Spiro Compounds. Группа авторов

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СКАЧАТЬ alt="Schematic illustration of the chemical structure of Trospium chloride."/> 1 Trospium chloride (Flotros) Overactive bladder 3 Spironolactone (Aldactone) Heart failure, edema, hypertension 4 Cevimeline (Evoxac) Dry mouth (Sjögren's Syndrome) 5 Griseofulvin (Crivicin) Antifungal antibiotic for ringworm infections 6 Guanadrel (Hylorel) Hypertension 7 Amcinonide (Cyclocort) Inflammatory and pruritic manifestations 8 Ivermectin (Ascapil) Anti‐parasitic 9 Fenspiride (Eurespal) Antitussive 10 Rifabutin (Ansatipin) Antibiotic, tuberculosis 11 Homo‐harringtonine (Ceflatonin) Chronic myeloid leukemia 12 Irbesartan (Avapro) Hypertension 13 Fluspirilene (Imap) Schizophrenia 14 Spirapril (Renormax) Hypertension 15 Buspirone (Buspar) Anxiety disorders

Figure 2.1 X‐ray crystal structure (pdb 2gfx¹²) of Platensimycin (2, sticks representation) bound to the active site of FabF (surface representation) highlights hydrophobic contacts and hydrogen bonds in the complex.

Scheme 2.1 Key enyne cycloisomerization step in Nicolaou’s total synthesis of platensimycin.

      Source: Adapted from Nicolaou et al. [15].

In contrast, a comparatively small number of spirocycle containing drugs have been investigated in the last decades, and spirocyclic molecules are still under‐represented in marketed drugs [2]. Selected examples of spirocycle containing drugs are shown in Table 2.1, including spironolactone 3 which has been known for over 50 years [20]. It seems fair to state that historically drug design strategies in medicinal chemistry have been heavily inspired (or biased?) by the advances in synthetic chemical methods toward new molecular scaffolds. This raises the question of chemical diversity and unconscious bias toward traditional/ubiquitous building blocks and reliable reactions/protocols for assembling increasingly complex molecules. As a compelling example, the phenyl ring and its related (hetero)aromatic analogues are over‐represented and virtually all best‐selling, over‐the‐counter drugs contain at least one such unit in their core scaffold or as a substituent. It is not particularly surprising as a plethora of synthetic methods for aromatic functionalization have been conceptually and experimentally well established for decades [21]. Such methods include, for example, a wide range of additions and substitutions, cross‐couplings, and aromatization strategies. While this is obviously a significant advantage for the rapid access to a wide range of analogues from a core structure, this bias is an important factor slowing down the discovery of new bioactive scaffolds. Historically, spirocycles СКАЧАТЬ