Making Custom Synthesis Happen: Functionalised Indole Building Blocks
Making Custom Synthesis Happen: Functionalised Indole Building Blocks?
Functionalised Indole Building Blocks?
Nitrogen-containing heterocycles continue to play a pivotal role in the modern rational drug design of small molecule therapeutic drugs. This propensity is illustrated by the fact that 85% of all FDA-approved small molecule drugs contain a heterocyclic substructure, featuring a nitrogen atom. The presence of these nitrogen heterocycles substructures has a marked effect on the Pharmacodynamic and Pharmacokinetic properties (ADME) influencing solubility, lipophilicity, polarity, and enzyme binding affinity.??
Amongst the structural diversity of nitrogen-containing heterocyclic moieties available, indoles are considered highly privileged nitrogen-containing heterocycles. The diverse pharmacological properties of the indole nucleus are well illustrated in hundreds of naturally occurring alkaloid families which include lysergic acid diethylamide (LSD) and strychnine; also in cruciferous plants as glucobrassicin and indole-3-carbinol, in amino acid tryptophan and in the neurotransmitter serotonin, which is a precursor to melatonin and indoleacetic acid a plant Auxin A. They can also be found in the skin of toads and in poisonous mushrooms such as bufotenine and psilocybin, and vallesiachotamine, a potent anticancer alkaloid as shown in Figure 1.?
Figure 1 Naturally Occurring Indoles
Moreover, this important substructure is found in numerous FDA-approved drugs which include Zafirlukast, Vilazodone, Panobinostat, Osimertinib, Rucaparib, Tezacaftor, Pindolol, Yohimbe, indomethacin, Beclabuvir and Vincristine. The pharmacophore exhibits an extraordinarily wide spectrum of Pharmacological activity encompassing areas such as anti-fungal, anti-inflammatory, anti-viral, anti-bacterial, anti-antibiotic, antiparasitic, antihistaminic, antiulcer, antihypertensive, osteoporosis, radiosensitizer and anti-cancer. The structural architecture of some of these indole-containing marketed drugs is shown in Figure 2 - coloured in blue for clarity.
Figure 2 Structural Diversity of Indole Containing Marketed Drugs
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Ubichem brings to the market a product portfolio of diverse and highly functionalised indole building blocks that carry functionality both in the fused benzene and pyrrole rings. Additional structural features include spiro centres and fused carbocycles, the inherent functionality in these scaffolds can provide rapid access to generate new chemical entities through the application of synthetic methodologies incorporated in the indole skeleton. These indole-containing building blocks contain functionality in the form of amino, choro, bromo, boc, methyl bromide, methoxy, methyl trifluoro, carboxy and sulphonamide. Shown in Figure 3.
Figure 3 Ubichem Product Portfolio of Functionalised Indoles
The indole pharmacophore is considered a highly privileged fused nitrogen heterocycle, consisting of a benzene ring fused to a pyrrole ring. The aromaticity is due to its 10π-electron delocalisation, making it susceptible to electrophilic substitution in the indole ring 3-position. The NH lone pair contributes to the aromaticity making it weakly acidic (Pka 21 in DMSO), but it can also act as a lone pair donor in binding to an active site in a protein. Therefore, it can facilitate both ligand-enzyme interactions and its electron-rich indole and fused aromatic ring can assist in π-π and cationic-π stacking interactions. These physiochemical features coupled with structural architecture are the main drivers that impact the pharmacokinetic and pharmacodynamic parameters that contribute to the drugs’? lipophilicity, solubility, and enzyme binding affinity. The synthesis of the indole skeleton can readily be achieved through several named methodologies which include Leimgruber-Batch, Fisher, Fukuyama, Gassman, Reissert, Baeyer-Emmerling, Larock, Bartoli and others, however, the synthetic drawback is that the chemistries require specific starting materials and in some cases the involvement of multicomponent chemistries. Ubichem offers a product portfolio of already constructed indole building blocks carrying functionality both in the aromatic ring and the pyrrole ring's 2 and 3 positions?(Figure 3). These functionalised indole scaffolds hold the promise to allow a rapid forward synthesis of new chemical entities using functional group transformations potentially creating pharmacologically active molecules.