Abstract
Rational drug design against a determined target (disease, pathway, or protein) is the main strategy in drug discovery. However, regardless of the main strategy, chemists really wonder how to maximize the utility of their new compounds by drug repositioning them as clinical drug candidates in drug discovery. In this study, we started our drug discovery “from curiosity in the chemical structure of a drug scaffold itself” rather than “for a specific target”. As a new drug scaffold, anomeric diarylamino cyclic aminal scaffold 1, was designed by combining two known drug scaffolds (diphenylamine and the most popular cyclic ether, tetrahydropyran/tetrahydrofuran) and synthesized through conventional Brønsted acid catalysis and metal-free α-C(sp3)–H functionalized oxidative cyclization. To identify the utility of the new scaffold 1, it was investigated through 2D and 3D similarity screening and chemocentric target prediction. The predicted proteins were investigated by an experimental assay. The scaffold 1 was reported to have an antineuroinflammatory agent to reduce NO production, and compound 10 concentration-dependently regulated the expression level of IL-6, PGE-2, TNF-α, ER-β, VDR, CTSD, and iNOS, thus exhibiting neuroprotective activity.
Highlights
In drug discovery, one of the important roles of a synthetic chemist is the rational design of novel drug scaffolds with a high selectivity and promising activity, and another important role is to synthesize them
As a part of the CHOS project, we have studied the trilogy on the unprecedented scaffold 1 and reported the synthetic methodology of the unprecedented scaffold 112 and mechanistic pathway of the metal-free α-C(sp3)–H functionalized oxidative cyclization[13]
The tertiary amino alcohols were subjected to free radical TEMPO (2,2,6,6-tetramethyl-1-piperidinyloxy)/iodine-mediated oxidative cyclization reaction[12], affording the corresponding cyclized compounds (4a–f and 5)
Summary
One of the important roles of a synthetic chemist is the rational design of novel drug scaffolds with a high selectivity and promising activity, and another important role is to synthesize them. Since the 21st century, synthetic organic chemists or medicinal chemists have strongly studied useful approaches for which compounds should be synthesized and how to synthesize them[1,2,3,4] Using these approaches, the therapeutic potential of privileged scaffolds has been well investigated, it is still rare to select unprecedented scaffolds (with structural novelty) as a starting point of in silico target fishing due to insufficient clues or evidence on plausible targets[5,6,7]. Our starting point is the selected unprecedented scaffold 1 without any known target (target molecule, target disease, target pathway, etc.), we couldn’t use structure-based approaches (generally, ‘after choosing molecular target, getting PDB’)[14,15]. We intend to investigate the biological utility of the new scaffold 1 through molecular similarity calculation and chemo-centric target prediction
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