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Title: Azaheterocycles and Peptides; Design, Synthesis, Bioevaluation and Computational Studies
Authors: Jabeen, Farukh
Keywords: Natural Sciences
Chemistry & allied sciences
Physical chemistry
Techniques, equipment & materials
Analytical chemistry
Inorganic chemistry
Organic chemistry
Issue Date: 2014
Publisher: Quaid-i-Azam University Islamabad
Abstract: A chemical library of small drug-like heterocylic compounds, 2,3-dihydro-1,5- benzothiazepines was synthesized using Silica gel as an inorganic support. All the synthesized 2,3-dihydro-1,5-benzothiazepines were obtained in excellent yields. Another library of 1,4-disubstituted-1,2,3-triazoles was synthesized by a Cu(I) catalyzed click reaction, where organic azides, with electron donating and electron withdrawing groups acted as 1,3-dipoles and 1-ethynyl-1-cyclohexanol and acetylene served as the terminal alkyne counterparts. The [3+2] cycloaddition was highly regiospecific and lead exclusively to 1,4-disubstituted triazoles in high yields. Seven sets of triazoles were synthesized, the synthesized triazoles were obtained in good yields. Some hetero-aryl 1,2,3-triazoles were also synthesized successfully in good yields. “On water”, one pot synthesis of triazoles of set 4, under the same click conditions was also employed. The method proved to be facile and more economic. Characterization of all the synthesized 2,3-dihydro-1,5-benzothiazepines, azides and triazoles was carried out through their physical constants and spectroscopic data. Regioselective chiral synthesis of peptides and iso-peptides was also carried out by employing benzotriazole mediated synthesis where benzotriazole acts as both activating and leaving group. All the synthesized peptides were obtained in good to excellent yields with retention of original chirality as confirmed through the single set of signals in 1 H and 13 C NMR spectra. Peptidyl triazoles were also synthesized for fragment based coupling to obtain longer chain iso-peptides. Microwave assisted ON acyl migration in iso-tri peptides and iso-tetrapeptide was carried out for the synthesis of native peptides from iso-peptides. Moreover Traceless Native Chemical Ligation (TNCL) on the serine site was successfully achieved through 8- and 11- membered transition states in iso-tri- and iso-tetrapeptides respectively. The synthesized chemical libraries of heterocycles were screened for their potential as, α-glucosidase and Butyrylcholinesterase (BChE) inhibitors, BChE is a tetrameric glycoprotein BChE, distributed in the body of vertebrates specially Central Nervous System (CNS). Some 1,4-di-substituted 1,2,3-triazoles such as 37, 40, 45, 53 and 60 were found active against α-glucosidase and BChE. These dual inhibitors may be important for developing drugs for the treatment of AD and T2D. Peptides and iso- iiiAbstract peptides were subjected to chemo-preventive assays on breast cancer cell lines along with cytotoxicity assays. Some of these peptides exhibited moderate activities against cancer cell lines. Antibacterial and antifungal activities of synthesized heterocycles and peptides were also studied but activities were not remarkable. Computational studies were carried out on active compounds, with an objective to provide an insight to binding mode analysis of active compounds against different targets by using the molecular docking tools and physical descriptor module of Molecular Operating Environment (MOE). All the compounds except few deviations from only one parameter, showed compliance with Ro5 and hence found to be druglike. Human BChE (PDB code:1POI) was selected for docking studies of active compounds. Homology modeling of α-glucosidase was carried out for maximum sequence similarity. Modeled α- glucosidase was used for molecular docking studies. A good relationship was observed between the activity and ligand receptor interaction of active compounds. Molecular docking of peptides were also carried out against kinases and two of the proteins were imported from the protein data bank with PDB codes, 3BRT (1kkα) and 3BRV (1kkβ) respectively. The binding mode was analyzed by studying ligand-receptor complex interaction of these peptides.
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