Bioisostere medicinal chemistry

Bioisosteric relations constitute one of the more familiar tools in medicinal chemistry. There are thus sets of atoms that can often be interchanged without much... 

The synthesis of nitriles from halides is valuable in medicinal chemistry because nitriles are flexible building blocks readily converted into carboxylic acids, amides, amines, or a variety of heterocycles, e. g. thiazoles, oxazolidones, triazoles, and tetrazoles. The importance of the tetrazole group in medicinal chemistry is easily understood if we consider that it is the most commonly used bioisostere of the carboxyl group. 

Thiophene-containing molecules can be found in both natural products and synthetic chemotherapeutics. Bithiophene 1, a naturally occurring nematocide, is isolated from the roots of Echinops spaerocephalus, whereas tiaprofenic acid, an anti-inflammatory agent, is a synthetic thiophene derivative. Moreover, thiophene is a useful template for four-carbon homologation via reduction [1], as well as a bioisostere of the benzene ring and other heterocycles in medicinal chemistry. 

Furan-containing molecules are found in both natural products and pharmaceuticals. At one time, furfural was produced in great quantities from corncobs. Perillene, a secondary plant metabolite, is an example of naturally occurring furans. Furan is frequently used as a bioisostere of a benzene ring in medicinal chemistry. For example, Ranitidine (Zantac) marketed by Glaxo was one of the first blockbuster drugs with annual sales over 1 billion dollars. 

The thiocarbonyl group is a classic bioisosteric replacement for the carbonyl group which has been widely exploited in medicinal chemistry. This is illustrated with the preparation of thioketones derived from thiocolchicine283 and isothiocolchicine284 which exhibited high antitubulin activity (equation 38). 

In the parlance of medicinal chemistry, bioisosteres are groups of atoms that might be expected to impart similar physical and chemical properties when substituted from one biologically active molecule to another. They are frequently employed to try to generate additional active molecules from a known active lead—occasionally they even work ... 

The Uppsala team then turned their attention to the development of a fast and efficient procedure that allowed conversion of aryl halides to benzoni-triles and aryl tetrazoles by microwave heating. The aryl bromide 11 was subjected to the optimized reaction conditions, which delivered the bis-tetrazole 15 in a two-step yield of 82% (Scheme 8, Kt = 0.56 nM), demonstrating the potential of the method for medicinal chemistry [61]. The tetrazole functionality is one of the most utilized carboxylic acid bioisosteres. 

Bioisosteric substitutions are a commonly used strategy in medicinal chemistry drug design as an approach to enhance the desired biological or physical... 

With these early successes in hand, a key question arising is that of whether RNA-targeted DCC yields compounds that can serve as relevant leads for further medicinal chemistry studies Our group is currently engaged in efforts to demonstrate that the answer to this question is in the affirmative. For example, building on the efforts with the HIV-1 FSS RNA detailed above, non-reducible analogs incorporating a hydrocarbon (olefin or saturated alkane) bioisostere for the disulfide... 

The phenothiazines and thioxanthenes have the characteristic of two phenyl groups fused to a central six-member ring giving a so-called 6-6-6 system. An ethylene is a commonly used bioisostere for a thio linkage in medicinal chemistry. Continued research in... 

The nse of the word isosterism has been largely taken beyond its original meaning when employed in medicinal chemistry and Thomber " proposes a loose and flexible definition of the term bioisostere ... 

Lanter, J.C., Fiordeliso, J.J., Allan, G.F., Musto, A., Hahn do, W. and Sui, Z. (2006) A bioisosteric approach to the discovery of indole carhinol androgen receptor ligands. Bioorganic et Medicinal Chemistry Letters, 16, 5646-5649. 

The tetrazole functional group is of particular interest in medicinal chemistry, because of its potential role as a bioisostere of the carboxyl group. In this context, Schulz et al. have demonstrated the synthetic utility of the cyano group of arylni-trile boronates as a source of tetrazole derivatives under microwave conditions. The reaction is conducted with azidotrimethylsilane and dibutyltin oxide as catalyst to provide aryltetrazole boronates in yields ranging from 60 to 93% [56]. In the same manner, microwaves may assist successful conversion of sterically hindered nitriles into tetrazoles [57]. 

The importance of the tetrazole group in medicinal chemistry is easily understood if one remembers it is the most commonly used bioisostere of the carboxyl group. 

Kiyama, R., Honma, T., Hayashi, K., Ogawa, M., Hara, M., Fujimoto, M., and Fujishita, T. (1995) Novel angiotensin 11 receptor antagonists. Design, synthesis, and in vitro evaluation of dibenzo[o, d] cycloheptene and dibenzo[fc, J]oxepin derivatives. Searching for bioisosteres of biphenyltetrazole using a three-dimensional search technique. Journal of Medicinal Chemistry, 38, 2728-2741. 

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