Heterocycles in Medicine 175Statins reduce the amount of cholesterol in the blood by inhibition of one of the enzymes (HMG CoA reductase)
involved in its biosynthesis and are therefore very useful for prevention of heart disease. The original statins are com-
plex aliphatic fungal metabolites but a number of synthetic heterocyclic drugs, carrying only a small portion of the
original structures, are now available, for example atorvastatin and rosuvastatin (page 167). The relationship of the
inhibitory portion of the statins to the product, mevalonic acid, can clearly be seen.
Other useful enzyme inhibitors include acetazolamide (carbonic anhydrase) for the treatment of glaucoma, congestive
heart failure, epilepsy and motion sickness (a very useful drug!). Sildenafi l (Viagra), famous for the effective treatment
of impotence, inhibits a phosphodiesterase enzyme (PDE5) that is involved in the breakdown of adenosine triphos-
phate (ATP).
As an aside, but particularly of relevance to statins, some foods contain enzyme inhibitors that may have important
effects. A notable example is grapefruit (juice), containing substances such as bergamotin and naringin, which inhibit
the enzymes involved in breaking down a number of drugs. Because drug doses are based on standard rates of metabo-
lisim, inhibition of the enzymes involved can result in much higher, often toxic, blood levels of the drug.
Anti-infective agents
The next three sections cover drugs against parasitic (protozoa and helminths (‘worms’)), bacterial and viral diseases.
The mechanisms of action of many of these agents are complex and diverse and, in some cases, not fully understood,
but enzyme inhibition is common to many.
Antiparasitic drugs
The most important protozoan infection is malaria and this was an early target for medicinal chemical research. The
traditional treatment was an extract of the bark of the cinchona tree, which contained the quinoline alkaloid quinine.
Current emphasis is on prevention by continuous dosing during exposure using synthetic antimalarial drugs, which
must be under constant review as resistance eventually develops. Many of these drugs are quinolines with obvious simi-
larities to quinine. Proguanil is of particular interest because the active species, formed in vivo, is a triazine (cycloguanil).