-1,3-butadienes with 3-Alkoxyand 3-Silyloxy-2-acetyl-2-en-1-ones

Regioselective synthesis of CF2Cl-substituted biaryls by [3+3] cyclocondensation of 1,3-bis(trimethylsilyloxy)-1,3-butadienes with 4-aryl-1-chloro-1,1-difluoro-4-(trimethylsilyloxy)-3-en-2-ones

The TiCl4-mediated [3+3] cyclocondensation of various 1,3-bis(trimethylsilyloxy)-1,3-butadienes with 4-aryl-1-chloro-1,1-difluoro-4-(trimethylsilyloxy)-3-en-2-ones provides a regioselective approach to novel 4-aryl-6-(chlorodifluoromethyl)salicylates (CF2Cl-substituted biaryls) with very good regioselectivity.Graphical abstract

Synthesis of Methyl 2-arylthio-5 -aryldiazenylbenzoates by Formal [3+3]Cyclizations of 3-arylthio-1-silyloxy-1,3-butadienes with 2-aryldiazenyl-3-silyloxy-2-en-1-ones

Abstract The formal [3+3]cyclization of 3-arylthio-1-silyloxy-1,3-butadienes with 2-aryldiazenyl-3-silyloxy-2-en-1-ones afforded a variety of 2-arylthio-5-aryldiazenylbenzoates. GRAPHICAL ABSTRACT

Regioselective Synthesis of 5-(2-Methoxyethyl)biphenyls by Formal [3+3] Cyclocondensations of 1,3-Bis(trimethylsilyloxy)-1,3-butadienes

5-(2-Methoxyethyl)biphenyls have been prepared by regioselective formal [3+3] cyclocondensations of 1,3-bis(trimethylsilyloxy)-1,3-butadienes. Graphical Abstract Regioselective Synthesis of 5-(2-Methoxyethyl)biphenyls by Formal [3+3] Cyclocondensations of 1,3-Bis(trimethylsilyloxy)-1,3-butadienes

Standardization, biological activity and application of medicines from plants Limonium gmelinii

There are the data on the chemical study for plants of the genus Limonium gmelinii and of the creation on their basis the effective medicines of wide action range which introduced into practical medicine.