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The cubane phenyl ring bioisostere paradigm was further explored in an extensive study covering a wide range of pharmaceutical and agrochemical templates, which included antibiotics (cefaclor, penicillin G) and antihistamine (diphenhydramine), a smooth muscle relaxant (alverine), an anaesthetic (ketamine), an agrochemical instecticide (triflumuron), an antiparasitic (benznidazole) and an anticancer agent (tamibarotene). This investigation highlights the scope and limitations of incorporating cubane into bioactive molecule discovery, both in terms of synthetic compatibility and physical property matching. Cubane maintained bioisosterism in the case of the Chagas disease antiparasitic benznidazole, although it was less active in the case of the anticancer agent (tamibarotenne). Application of the cyclooctatetraene (COT) (bio)motif complement was found to optimize benznidazole relative to the benzene parent, and augmented anticancer activity relative to the cubane analogue in the case of tamibarotene. Like all bioisosteres, scaffolds and biomotifs, however, there are limitations (e.g. synthetic implementation), and these have been specifically highlighted herein using failed examples. A summary of all templates prepared to date by our group that were biologically evaluated strongly supports the concept that cubane is a valuable tool in bioactive molecule discovery and COT is a viable complement.

Pharmaceutical and agrochemical discovery programs are under considerable pressure to meet increasing global demand and thus require constant innovation. Classical hydrocarbon scaffolds have long assisted in bringing new molecules to the market place, but an obvious omission is that of the Platonic solid cubane. Eaton, however, suggested that this molecule has the potential to act as a benzene bioisostere. Herein, we report the validation of Eaton's hypothesis with cubane derivatives of five molecules that are used clinically or as agrochemicals. Two cubane analogues showed increased bioactivity compared to their benzene counterparts whereas two further analogues displayed equal bioactivity, and the fifth one demonstrated only partial efficacy. Ramifications from this study are best realized by reflecting on the number of bioactive molecules that contain a benzene ring. Substitution with the cubane scaffold where possible could revitalize these systems, and thus expedite much needed lead candidate identification.

In this Communication, a La Trobe University affiliation is missing for the author David A. Winkler. The penultimate author address entry must read: Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, 3052 (Australia) and La Trobe Institute for Molecular Science, La Trobe University, Bundoora, 3084 (Australia).

The cubane core has been shown to be physically similar to benzene across the body diagonal, yet remains electronically and physically different in all other ways. It is proposed that this similarity may allow cubane to act as a bioisostere for benzene in pharmaceutical applications. As such, a number of novel synthetic approaches have been used to develop new routes to previously unknown cubane derivatives. The synthesis of several novel cubane based compounds is described herein. The synthetic routes contained within provide further insight into the potential functional group modifications for the cubane framework. These derivatives form key intermediates in the synthesis of a number of target analogues based in a variety of drug classes. These classes include anticancer chemotherapeutic drugs, novel Alzheimer’s disease compounds, antibacterial compounds, topical scabies medications as well as a well known antifungal compound. The overall study is designed to act as a base level investigation into the potential of cubane to act as a bioisostere for benzene in pharmaceutical analogues. Compounds were selected based upon the presence of a benzene ring, drug class as well as potential synthetic approach. The described compounds are thus designed to be analogous to current pharmaceutical drugs which are undergoing Phase I clinical trials, later testing, or are already available for purchase. Biological tests of these novel compounds have been subjected to, at least, base level comparison to the known drug analogue. Results of these studies have demonstrated that cubane analogues have similar biological activity to a number of benzene analogues in a variety of classes and thus merit further investigation into the use of cubane as a bioisostere for benzene. Further to this a P450 oxidation study has also been performed to help understand the metabolic processes that may be imparted upon the cubane core in a biological system. The results herein also demonstrate that cubane derived compounds hold great potential for their application in pharmaceutical compounds, yet underline the fact that cubane remains a diamond in the rough, for which many syntheses remain undiscovered.