Natural products: Leads for new pharmaceuticals

Advances in molecular biology and automation technology will allow even greater number of samples to be tested against more pharmacological targets, say Ravinder Reddy B, Asif Ansari and Shivkumar I

The use of plants for medicinal purposes dates back thousands of years and even early inhabitants of the earth have been known to chew certain leaves only when suffering from gastro intestinal disturbances. Well-known ancient remedies are morphine, codeine, belladona alkaloids like atropine used as mydriatic and digitalis glycosides used as cardiac stimulant. In more recent times microbial metabolites have been utilized in medicine ex; naturally occuring fungal metabolities cyclosporin and lovastatin used for immunosuppression and to treat hypocholesterolemia.

Natural products have also been utilized as chemical models or templates for the design of synthesis of many other important drugs. Another opium alkaloid papavarine was used to the synthesis of the open chain analog, verapamil which is used to treat the cardiovascular disease and hypertension.

Aspirin of which 25kg is produced, actually is derived from salicin, a secondary metabolite produced by the willow tree. The plant steroids diosgenin and hecogenin remain key precursor for the synthesis of many modern contraceptive drugs and other useful pharmaceuticals including betamethasone for the treatment of eczema and psoriasis and beclomethasone for treating asthma. The abundance of plant and microbial secondary metabolites and their values in medicine are undisputed.

Mammals are producing morphine type metabolites and its congeners in their tissues but a highly regio and stereo selective cytochrome P-450 enzyme has been discovered in pig’s liver which is also responsible for the oxidative coupling of (R) - reticuline to salutaridine and thus the formation of morphine type metabolites in mammals. The challenge to medicinal chemist is to exploit this unique chemical diversity.

Drugs affecting Central Nervous System

Morphine Alkaloids: Morphine is a lead molecule which acts as a analgesic and it’s derivatives like codeine used for treatment of moderate pain, a semi-synthetic derivative heroin used in terminal cancer, where its addictiveness is irrelevant. Actylation masks the polar hydroxyl groups, so that generation into CNS is enhanced. Modification of “C” ring of morphine are legion, but none of the derivatives are free from addictive liability. N-demethylation, re-alkylation gives more interesting analogs, which is a morphine antagonist, some more drugs are developed by morphine lead like naloxone, benzomorphans, buprenorphine, thebaine, etc.

Cannabinoids: Cannabis sativa, which possesses cannabinol which has sedation effect, CNS effects cardiovascular effects (tachycardia, postural hypotension). The measured dose of Cannabinol dissolved in sesame oil and administered in gelatin capsule. The multiplicity of effects of cannabinol have led to the synthesis of large number of analogs, particularly non-morphine, like analgesics without addictiveness and without the other CNS effects of cannabinol. Nabilone, a derivative of cannabil, is formed to be less effective on cardiovascular system than cannabinol, while retaining the mixture of CNS actions, including analgesics, antianxiety and antipsychotic properties. When testing as an antiemetric nabilone proved to be superior to cannabinol.

The recent ‘cannabinol receptor’ is anandamine, a little obvious structural similarity between cannabinol and anandamide, opening up new areas for research into analogs of the latter which may achieve the ultimate goal of separation of all the mixed effects of cannabinol. Without cannabinol, nobody would have looked for the endogenous ligand.

Asperlicin: Asperlicin is moderately potent poorly soluble in water and not bio-available by the oral route. It was an interesting target for synthetic modification. Particularly viewed as a benzodizepine derivative with potential CNS activity.

Neuro muscular blocking drugs: Curare, decamethonium and atracurium are obtained from plants and their derivatives are synthesised like tubocurarine, metocurine, C-toxiferine-I, alcuronium, laudexium, mivacurium etc.

Anti-cancer drugs: Catharanthus roseuse, which possess around 55 alkaloids is pharmacological interest. Vinblastine used in Hodgkin’s disease and metastatic testicular tumour, where as Vincristine is used for the treatment of lymphocytic leukaemia in children.

Taxol and Taxotere, obtained from Taxus baccata and Taxus brevifolia respectively are used for treatment of leukaemia. The derivatives available are baccatin II, 10-desacetyl bacctin III, phenyl isoserine.

Podophyllotoxin, etoposide and Teniposide are obtained from Podophyllum Peltatum P.emodi and inhibits cell proliferation by binding to tubulin and preventing formation of microtubules.

Antibiotics: B lactum antibiotics are produced from Penicillium chrysogenum which possess 6-APA nucleus use full for development of new antibiotics.

Clavulanic acid, isolated from Streptomyceclavuligerus, which is a potential inhibitor of B lactamases is useful for development of new antibiotics.

Streptomycin, aminoglycosides which is isolated from Streptomyces griseus in a potent antibiotic, useful for development of new therapeutics.

Cephalosporins are isolated from fungus called cephalosporium acremonium, which acts as antibiotics.

Thienamycin, isolated from streptomyes cattleya which is a potent antibiotic. Psuedomonas acidophila, Chromobacterium violacium are also produce B lactam antibiotics.

Erythromycin, isolated from saccharopolyspora erythraea, which is a broad spectrum antibiotic. The derivative of erythromycin are roxithromcyin, clacithromycin, dithromycin, azithromycin.

Echinocandin B, which is produced by Asperigillus nidulans, acts as potent antibiotic:

Cardiovascular drugs: Lovastatin, simvastatin and pravastatin are inhibits enzymes. The similar compounds are isolated from Pencillium citrinum and possess same action. Development of these compounds are done for the treatment drug ML-236B.

Teprotide and Captopril are the specific compounds in the venom of pitviper Bothops jararaca, which acts as ACE inhibitors.

Khellin is isolated from Ammi vishanaga which possesses antiasthama effect.

Antiparasitic drugs: Artimisinin, artemether and arteether are isolated for artemisia annua which posses antiparasitic activity, the active constituents obtained from Cinchona succirubra (quinine, chloroquine mefloquine) posses antimalarial activity.

Conclusion

Natural product samples represent a rich chemical diversity which will continue to be an important source of lead compounds for medicinal chemistry programs and will also provide biochemical tools for mechanistic studies. Advances in molecular biology and automation technology will allow even greater number of samples to tested against more pharmacological targets. This fact, coupled with the knowledge that perhaps over 90 per cent of bacteria, fungal and plants species are still waiting to be investigated, means that medicinal chemist has a unique opportunity to continue utilizing the rich chemical diversity offered by the nature.

The writers are with SCS College of Pharmacy, Davanageri, Karnataka