Skip to 0 minutes and 6 secondsFollowing the discovery and isolation of benzylpenicillin, or penicillin G, a large number of compounds with slightly different structures were then prepared. We call these compounds penicillin analogues. There were several reasons for preparing so many penicillin analogues. This included looking to solve problems associated with using penicillin G. For example, penicillin G cannot be taken orally as it is acid sensitive and so needs to be administered by injection. One such analogue is amoxicillin, which is the most commonly prescribed antibiotic in the UK National Health Service. Varying the structure of penicillins was also needed to find out what features of the penicillin molecule are important to its biological activity - we call this establishing a structure-activity relationship, or SAR.
Skip to 0 minutes and 58 secondsFinally, several analogues were designed to overcome the problem of increasing antibiotic resistance. Unfortunately, we know that bacteria have proved adept at developing resistance to new antimicrobial agents. Analogues can be created in order to increase the solubility, lifetime or biological effectiveness of a compound. However, they also provide a method through which the active sites of a medicine can be categorised. If the lead compound bound to its target molecule cannot be crystallized and analysed then a structure-activity relationship, or SAR, can be used to identify the most important functional groups within the lead compound. Analogues are synthesised which are lacking one or more functional groups, relative to the lead.
Skip to 1 minute and 49 secondsThe antimicrobial properties of each analogue are measured and compared in order to identify which groups are necessary for the activity of the molecule. Where there has been a marked reduction in antimicrobial activity it can be assumed that the functional group absent in this analogue was responsible for a portion of the antimicrobial activity of the lead. For example, an imaginary lead compound may contain a phenolic group with two OH groups. These groups could form hydrogen bonds with a complimentary site within the active site of the enzyme. However, if we replace the two -OH groups with two ethers (R-O-R) then we will lose any hydrogen bonding resulting from the OH groups acting as hydrogen bond donors.
Skip to 2 minutes and 35 secondsIf hydrogen bonding at this site is an important part of the binding interaction (between the medicine and enzyme), then the effectiveness of the analogue will be reduced. As such we can deduce that the -OH groups are an important part of the lead molecule and should not be replaced by a group that is not a hydrogen-bonding donor. Once the active functional groups of a lead compound have been identified then other parts of a compound can be modified in a variety of ways. For example, it can be helpful to shield a vulnerable part of a molecule, such as protecting the most reactive site within a medicine. For example, the bulky tertiary-butyl group, Me3C-, makes an excellent steric 'shield'.
Skip to 3 minutes and 15 secondsThis large, bulky hydrocarbon group can protect areas of the molecule that are vulnerable to, for example, hydrolysis or nucleophilic attack by providing a sterically hindering barrier. This approach can be effective to protect medicines from certain enzymes that may react and degrade them. Another 'trick of the trade' is to convert ketones into alcohols as this can increase the solubility of a lead compound in water, whilst retaining the hydrogen bond accepting oxygen atom. An O-H group can act as both a hydrogen bond donor and a hydrogen bond acceptor. Hence the resulting structure is more likely to be soluble in the aqueous environment within the human body.
Skip to 3 minutes and 58 secondsInterestingly, the protonation or de-protonation of a molecule can be used to increase the ionic bonding attractions between the analogue and target enzyme. For example, a carboxylate ion will have a much greater ionic interaction with a positively charged site within an enzyme active site, compared to the neutral carboxylic acid. It can take years to synthesise the analogues of a single lead compound, involving much trial and error in order to find out the mechanism of action of a medicine (e.g. how medicine interacts with an enzyme). Once the important functional groups have been identified, analogues can be prepared and tested in order to ensure that the final medicine is as effective as possible.
Skip to 4 minutes and 39 secondsThrough increasing affinity to the target enzyme or combating the resistance mechanisms of microorganisms, modification of analogues gives chemists a valuable tool to explore the mechanisms of microbial infection.
Understanding the synthesis of analogues and SARs
The successful progress in treating several diseases has led to the development of a pharmaceutical industry with an estimated market of around £1 trillion. The development of marketing and marketing has become a major business it has adopted the rules common to other commercial fields.
The huge market for medicines has lead to a competition among pharmaceutical firms – as soon as a prototype drug becomes available several other similarly active compounds immediately follow, called ‘me-too’ medicines or drugs. Me-too (or ‘copy-cat’) medicines have an identical mechanism of action to the original prototype, and there are only minor pharmacological differences.
This increasing marketing of me-too drugs has been questioned, so pharmaceutical firms are justifying the development of not-so-innovative medicines. Arguments include: me-too drugs offer an improvement on the efficacy of the prototype; they show a different profile of adverse effects; they are effective in patients resistant to the prototype; they improve compliance in long-term treatment; they are less expensive than the prototype.
But, are me-too medicines justified? Do they diminish the incentives for innovation in pioneering medicines without adding therapeutic value? Or, is increased choice between medicines valuable, keeping prices down, and particularly for patients for whom the pioneer medicine is ineffective or entails undesirable side effects.
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