Structure Activity relationship of Bioactive Compounds from Medicinal Plants

Mahendran, S (2011) Structure Activity relationship of Bioactive Compounds from Medicinal Plants. Doctoral thesis, The Tamilnadu Dr. M.G.R. Medical University, Chennai.


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Natural products provide a starting point for new synthetic compounds with diverse structures and often with multiple stereocenters that can be challenging synthetically. Many structural features common to natural products (e.g., chiral centers, aromatic rings, complex ring systems, degree of molecule saturation, and number and ratio of heteroatoms) have been shown to be highly relevant to drug discovery efforts. Furthermore, since the escalation of interest in combinatorial chemistry and the subsequent realization that these compound libraries may not always be very diverse, many synthetic and medicinal chemists are exploring the creation of natural product and natural-product like libraries that combine the structural features of natural products with the compound-generating potential of combinatorial chemistry. Drugs derived from medicinal plants can serve not only as new drugs themselves but also as drug leads suitable for optimization by medicinal and synthetic chemists. Even when new chemical structures are not found during drug discovery from medicinal plants, known compounds with new biological activity can provide important drug leads. • Since the sequencing of the human genome, thousands of new molecular targets have been identified as important in various diseases. With the advent of highthroughput screening assays directed towards these targets, known compounds from medicinal plants may show promising and possibly selective activity. Hence, in the present study, embelin and mangiferin were selected as lead compounds for semi synthetic drug development. Embelin showed antifertility, anti-implantation, antitumour, anti-inflammatory, analgesic, antioxidant, hepatoprotective, wound healing and antibacterial activities [13-19]. Except these studies so far no other biological studies have been carried out. However, embelin has not been tested so far for anticonvulsant, antidiabetic, effect against inflammatory bowel disease and neuroprotection activities, though the plant (Embelia ribes) is reported against such a disorders [9,10,32,63,64,76,77]. Hence, in the present study, anticonvulsant, antidiabetic, effect in inflammatory bowel disease and neuroprotective activities of embelin were also carried out. • The plants selected for the study were berries of Embelia ribes and leaves of Mangifera indica. The plant materials were collected and authenticated. The dried materials were extracted and isolation of embelin and mangiferin was carried out from the respective plants. • Structural modification of embelin was carried out for structure activity relationship studies. Embelin was condensed with various aromatic substituted primary amines to yield sixteen new and eight known derivatives along with novel embelin-ninhydrin adduct were prepared. All these compounds were synthesized and purified by standard procedures, identified by using physical and spectral (IR, 1H NMR, 13C NMR and MS) properties. • During the last two decades, there has been a growing interest in studies that concern with prevention of uncontrolled oxidative process leading to various diseases in living system. Several studies have shown the role of oxidative stress in the causation and progression of various diseases including atherosclerosis, carcinogenesis, neurodegenerative diseases, radiation damage, aging and various other pathological effects. Antioxidant and related properties of the plant Embelia ribes and embelin are well known. Hence, all the synthesized compounds along with embelin were tested for in vitro antioxidant activity using ABTS and DPPH methods. When p-hydroxy aniline (10), sulphanilamide (13) phenyl alanine (21), phenyl hydrazine (22), 2,4-dinitro phenyl hydrazine (23) and tryptophan (24) were substituted at C-5 of embelin and substitution of o-phenylene diamine (25), the activity was found to be more potent than embelin in ABTS and DPPH methods. These compounds along with embelin were studied for analgesic and anti-inflammatory activities at 10 and 20 mg/kg doses by standard methods. Potent analgesic activity higher than the standard pentazocine was observed. Embelin and its derivatives almost completely abolished the acetic acid induced writhing. p-Sulfonylamine, phenyl propionic acid and phenazine derivatives showed better anti-inflammatory activity than embelin. • Based on a reaction of ninhydrin with phenols, embelin-ninhydrin adduct was prepared and characterized. It exhibited better antioxidant activity in DPPH method. The analgesic and anti-inflammatory activities were also found to be better than the parent moiety, embelin. In the acetic acid induced writhing almost complete abolition of writhing was observed at 10 and 20 mg/kg body weight doses of embelin-ninhydrin adduct and the results were found to be better than the standard pentazocine. • Structural modification of mangiferin was carried out for structure activity relationship studies. One new compound and three known derivatives were prepared from mangiferin. All these compounds were synthesized and purified by standard procedures, identified by using physical and spectral (IR, 1H NMR, 13C NMR and MS) properties. • The synthesized mangiferin derivatives were tested for in vitro antioxidant properties. Benzyl and methyl substituted mangiferin showed poor activity than mangiferin. However, mangiferin derivatives substituted with acetyl and benzoyl groups were showed potent activity than mangiferin in lipid peroxidation, p-NDA, deoxyribose and alkaline DMSO methods. But both the compounds failed to show potent analgesic and anti-inflammatory activities. In all these methods, standard drugs showed better activity than mangiferin and its derivatives. • Anticonvulsant activity of embelin (2.5, 5 and 10 mg/kg, i.p.) was studied. It showed a significant inhibition of the seizures induced by electroshock and pentylenetetrazole in a dose dependent manner and the activity was comparable to phenytoin and diazepam. Significant decrease in locomotion revealing its CNS depressant activity was observed. The findings suggest that embelin possess anticonvulsant activity against both grand mal and petit mal epilepsies. • In the antidiabetic activity, embelin (25 and 50 mg/kg, p.o.) administered orally to alloxan induced diabetic rats for 21 days caused a significant reduction in fasting serum blood glucose levels and significant improvement in body weights. Significant antidiabetic effects were obtained as evident from the restoration of biochemical parameters altered by alloxan towards the normal. Almost normal histological appearance of liver, kidney and pancreas tissues were observed in treated groups. Among the two doses, 50 mg/kg showed better activity. However, the activity was found to be less than the standard glibenclamide given at 10 mg/kg dose. The results showed that embelin has potential hypoglycemic effect along with recovery of liver, kidney and pancreas functions. • In the present study, protective activity of embelin against acetic acid induced colitis was investigated Experimental animals received embelin (25 and 50 mg/kg, p.o.) and sulfasalazine (100 mg/kg, p.o.) for five consecutive days before induction of colitis by intra-rectal acetic acid (3% v/v) administration and the treatment continued upto 7 days. The colonic mucosal injury was assessed by clinical, macroscopic, biochemical and histopathological examination. Embelin treatment significantly decreased clinical activity score, gross lesion score, percent affected area and wet colon weight when compared to acetic acid induced controls. The treatment also reduced significantly the colonic myeloperoxidase activity, lipid peroxides and serum lactate dehydrogenase and significantly increased the reduced glutathione. The histopathological studies also confirmed the above findings. The protective effect may be due to its antioxidant and antiinflammatory activities. • In the neuroprotective activity of embelin, global ischemia and reperfusion were induced by occluding bilateral common carotid arteries for 30 min followed by 24 h reperfusion. Neurological functions were measured by using sensorimotor tests. Ischemia reperfusion induced neuronal injury was assessed by cerebral infarct volume, biochemical and histopathological examination. Pretreatment of embelin (25 and 50 mg/kg, p.o.) significantly increased locomotor activity and hanging latency time and decreased beam walking latency when compared to ischemic control. The treatment also reduced significantly the lipid peroxidation and increased the total thiol and glutathione-S-transferase activity. Cerebral infarction area and histopathological findings also confirmed the above findings. These findings suggested that embelin is a neuroprotective and may prove to be useful adjunct in the treatment of stroke. • In conclusion, in the present study structural modification of two natural products was carried out for structure activity relationship studies. Including sixteen new compounds twenty four derivatives along with a novel embelin-ninhydrin adduct were prepared from embelin. A new and three known mangiferin derivatives were also prepared. All these compounds were characterized by physical and spectral properties. The derivatives of embelin and mangiferin were tested for in vitro antioxidant properties. Some of the derivatives showed potent in vitro antioxidant properties compared to the parent moieties. The potent antioxidant compounds also exhibited potent analgesic and anti-inflammatory activities. Hence, the structural modification of natural compounds played an important role to improve the biological activities. Embelin exhibited potent anticonvulsant properties. It exhibited potent antidiabetic properties in alloxan induced diabetes, protective effect against acetic acid induced colitis and neuroprotective effect against global cerebral ischemia in rats. Hence, new biological properties of embelin were established, which supports the traditional claim of the plant. Further research would be of interest to explain the exact mechanism of the parent compounds and their chemical modifications.

Item Type: Thesis (Doctoral)
Uncontrolled Keywords: Structure activity, bioactive compounds, medicinal plants.
Subjects: PHARMACY > Pharmaceutical Chemistry
Depositing User: Subramani R
Date Deposited: 19 Aug 2017 03:47
Last Modified: 27 Oct 2022 14:25

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