Dinesh Kumar, V (2021) Design, Synthesis and Pharmacological Evaluation of Novel Heterocyclic PCSK9 Inhibitors as Antihyperlipidemic Agents. Masters thesis, College of Pharmacy, Madras Medical College, Chennai.
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Abstract
Medicinal chemistry primarily aims to discover novel chemical molecule which have the potential to prevent or treat a disease / infection. According to the WHO reports, Hyperlipidemia is one of the leading causes of death globally. Therefore, the current work aimed to design and synthesize some novel antihyperlipidemic compounds. Based on the literature review, PCSK9 has been considered as potential therapeutic target for selective LDLR regulation in the treatment of hyperlipidemia. Based on the literature review, pharmacophoric features such as 1 HBD, 1 HBA and 1 Aromatic ring were identified. Hence a scaffold library has been generated with 150 newly designed ligands which were screened with high docking score against PCSK9 using Autodock4.2.6. software and further optimized by drug likeliness properties such as Lipinski rule of five and ADMET properties. All the designed ligands were found to obey lipinski’s rule of five and possess drug likeliness property. Results of the in silico toxicity studies showed that all the designed compounds found to be non-toxic. Based on high docking scores and synthetic feasibility ligand 7, ligand 8, ligand 10, ligand 12 and ligand 13 was selected for synthesis. All the selected ligands were chemically synthesized with different aromatic carboxylic acids. Completion of the reaction was determined by TLC. The synthesized compounds are labelled as VD1, VD2, VD3, VD4 and VD5. The purity of the synthesized compounds was checked by determining Melting point. The chemical nature of synthesized compounds was characterized by different spectral studies such as IR, 1HNMR and LC- MS spectroscopy. All the synthesized compounds were subjected to acute oral toxicity studies as per the OECD Guidelines 423 to access the toxicity and also to fix the dose. The LD50 value of the test compound VD1, VD2, VD3, VD4 and VD5 does not found to 2000mg/kg and also no mortality was observed. Based on high docking score CompoundVD1 was selected for further pharmacological evaluation. The dose 100mg/kg and 200mg/kg were selected. In vivo antihyperlipidemic activity was evaluated for compound VD1 against HFD induce Hyperlipidemia in wistar rats. The rats were divided into five groups of 6 animals each. From In vivo activity study, it was found that the body weight of Group B rats (rats treated with HFD) were significantly increased (P < 0.001) in comparison with normal control rats. The increment in the body weight was reduced considerably (P < 0.001) by the administration of Atorvastatin and test compound VD1 (200mg/kg and 100mg/kg). However, Group D (200mg/kg) showed decrease in body weight to normal as that of Group E. The level of serum TC, TG, LDL, VLDL were significantly increased (P < 0.001) in disease Control group in comparison with normal control group. Administration of test compound VD1 at the dose of 100mg/kg and 200mg/kg showed considerable reduction in serum TC, TG, LDL, VLDL in comparison with disease control. In comparison of the two doses of test group, the test compound at the dose of 200mg/kg was revealed considerable reduction of LDL and VLDL as that of Atorvastatin treated group. The level of serum HDL were significantly decreased (P<0.001) in disease Control group in comparison with normal control group. Administration of test compound VD1 at the dose of 100mg/kg and 200mg/kg showed considerable raised serum HDL in comparison with disease control. In comparison of the two doses of test group, the test compound at the dose of 200mg/kg was revealed considerable raise in HDL as that of Atorvastatin treated group. It has been shown that the Atherogenic index is strong marker to predict the risk of atherosclerosis and CVD. Test compound showed significant reduction of AI in compared to disease control group. From the histopathological studies, the compound VD1 at 200mg/kg normalize the tissue of both liver and heart compared to disease control group. CONCLUSION: Drug design approach as well as clinical studies has revealed that the PCSK9 have a crucial role in LDLR regulation for the treatment of Hyperlipidemia. The present study also provides important structural insight of benzoxazole, amino triazole and oxadiazole in designing better PCSK9 inhibitor as potent antihyperlipdimic agents. The designed compounds were docked against PCSK9 using Autodock4.2.6. The synthesized compounds VD1, VD2, VD3, VD4 and VD5 found to obey Lipinski’s rule of five and also possess drug likeliness property. Based on high docking score Compound VD1 has been selected for evaluating in vivo antihyperlipidemic activity and it found to reduce LDL level effectively with significance of P value 0.001 when compared to the standard drug Atorvastatin. Further evaluation studies including in vitro, in vivo antihyperlipidemic screening and PCSK9 enzyme Inhibition assay method using ELISA kit. will be performed for all the remaining synthesized compound (VD2, VD3, VD4, VD5) in future.
| Item Type: | Thesis (Masters) |
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| Additional Information: | 261915703 |
| Uncontrolled Keywords: | Design, Synthesis, Pharmacological Evaluation, Novel Heterocyclic PCSK9 Inhibitors, Antihyperlipidemic Agents. |
| Subjects: | PHARMACY > Pharmaceutical Chemistry |
| Depositing User: | Subramani R |
| Date Deposited: | 02 Nov 2022 17:45 |
| Last Modified: | 03 Nov 2022 14:11 |
| URI: | http://repository-tnmgrmu.ac.in/id/eprint/20927 |
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