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Abdildinova, Aizhan,Yang, Seung-Ju,Gong, Yong-Dae Elsevier 2018 Tetrahedron Vol.74 No.6
<P><B>Abstract</B></P> <P>Design and solid phase synthesis of the 1,3,4-oxadiazole based peptidomimetic library is presented. Library synthesis starts from the coupling of the thiosemicarbazide resin with Fmoc-protected amino acid following desulfurative cyclization to 1,3,4-oxadiazoles. Following substitution of the secondary amine with the 3-nitrobenzoyl functional group and its further reduction were performed. Thus, the functionalization with amino acids could be performed on both sides of the core skeleton. After diversification and cleavage from the resin using TFA: DCM cleavage cocktail, an enantiopure library of compounds was obtained. Further evaluation of physicochemical properties was performed.</P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>
Abdildinova, Aizhan,Gong, Young-Dae American Chemical Society 2018 ACS Combinatorial Science Vol.20 No.6
<P>Solid-phase organic synthesis is a powerful tool in the synthesis of small organic molecules and building of libraries of compounds for drug discovery. Heterocyclic compounds are important components of the drug discovery field as well and serve as a core for hundreds of marketed drugs. In particular, oxadiazole and thiadiazole cores are compounds of great interest due to their comprehensive biological activities and structural features. Therefore, a plethora of oxadiazole and thiadiazole synthesis methodologies have been reported to date, including solution and solid-phase synthesis methodologies. In this review, we concentrate on and summarize solid-phase synthetic approaches of the oxadiazole and thiadiazole derivatives.</P> [FIG OMISSION]</BR>
Abdildinova, Aizhan,Yang, Seung-Ju,Gong, Young-Dae American Chemical Society 2016 ACS Combinatorial Science Vol.18 No.12
<P>A novel solid-phase synthesis methodology of N-substituted-2-aminothiazolo[4,5-b]pyrazine derivatives was developed. The key step in this synthesis strategy is the tandem reaction of isothiocyanate terminated resin 2 with o-bromo-2-aminopyrazine, affording cyclized 2-aminothiazolo[4,5-b]pyrazine resin 4. To increase the diversity of our library, Suzuki coupling reaction was performed at the position C6. Further functionalization of 2-aminothiazolo[4,5-b]pyrazine core skeleton with various electrophiles such as alkyl halides, acyl chlorides, and sulfonyl chlorides and cleavage from the resin with TFA in DCM generated N-alkyl-, N-acyl-, and N-sulfonyl-2-aminothiazolo[4,5-b]pyrazine derivatives. The physicochemical properties and the polar surface areas of synthesized compounds were evaluated.</P>
김영창,Abdildinova Aizhan,신예진,한동균,Hwang Jong Yeon,천혜경,공영대 대한화학회 2023 Bulletin of the Korean Chemical Society Vol.44 No.11
5-Lipoxygenase (5-LO) is one of the significant drug targets for the development of various anti-inflammatory drugs. Herein, we designed, optimized, and synthesized a novel N-((6-(substituted-amino)-2-methyl-2H-chromen-2-yl)methyl)-Nmethylbenzenesulfonamide derivatives as potential 5-LO inhibitors. Among the synthesized compounds, 10a, 10b, and 10g exhibited inhibitory activity toward 5-LO according to the in vitro studies including enzyme activity assay (≥78% inhibition rate at 1 μM) and cell-based assay (≥72% inhibition rate at 1 μM). 10b was selected for further in vivo efficiency using an ear edema mouse model, which was induced by arachidonic acid. Oral administration of 10b successfully suppressed ear edema and myeloperoxidase activity (MPO activity). Molecular docking studies showed alkyl and pi-alkyl interactions of compound 10b with Ile126 and Val110 of 5-LO as well as a hydrogen bonding with Arg138 as key protein-ligand interactions.
Lee Hwa‐Sung,Abdildinova Aizhan,Cho Young Sik,Cheon Hyae Gyeong,Gong Young‐Dae 대한화학회 2022 Bulletin of the Korean Chemical Society Vol.43 No.6
5-LO inhibitors can potentially be employed for the treatment of various inflammatory disorders. In this study, we have designed and synthesized new N-alkyl-10-(substituted sulfonyl)spiro[chromene-2,40-piperidin]-6-amine-based library as potential and novel 5-LO inhibitors. In vitro results showed that several synthesized compounds exhibited high 5-LO inhibitory activity, in parallel with the inhibition of leukotriene B4 (LTB4) production in the rat basophilic leukemia (RBL-1) cells. Among the synthesized compounds, 8l was selected for in vivo study using a mouse ear edema model: oral administration of 8l (100 mg/kg) inhibited arachidonic acid-induced ear edema, myeloperoxidase (MPO) activity, and LTB4 synthesis. SAR analysis and molecular docking studies demonstrated the allosteric binding mode between 5-LO and the synthesized compounds including 8l.
Yang, Seung-Ju,Choe, Ji-Hye,Abdildinova, Aizhan,Gong, Young-Dae American Chemical Society 2015 ACS Combinatorial Science Vol.17 No.12
<P>A 2-amino/amido-1,3,4-oxadiazole and 1,3,4-thiadiazole library has been constructed on solid-phase organic synthesis. The key step on this solid-phase synthesis involves the preparation of polymer-bound 2-amino-1,3,4-oxadiazole and 1,3,4-thiadiazole core skeleton resin by cyclization of thiosemicarbazide with EDC·HCl and <I>p</I>-TsCl, respectively. The resulting core skeleton undergoes functionalization reaction with various electrophiles such as alkyl halides, and acid chlorides to generate <I>N</I>-alkylamino and <I>N</I>-acylamino-1,3,4-oxadiazole, and 1,3,4-thiadiazole resin, respectively. Finally, the 2-amino and 2-amido-1,3,4-oxadiazole and 1,3,4-thiadiazole library was then generated in good yields and high purities by cleavage of the respective resin under trifluoroacetic acid(TFA) in dichloromethane(DCM). The constructed library shows reasonable, oral bioavailability drug properties as determine by using the Lipinski’s Rule and similar parameters.</P><P><B>Graphic Abstract</B> <IMG SRC='http://pubs.acs.org/appl/literatum/publisher/achs/journals/content/acsccc/2015/acsccc.2015.17.issue-12/acscombsci.5b00140/production/images/medium/co-2015-001407_0011.gif'></P><P><A href='http://pubs.acs.org/doi/suppl/10.1021/co5b00140'>ACS Electronic Supporting Info</A></P>
Lim Sungsu,Shin Seulgi,Sung Yoonsik,Lee Ha Eun,Kim Kyu Hyeon,Song Ji Yeon,Lee Gwan-Ho,Aziz Hira,Lukianenko Nataliia,Kang Dong Min,Boesen Nicolette,Jeong Hyeanjeong,Abdildinova Aizhan,Lee Junghee,Yu By 생화학분자생물학회 2023 Experimental and molecular medicine Vol.55 No.-
Tau oligomers play critical roles in tau pathology and are responsible for neuronal cell death and transmitting the disease in the brain. Accordingly, preventing tau oligomerization has become an important therapeutic strategy to treat tauopathies, including Alzheimer’s disease. However, progress has been slow because detecting tau oligomers in the cellular context is difficult. Working toward tau-targeted drug discovery, our group has developed a tau-BiFC platform to monitor and quantify tau oligomerization. By using the tau-BiFC platform, we screened libraries with FDA-approved and passed phase I drugs and identified levosimendan as a potent anti-tau agent that inhibits tau oligomerization. 14C-isotope labeling of levosimendan revealed that levosimendan covalently bound to tau cysteines, directly inhibiting disulfide-linked tau oligomerization. In addition, levosimendan disassembles tau oligomers into monomers, rescuing neurons from aggregation states. In comparison, the well-known anti-tau agents methylene blue and LMTM failed to protect neurons from tau-mediated toxicity, generating high-molecular-weight tau oligomers. Levosimendan displayed robust potency against tau oligomerization and rescued cognitive declines induced by tauopathy in the TauP301L-BiFC mouse model. Our data present the potential of levosimendan as a disease-modifying drug for tauopathies.