NEW PHARMACOPHORES FROM MEDICINAL PLANTS
M. Iqbal Choudhary and Atta-ur-Rahman
International Center for Chemical and Biological Sciences, H.E.J. Research Institute of Chemistry and Dr. Panjwani Center for Molecular Medicine and Drug Research, University of Karachi, Karachi-75270, Pakistan
Abstract
Biodiversity is an outward manifestation of chemical diversity. Plants contain a fascinating array of highly evolved, specific, and effective gene products. Their diverse structural and stereochemical characteristics make them valuable templates for exploring novel molecular diversity. Nature has been the first source of cure for diseases and discomforts, which have led to the foundation of many empirical therapeutic systems. Even today over 50% of prescription drugs owe their origin to plants. Therefore, the need of systematic scientific research on folk remedies is essential for the future development of integrated healthcare system and medicines for poor man diseases.
During last four decades, our research has been focused on the discovery of chemical constituents from medicinal plants used in traditional medicines. This has resulted in the identification of several novel series of bioactive natural products. This work has also validated the traditional uses of many common traditional and folk medicines in many cases. During this presentation, some recent examples of our studies will be presented.
Inhibitors of the enzyme dipeptidyl peptidase IV (DPP IV) provide a strategy for the treatment of type 2 diabetes since it breaks down two important gut hormones glucagon-like peptide-1 (GLP-1) and gastric inhibitory polypeptide (GIP). We have screened natural compounds of various chemical classes such as flavonoids, coumarins, polyphenols, alkaloids, glycosides, and xanthonoids and their derivatives for evaluation of DPP IV inhibitory potential which showed moderate inhibition of activities IC50 ranging from 28.9 to 84.9 µM as compared to the standard sitagliptin IC50 0.033 µM.
Glycation is a nucleophilic reaction which leads to post-translational modifications of biomolecules (e.g., proteins, lipids, nucleic acids, etc.) and results in the long-term complications in diabetes. Diabetes is a collection of heterogeneous disorders with the familiar manifestation of hyperglycemia, and glucose intolerance.
Several natural compounds of natural origin were evaluated for their antiglycating ability such as polyphenols, cyclopeptide alkaloids, steroids, coumarins, flavonoids, and etc. We found that compounds isolated from the Parmotrema cooperi have exhibited significant antiglycation activities such as ethyl haematommate (IC50 = 220.55 ± 1.16 µM), orsellinic acid (IC50 = 857.92 ± 2.7 µM), and orsellinic ethyl ester (IC50 = 865.34 ± 2.01 µM). Two compounds from Ziziphus oxyphylla Edgw i.e., Numularin-R and Hemsine-A were found to be active, IC50 720.24 ± 10.9 and 277.73 ± 7.6 µM, respectively as compare to standard rutin IC50 294.5 µM. Plant extracts of Acorus calamus L. Quercus infectoria L., Polygonum bistorta L. Acacia nilotica L., Aloe vera (L.) Burm. F. Myrtus communis L. and L-menthol have been selected for STZ- diabetic model and they were found to decrease the complications associated with diabetic melitus. The levels of hydroxyproline and total collagen content are significantly increased in diabetic rats compared to normal rats. Administration of above mentioned plant extracts at different concentrations significantly decreased the level of hydroxyproline and collagen content compared to diabetic rats.
Xanthine oxidase is a molybdoflavo enzyme catalyzes the oxidative hydroxylation of hypoxanthine to xanthine and subsequently xanthine into uric acid. Over-expression of xanthine oxidase leads to hyperuricemia which in turn associated with inflammatory diseases, ischemic and vascular injuries, and cardiovascular diseases. The XO inhibitors are used in the treatment of gout, arthritis, and kidney stones. We have discovered flavonoids, coumarins, polyphenolic aldehyde, and alkaloids as potent inhibitors of xanthine oxidase. In addition, in vivo anti-hyperuricemic were also evaluated.