Rationally Designing Safer Anilines: The Challenging Case of 4-Aminobiphenyls

Abstract

We describe how we have been able to design 4-aminobiphenyls that are nonmutagenic (inactive in the Ames test). No such 4-aminobiphenyls were known to us, but insights provided by quantum mechanical calculations have permitted us to design and synthesize some examples. Importantly, the quantum mechanical calculations could be combined with predictions of other properties of the compounds that contained the 4-aminobiphenyls so that these remained druglike. Having found compounds that are not active, the calculations can provide insight into which factors (electronic and conformational in this case) are important. The calculations provided SAR-like information that was able guide the design of further examples of 4-aminobiphenyls that are not active in the Ames test.

Can we accelerate medicinal chemistry by augmenting the chemist with Big Data and artificial intelligence?

“…In the absence of an instruction manual of medicinal chemistry, which would describe how to change the structure of a compound to transform it into a drug, the practitioner must adhere to broad "rules" and theoretical principles. These necessitate playing safe and although no "transgressions against medicinal chemistry rules" might be made such as "never make an aniline" [18], by avoid challenging assumptions, they may also result in avoiding innovative solutions [19]. In an alternative extreme strategy, the practitioner may choose to believe in the "exceptionalism of the drug", the "special" molecule that balances the conflicting properties; once this can be found, all will be well.…”

Property-Based Design in the Optimisation of Benzamide Glucokinase Activators

“…The initial focus of structural changes in the aminoheterocycle portion of the molecule was on larger N-ethyl (32) and N-isopropyl pyrazoles (33) ( Table 1.12). These groups maintained GK activity but unfortunately both 1-ethyl-3-aminopyrazole and its isopropyl homologue were active in the Ames test.…”

“…This reaction is considered likely to be subject to similar energetic considerations as the transformations involving generation of electrophilic species that are able to react with DNA [32] (Figure 1.19).…”

“…Conversely, amines which show higher dissociation energies prove to be Ames negative. Although in this example, these data were calculated after empirical data had been generated, it is pertinent to note that the successful use of such an approach to predict Ames outcomes has been reported in other series containing aromatic amines [32].…”

Sustainable and recyclable palladium nanoparticles–catalyzed reduction of nitroaromatics in water/glycerol at room temperature

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