New Medicinal Derivatives from Santonin

Abstract

Santonin is an anthelmintic drug and Pakistan used to be one of the largest suppliers of this drug in the world. This drug is extracted from Artemisia maritima, a herb occurring in kurram valley near Parachinar, Gilgit and Skardu, by karram chemical company, Rawalpindi. Use of this drug has now decreased due to its toxicity and synthetic anthelmintics have nearly replaced it in the world market. As a result, export of this drug from Pakistan has nearly stopped. Santonin is thus a source of foreign exchange earnings to our country but very little research work has been done on this drug in Pakistan. Synthesis of new medicinal derivatives from Santonin was, therefore, submitted to Pakistan Science Foundation to carry out literature survey and to make new derivatives of santonin, to find alternate uses or better substitutes of this drug. Aziridines are useful as tumor inhibiting compound and synthesis of aziridinosantoninns was planned along with other derivatives. In addition, collection of Artemisia species from Northern areas and a literature survey on these herbs were also planned to find uses for these herbs, distributed widely in Pakistan. Pakistan Science Foundation gave a research grant to carryout work for a year on the project. Work on this project was started on March 24, 1981 and a half-yearly report was submitted in September, 1981. A final report on the project is now submitted here. Artemisia (Family compositae) is a large genus of small herbs and its 280 species are found in Northern hemisphere in arid regions. About thirty species of Artemisia have been reported to grow naturally in Pakistan. A detailed literature survey was done on Pakistani Artemisia species and it was found out that although some work on chemical constituents of these plants has been reported but no work has ever been carried out on nineteen Pakistani Artemisia species. Nearly all the work on the other Artemisia specie has also been carried out abroad and thus a tremendous scope of work appears to exist on these species in Pakistan. Artemisia herbs are of economic importance to Pakistan and some of these are of medicinal value and Yield essential oils while few are useful as fodder. Some of these species contain santonin, an anthemintic drug. Several santonin containing species of Artemisia like A.maritima Linn. , A.brevifolia, A.herba-alba, A.kurramensis occur in Pakistan but these different species appear to only varieties of A.maritima instead of being separate species. Artemisia maritima Linn. Is found in Karram Valley, Gilgit Agency, kaghan Valley, chitral, Dir, swat, Khyber Agency, Indua Kohistan, Waziristan and large barren areas of Baluchistan. Santonin is extracted at Kurram Chemical Co., Rawalpindi, one of the largest manufacturers of this drug in the world, from Artemisia mainly collected near Parachinar in kurram valley. Literature review indicated that Pakistan aremisias contain essential oils of potential use in perfumery industry, sesquiterpene lactones of medicinal interest, flavones, coumarins, furans, acetylenes, lignans and other compounds of potential pharmacological interest. It is reported that Parachinar Artemisia is the richest in santonin content while Artemisia plants from gilgit and Baluchistan are poorer while Baluchistan samples, lack santonin. It, therefore, appeared useful to collect Artemisia samples from various areas for sake of comparison as many samples lacking santonin may contain other useful sesquiterpene lactones. Due to lack of time and financial restraints, a short trip of the duration of a week was taken by Dr.S.K Hasan,Co-principal Investigator of the project, and Artemisia samples were collected from Islamabad, Rawalpindi, and several villages around Parachinar city. Pakistan Forest Institute at Peshawar and kurram Chemical Company, one of the largest producers of Santonin in the world were also visited to hold useful discussions about Artemisia with concerned authorities there. On the way to Parachinar, stops were made at Nowshera, Amangarh and Peshawar but no Artemisia plants could be detected in the visited areas. Santonin content of plants is highest in September therefore, Northern area were toured for duration of a week during the third week of September 1981. Artemisia grows wild around Rawalpindi and Islamabad, Artemisia samples were collected on the morning of September 15, 1981 from 1-9 area of Islamabad and shahdad kot near Sihala. Died samples of plants of A. elegantissima from Islamabad and Shahdad Kot areas were extracted with chloroform and the residue, obtained on evaporation of the extract, was worked up by a standard procedure. Both samples did not yield santonin but afforded a new compound, m.p. 136-1380, as colourless crystals. Both samples contained this compound, besides this new compound, was isolated from these samples. This compound was identified as 6-7-dimethoxycoumarin on the basis of i.r., u.v, n.m.r., high resolution mass spectra and microanalyses. Artemisia samples were also collected on the morning of September 19, 1981 from Parachinar city, situated in Kurram Valley and neighbouring villages on Parachinar-burki road to study santonin content of the plants. Methods for determination of santonin in Artemisia herb appear to be tedious and involve gravimetric determination by precipitation with barium hydroxide and chromatography or colorometric methods. A very simple procedure has been developed by us for gravimetric determination of santonin in the fried herb. In contrast to the procedures developed earlier, residue from benzene extract of the herb was charcolated and refluxed in aqueous ethanolic solution removing thus most of the other components and santonin could later be extracted from the refluxed solution by chloroform. The santonin content of various samples collected from Parachinar area varied. These result appear to confirm another report which mentioned santonin content in the samples of this area also in the range of 1.5-2.5%. As use of santonin has decreased recently as an anthelmintic drug, therefore, it is important to find alternate uses of santonin or other synthetic compounds based on santonin, and also of other Artemisia plants in Pakistan. Our work on Artemisia appears to indicate that these plants could be used for isolation of essential oils which are used in perfumery industry. Artemisia oil is already obtained as a by-product of santonin at Kurram Chemical Company. The manufacture of the essential oils from other Artemisia plants for the perfumery industry or for export purposes should be examined. For economic exploitation of these plants, however, it is necessary to survey various Artemisia species in Northern areas of Pakistan and to determine their available quantities. 6.7-Dimethoxycoumarin appears to possess choleretic and hypotensive activities, therefore, crude A. elegantissima, occurring in Islamabad area, or 6, 7-dimethoxycoumarin can be developed as useful drug. Other Artemisia plants are also of medicinal value and more research work is necessary to isolate and evaluate new drugs from these plants. A. herba-alba and A. sieversiana can also be used as fodder.