Chemistry-oriented synthesis (ChOS) and target deconvolution on neuroprotective effect of a novel scaffold, oxaza spiroquinone

Comparing a Query Compound with Drug Target Classes Using 3D-Chemical Similarity

“…In addition, the increase of data points, according to the conformer sampling sizes, makes the computing cost of 3D features increase more rapidly than 2D features. However, despite it being less cost-effective, 3D similarity is the best feature for in silico target screening of unprecedented drug scaffolds and new drug-like molecular frameworks [ 6 ] because (1) novel, unprecedented drug scaffolds have very low 2D similarity to known bioactive molecules [ 7 , 8 , 9 ], (2) novel pharmacological profiles of drugs are more frequently found using 3D similar off-target predictions [ 5 ], and (3) realistic drug properties can be generated from their factual and flexible 3D structures [ 10 , 11 , 12 ].…”

“…The internalization of Michelangelo Buonarroti’s quote, “Every block of stone (chemical) has a statue (utility) inside it, and it is the task of the sculptor (chemist) to discover it”, inspired this research for the ‘chemistry-oriented synthesis’ of an unprecedented drug scaffold [ 7 , 8 , 9 ] and the chemocentric target profiling of this scaffold [ 7 ]. For this purpose, we have intensively studied the 3D similarity of unprecedented drug scaffolds (the query compounds) with known molecular frameworks (the reference compounds).…”

Positioning of an unprecedented spiro[5.5]undeca ring system into kinase inhibitor space

“…Therefore, compounds 2, obtained by merging oxaza spiroquinone 1 with N-benzyl-or N-aryl-1,2,3-triazole derivatives, could be designed based on the kinase-likeness concept. Compound 7 was synthesized from malonamide ester 3 and used conditions identical to those we reported previously except for a modification of the oxidative cyclization 10 . The general conditions of the hypervalent iodine (III)-mediated oxidative cyclization (PIFA, anhydrous K2CO3, dry ACN, 0-25 °C) rely on the synthetic skill and maintaining rigorously anhydrous conditions, or else the isolated yields can decrease less than 10%.…”

“…In other words, induced pro-inflammatory cytokines were diminished by GSK-3 inhibitors (through the control of transcriptional factors) and NO production is also dependent on GSK-3 [56][57][58][59] . On the other hand, the JNK signaling pathway mediates apoptosis and is critical for neuronal cytotoxicity, and JNK can be activated by nitric oxide stimulation 10 . Although studies on the role of GSK-3β in JNK activation are controversial, it was reported that GSK3 inhibition also promotes LPS-stimulated IFNb production via its ability to regulate c-Jun activity 60 .…”

“…Chemistry. Every general chemistry procedure of this study is identical to our previous study on the scaffold 10 . All of the reagents and solvents were used without further purification.…”