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Title: Biological Activities of Thioureas Derived From New Primary Amines and Their Prepressive Effects on Glucose-6-Phosphatase
Authors: Naz, Sumaira
Keywords: Chemistry
Issue Date: 2019
Publisher: University of Malakand, Malakand
Abstract: The role of thioureas in medicinal chemistry is immense; they possess polypharmacology in their nature which explains the so many and diverse bio activities associated with them. Having this in view, the current study was planned to explore some new potential drugs from thioureas class of organic compounds. Initially 10 thioureas were synthesized which were obtained in good yields and then characterized by different spectroscopic techniques. These compounds were given arbitrary numbers from 1 to 10. The biological activities of the synthesized compounds were assessed and in vitro antibacterial, antioxidant, antidiabetic and anticholinesterase potentials of the compounds were examined. The compounds were also fed to the experimental mice to find their in vivo antilipidemic, antihyperglycemic and toxicological effects. The compounds showed fair anti Alzheimer’s potential (in vitro) which is evident from their inhibition potentials against the two cholinesterases AChE and BChE. They also delivered very good in vitro antidiabetic activity by inhibiting the enzymes α-amylase, alpha-glucosidase and glucose-6-phosphatase; glucose-6-phosphatase was inhibited the most followed by α-amylase and then α-glucosidase. Moreover, the in vitro antidiabetic activity seemed to be more pronounced as compared to that of anti-AD. Of the compounds, compound 8 was more effective inhibitor of AChE (IC50 of 63 μg/ml) and also of BChE (IC50 of 80 μg/ml) than the rest of synthesized compounds. As for antidiabetic potential, against α-amylase, compound 9 turned out to the best inhibitor with IC50 of 62 μg/ml; alpha glucosidase was efficiently inhibited by compound 8 with of IC50 75 μg/ml, and glucose-6-phophatase was more potently inhibited by compound 10 which decreased the enzyme’s activity to a much lower level of 3.12± 1.1 (at concentration of 1000 mg/ml). All the compounds showed good scavenging potentials against DPPH and ABTS free radicals. DPPH was more potently scavenged by compound 1 with IC50 45 μg/ml while ABTS was also efficiently inhibited by compound 1 with IC50 45 μg/ml. The synthesized compounds were also assessed for their antibacterial spectrum against selected bacterial strains. Against Agrobacterium tumefacien compound 6 was more active (MIC of 4.02 μg/ml) as compared to other bacterial strains while against Proteus vulgaris compound 2 was more active (MIC value 4.45 μg/ml). The growth inhibition of Staphylococcus aureus was more pronounced for compound 9 (MIC= 4.03 μg/ml). The in vivo inhibition of glucose-6-phosphatase was greater for compound 7 that decreased the activity of enzyme to an extent of 21.42 at a dose of 1.5 mg/kg body weight of mice. The toxicity study of the compounds was then performed in Swiss albino mice; only four compounds (4, 7, 9 and 10) were turned out to be safe enough to be used for systemic uses as they produced no toxicological effects on biochemical and hematological parameters at the studied doses. The findings were also confirmed by histology study of liver specimens taken from the experimental animals. Blood glucose and lipid profiles of the experimental animals were also monitored at regular intervals and compounds declared as safe, viz., 4, 7, 9 and 10 were found to have notable hypoglycemic and antilipidemic potentials. These four compounds were then fed to STZ-induced diabetic mice; compound 7 was found to have a very potent antihyperglycemic potential as it decreased the blood glucose level up to 108.56±4.15 mg (of P released) being very close to 102.3 ± 3.73 mg (of p released), which was the glucose level recorded for the group that was treated with the commercially available antidiabetic medicine Glibenclamide. The body weight in the case of the group treated with compound 7 remained normal as compared to that of the negative control group. Compound 7 also effectively decreased triglyceride and LDL level and brought about a healthy increase in HDL level after 28 days of treatment. Although an array of different in vivo and in vitro activities was observed for the 10 compounds and these, in general, were found to have antioxidant, antibacterial, anticholinesterase, antidiabetic and antilipidemic potentials up to one extent or the other, but final selection for the in vivo testing was made based on toxicological screening in the experimental mice. Compound 4, 7, 9 and 10 were found safe and having enough antidiabetic therapeutic potential and thus could be used for treatment of hyperglycemia and hyperlipidemia in patients with type-2 diabetes mellitus. Further studies which are compulsory steps required in the development of any new potential drug like structure activity relationship (SAR) and "absorption, distribution, metabolism, and excretion" (ADME) are still required to be carried out to establish the formal therapeutic status of the compounds.
Gov't Doc #: 20051
Appears in Collections:PhD Thesis of All Public / Private Sector Universities / DAIs.

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