【MedChem Spark】Intramolecular Hydrogen Bond(IMHB) in Medicinal Chemistry (Issue 1)
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By Jin Li
The formation of intramolecular hydrogen bonds has a very pronounced effect on molecular structure and properties. [1] Medicinal chemists widely employ IMHB strategy to modify molecules with respect to locking conformation, increasing permeability, aqueous solubility, scaffold hopping, etc. In the circumstances, building blocks bearing HBD or HBA to form IMHB are of great value in drug discovery.
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As shown in Figure 1, scaffolds 1,5-naphthyridine in compound 3 and pyrazolo[1,5-a]pyrimidine in compound 4, which have nitrogen atoms highlighted in red color forming IMHB with adjacent hydrogen atoms highlighted in blue color, decreased efflux ratio significantly comparing with compound 1 and compound 2. [2] Quick access of dichloro building blocks listed in the right of Figure 1 as starting material for paralleled medicinal chemistry, enabled the structure-property relationship (SPR) study efficiently.
A fluorine atom ortho- to the NH of an anilide can influence conformation. Biological evaluation of isomers 5 and 6 demonstrated a 10-fold difference in CGPR affinity, with F-HN interaction favoring desired binding conformation (Figure 2). [3]
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Replacing a hydrogen atom ortho- to an anilide N-H in compound 7 by a fluorine atom in compound 8 increased water solubility by 30-fold, probably due to “mask effect” of F on N-H. A positive effect on permeability was observed when comparing compound 9 and 10, attributed to a weak interaction between F and one of N-H that reduces the number of HBD available to the environment. Building blocks with F able to form IMHB with adjacent N-H as exemplified in Figure 2, are extremely useful and have been widely utilized in medicinal chemistry to improve molecular properties. [3]
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Compound 11 was discovered as a potent GSK-3β inhibitor. However, cleavage of the cyclopropyl carboxamide group was observed in mouse serum. In co-crystal structure of 11 complexed with GSK-3β, a water-bridging hydrogen bond between the carbonyl of amide and the upper amide NH was observed, which may help to predispose the molecule to energetically favor the bioactive conformation (Figure 3). [4] With this in mind, the imidazo[1,2-b]pyridazine ring system appeared to be an attractive heterocyclic scaffold, with an interaction between amide NH (blue) and imidazole nitrogen atom (red) locking molecule in the desired bioactive conformation. When carboxylic acid building blocks, which have adjacent HBA to –COOH group, are converted to amide, IMHB are formed.
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References
[1] Bernd Kuhn; et al. Intramolecular hydrogen bond in medicinal chemistry. J. Med. Chem. 2010, 53, 2601-2611.
[2] Mark E. Layton; et al. Discovery of MK-8189, a highly potent and selective PDE10A inhibitor for the treatment of schizophrenia. J. Med. Chem. 2023, 66, 1157-1171.
[3] Nicholas A. Meanwell; Fluorine and fluorinated motifs in the design and application of bioisosteres of drug design. J. Med. Chem. 2018, 61, 5822-5880.
[4] Richard A. Hartz; et al. Design, structure-activity relationships, and in vivo evaluation of potent and brain-penetrant imidazo[1,2-b]pyridazines as glycogen synthase kinase-3beta inhibitors. J. Med. Chem. 2023, doi:10.1021/acs.jmedchem.3c00133.
About Author
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By Jin Li
Senior Director of PharmaBlock
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Find out more at www.pharmablock.com
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