Natural Products

2.5. Natural Products

There are quite a few natural products that are used extensively as anthelmintics i.e., as anti- infective agents. A few important as well as typical examples shall be discussed in the sections that follows :

MEDICINAL CHEMISTRY

2.5.1. Invermectin USAN, BAN, INN

USP ; Int. P. ; BP ; Invomec (R) ; Cardomec (R) ; Equalan (R) ; Mectizan (R) ; Invermectin is usually extracted from the soil of actinomycete Streptomyces avermitilis, the

natural avermectins are 16-membered macrocyclic lactones and is found to be a mixture of 22, 23- dihydro structural analogues of avermectins B 1a and B 1b prepared by catalytic hydrogenation (reduction). In reality, avermectins are members of a family of rather structurally complex antibiotics obtained by fermentative process with the pure isolated strain of S. avermitilis. An intensive screening of cultures for the anthelmintic drugs exclusively from the ‘natural products’ ultimately gave birth to this wonderful drug.

It has been amply demonstrated that the natural avermectins invariably exhibit minimal biologic profile of activity, whereas invermectin has proven to be extermely useful and hence recognized for the management and treatment of good number of nematode infections. Besides, it is found to be active

against arthropods that usually parasitize the animal folks.*

Mechanism of Action. There are two different modes of ‘mechanism of action’ for invermectin

have been suggested, namely : (a) Indirect Action. In this particular instance the motility of microfalaria is minimized

appreciably which subsequently permits the cytotoxic cells of the host to enable them adhere to the parasite thereby causing an elimination from the host finally. This specific action may be afforded due to the ability of invermectin to either exhibit its action a GABA agonist or as an inducer of Cl – ion influx that may ultimately cause hyperpolarization and muscle paralysis. However, the latter mechanism i.e., the Cl – ion influx seems to be the more logical and plausible explanation.** The overall net result of this action is a rapid lowering in the prevailing microfilarial concentrations.

*Burg RW et al. Antimicrob. Agents Chemother : 15 : 361, 1979. ** Campbell WC, Science, 221, 823, 1983.

ANTHELMINTICS

663 (b) Degeneration of Microfilaria in uterio. This specific action essentially would give rise

to relatively fewer microfilaria being released from the female worms and normally extends over a longer duration of time interval. The overall effect caused due to the presence of the degenerated microfilaria’ in uterio directly prevents fertilization phenomenon and the

production of microfilaria.

Metabolism. The ‘drug’ gets absorbed rapidly, bound to an appreciable extent to plasma protein ; and excreted ultimately either through the urine or faeces in two forms, namely : (i) unchanged invermectin ; and (ii) 3′′′′′-O-demethyl-22, 23-dihydro-avermectin B 1a or as dihydroavermectin B 1b monosaccharide. Ethanol is found to aggravate the absorption of the ‘drug’ even upto 100%.

HAPTER In fact, a plethora of naturally occurring pyrethrums have been used quite extensively as viabally

2.5.2. Pyrethrum and Pyrethroids

potent insecticides since the 1800s. A number of potent chemical entities have been successfully isolated

from the extract of the flowering portion of the Chrysanthemum plant. Importantly, the plants grown in Kenya (East Africa) contain upto 1.3% pyrethrins. The ‘pyrethrum extracts’ earn a sizable agricultural

revenue for the country. The Chrysanthemum Extract comprise of a mixture of ester e.g., chrysanthemic and pyrethric

acids ; alcohols e.g., cinerolone and pyrethrolone. As the ‘esters’ are usually more prone to get hydrolyzed and oxidized, hence it must be stored in sealed light-proof containers in a cool place.

Mechanism of Action. The mechanism of action of pyrethrins and pyrethroids (permethrin)

are due to their inherent characteristic feature as nerve membrane sodium channel toxins that fail to exert any action upon the potassium channels. In reality, most of these chemical entities get bound to

MEDICINAL CHEMISTRY

specific sodium-channel proteins and thereby slow down the rate of inactivation of the sodium current elicited by membrane depolarlization.. The net overall affect being the prolongation of the ‘open time’ of the sodium channel.

However, at low concentrations the pyrethroids (permethrin) is observed to display repetitive

action

potentials and also afford neuron firing ; whereas, at relatively higher concentrations the nerve membrane gets depolarized almost completely thereby causing a blockade of excitation.

Stereospecific Aspects. It has been well established that the ensuing receptor interaction of the pyrethrums with the sodium channel complex is absolutely stereospecific ; and, therefore, solely dependent on the stereochemistry of the carboxylic acid in question. Interestingly, in the case of permethrin the most active isomers are the IR, 3-cis- and IR, 3-trans-cyclopropane-carboxylates. However, the IS cis- and IR trans-isomers are inactive ; and are found to serve as antagonists to the therapeutic action of the corresponding IR-isomers.

Metabolism. The wide acceptance and enormous usefulness of the pyrethrum and pyrethroids

are that they pose to be highly toxic particularly to the ectoparasites, whereas they prove to be comparatively much less toxic (i.e., nontoxic) to mammals in case absorbed. The magnificent notoxic characteristic feature is associated with the excellent and rapid metabolism of these drug substances either via hydrolysis or oxidation. More specifically, the extent of either hydrolysis or oxidation is exclusively dependent upon the structure of the prevailing pyrethrins or pyrethroids.

Besides, the rapid breakdown of these drug substances also accounts for their low persistence in the surrounding environment.