Design, Docking, Synthesis of Certain Flavonoids and Evaluation of their Angiotensin Converting Enzyme Inhibitory Activity

Devika Gayatri, M (2017) Design, Docking, Synthesis of Certain Flavonoids and Evaluation of their Angiotensin Converting Enzyme Inhibitory Activity. Masters thesis, Sri Ramakrishna Institute of Paramedical Sciences, Coimbatore.


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INTRODUCTION:Drug discovery and development is a research process that identifies a new chemical entity and brings out its capabilities by designing and screening proper biochemical targets. It is an innovative science in which both knowledge and technologies are incorporated to convert a chemical moiety into useful therapeutic drugs. The discovery and development process of novel drugs generally takes a long time and it is recognized to be, risky and costly. It takes approximately 14 years to fulfil the typical drug discovery process and development cycle from concept to market and the cost ranges from 0.8 to 1.0 billion USD. Rapid developments in combinatorial chemistry and high-throughput screening technologies have provided an environment to expedite the drug discovery process by enabling huge libraries of compounds to be screened and synthesized in short time. Although the investment in new drug development has grown significantly in the past decades, the output is not directly proportional to the investment because of the low efficacy and high failure rate in drug discovery. Consequently, various approaches have been developed to shorten the research cycle and reduce the expense and risk of failure for drug discovery. Computer-aided drug design (CADD) is one of the most effective methods for reaching these goals.OBJECTIVE OF THE STUDY:High blood pressure or hypertension is a major cause of morbidity and mortality because of its association with coronary heart disease, cerebrovascular disease and renal disease. The extent of target organ involvement (i.e. heart, brain and kidneys) determines outcome. Worldwide, hypertension is estimated to cause 7.5 million deaths, about 12.8% of the total of all deaths and this also accounts for 57 million disability adjusted life years (DALYS) or 3.7% of total DALYS. The increasing prevalence of the condition is blamed on lifestyle and dietary factors such as physical inactivity, alcohol and tobacco use and a diet high in sodium. Angiotensin Converting Enzyme (ACE), the central component of the Renin-Angiotensin System (RAS) controls the blood pressure by regulating the volume of fluids in the body. It converts the hormone angiotensin 1 to the angiotensin ll. Therefore ACE indirectly increases blood pressure by causing blood vessels to constrict. The inhibition of ACE is considered as one of the most effective therapeutic strategy for the treatment of Hypertension. Enzyme inhibitors are used as potent therapeutic agents for the treatment of various diseases. More than 100 drugs used worldwide are enzyme inhibitors. ACE inhibitors such as captopril, enalapril, fosinopril and ramepril currently available in the market; exert antihypertensive effect by competitively binding to the active site of ACE. Flavonoids are fairly versatile compounds and are easy to synthesize. They are associated with a wide range of pharmacological properties including antimicrobial, antioxidant, anticancer, anti-inflammatory activities. In addition, literature review also revealed that flavonoids possess ACE inhibitory activity.SUMMARY:The present study is focussed on the designing and synthesis of some novel flavonoid derivatives and evaluation of their possible Angiotensin converting enzyme inhibitory activity. For this the following approaches has been adopted. Phase 1: Literature review Literature review provides a solid background to the back one’s investigation. It plays a critical role in analysing the existing literature. Literatures reported flavonoids as a good lead for ACE inhibition. Phase 2: Drug design approach It involves the following steps 1) Identification of drug target ACE was selected as the target enzyme for the antihypertensive activity. 2) Lead identification The lead molecule flavonoid was selected based on literature reviews. Various naturally occurring flavonoids were reported to have Angiotensin converting enzyme inhibiting activity. 3) Lead optimization Lead optimization is an operationally diverse stage in which the chemical structure of compounds is modified to improve the specificity and selectivity. Lead optimization was done by observing the computational drug likeness properties. All the 10 compounds possessed good drug likeness score and good oral bioavailability. Hence were eligible for further study.4) Molecular docking studies Molecular docking study was done by using Autodock4.2. The target enzyme ACE was downloaded from RCSB protein data bank (pdb ID: 1o86). The ligands were subjected to docking and most of the compounds showed binding energy to the enzyme higher than that of standard drug (Lisinopril) used. The ligands SB2, SB4, SB3, SB1, BF5, BF3 were showing best docked to1o86. Phase 3: Synthesis In this work, 10 new compounds were synthesized. Two schemes were developed for the synthesis of compounds. Resacetophenone was used as the starting material for both schemes. In the first scheme resacetophenone reacted with nitro substituted vanillin to form chalcone in presence of ethanol and sodium hydroxide. This formed chalcone was subjected to cyclisation in presence of iodine and DMSO. The product formed was nitro substituted flavonoid and was further reduced to convert the nitro group into amino group. Finally Schiff bases were prepared from this amino flavonoid by reaction with various substituted benzaldehydes. In the second scheme various substituted benzoyl chlorides were prepared from corresponding benzoic acids and treated with resacetophenone which was refluxed for 24 hours to obtain desired products (substituted benzoyl flavones). Phase 4: Physical characterisation Melting points and Rf value of all the compounds are found out. Phase 5: Spectral characterisation The structures of the synthesized compounds are established based on the UV, IR, 1HNMR and Mass spectral data.CONCLUSION: The basic aim of the present work is to identify the correct conformation of ligands in the active site of enzyme and also to predict their affinity towards the enzyme. Computational drug designing approach helps in minimizing the wearisome process of drug discovery and delivers a new drug candidate more rapidly. The drug likeness proved the compounds to be orally bioactive Docking results established the possibility of flavonoid moiety to possess Angiotensin converting enzyme inhibitory activity. The 10 derivatives were synthesized based on the schemes which are previously fixed and it led to good yields. Physical characteristics of the compounds were confirmed by melting point and Rf value. Structure of the compounds were finally confirmed by UV, IR 1HNMR and Mass spectral studies. The synthesized compounds were subjected to the in vitro ACE inhibitory activity. Derivatives of the flavonoids exhibited moderate activity against ACE. These leads to the inference that all the 10 newly synthesized compounds possess angiotensin converting enzyme inhibitory activity. Novel structure based drug designing methods helped to screen various compounds for a specific activity within a short period of time. Further in vivo studies with these tested synthetic flavonoids have to be carried out to corroborate the result of in vitro activity. The present work could be considered as a propitious step for finding the prominence of flavonoid moiety in the treatment of hypertension by inhibiting the key enzyme ACE.

Item Type: Thesis (Masters)
Additional Information: REGISTRATION No.261515101
Uncontrolled Keywords: Design ; Docking ; Synthesis ; certain Flavonoids ; Angiotensin Converting Enzyme ; Inhibitory Activity
Subjects: PHARMACY > Pharmaceutical Chemistry
Depositing User: Ravindran C
Date Deposited: 16 Mar 2018 05:53
Last Modified: 16 Mar 2018 05:53

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