Solid-Phase Synthesis of 5-Amino-1-(Substituted Thiocarbamoyl)pyrazole and 1,2,4-Triazole Derivatives via Dithiocarbazate Linker

Abstract

A general method is reported for the parallel solid-phase synthesis of 5-amino-1-(substituted thiocarbamoyl)pyrazole and 1,2,4-triazole derivatives based on the cyclization of polymer-bound dithiocarbazate 3 with various electrophiles, such as 3-ethoxyacrylonitriles 8 and cyanocarboimidates 9. The polymer-bound dithiocarbazate 3, produced by nucleophilic reaction with carbon disulfide and Fmoc-hydrazine on the Merrifield resin, served as the key intermediate for subsequent heterocycle diversification. Further nucleophilic substitution on these polymer-bound 5-amino-1-dithiocarboxypyrazoles 4 and 1,2,4-triazoles 6 with various amines under thermal cleavage condition produced the desired 5-amino-1-(substituted thiocarbamoyl)pyrazoles 5 and 1,2,4-triazoles 7. The progress of reactions could be monitored as polymer-bound intermediates by ATR-FTIR spectroscopy on single bead. The final compounds, obtained in good four-step overall yields and high purities upon cleavage from the resins, were characterized by LC/MS, 1H NMR, and 13C NMR spectroscopy.

Novel N‐(2,2′‐disubstituted‐2H‐cromenyl)‐N′,N″‐disubstituted Guanidine Derivatives as an S‐Nitrosoglutathion Reductase Inhibitor

“…Inactivation of GSNO reductase has been reported to elevate GSNO levels in airways, and thus provide a protective effect against airway diseases. In an effort to discover new types of GSNO reductase inhibitor, we screened 711 compounds of our library, which represents 10 000 structurally diverse compounds and is a druggable, heterocyclic compound library including benzopyrans, oxazoles, pyrazole, oxadiazoles, various thiazoles, and pyrimidinediones against the recombinant enzyme at a compound concentration of 10 μM. The screen identified a subset of guanidine derivatives able to inhibit the enzymatic activity of GSNO reductase by >70% at a concentration of 10 μM, as compared to DMSO control.…”

Nucleophile Cleavable Linker Units

“…In this context, Scheme 3.20 reports an elegant SPOS synthesis of 5-amino-1-(substituted thiocarbamoyl)-pyrazole (77) and 1,2,4-triazole (75) derivatives based on the cyclization of polymer-bound dithiocarbazate with various electrophiles, such as 3-ethoxyacrylonitriles and cyanocarboimidates. [34] The polymer-bound dithiocarbazate 77, key intermediate for subsequent heterocyclic diversification (74 and 76), has been prepared by nucleophilic reaction with carbon disulfide and Fmoc-hydrazine on the Merrifield resin (Scheme 3.20). Further nucleophilic substitution on these polymer-bound 5-amino-1-dithiocarboxypyrazoles and 1,2,4-triazoles with various amines under thermal cleavage condition produces the desired 5-amino-1-(substituted thiocarbamoyl)pyrazoles 77 and 1, 2, 4-triazoles 75 (Scheme 3.20).…”

Design and Synthesis of a Novel 4-aryl-N-(2-alkoxythieno [2,3-b]pyrazine-3-yl)-4-arylpiperazine-1-carboxamide DGG200064 Showed Therapeutic Effect on Colon Cancer through G2/M Arrest

“…To identify small molecule inhibitors of the G2/M-specific cell cycle, we screened 240 drug-like compounds via cell-based anti-colorectal activity HCT116 reporter assay. The compounds were selected from our in-house library of 30,000 structurally diverse druggable heterocyclic compounds including benzopyrans [ 24 ], oxazoles [ 25 ], pyrazoles [ 26 ], oxadiazoles [ 27 , 28 ], thiadiazoles [ 29 , 30 , 31 ], various thiazoles [ 32 , 33 , 34 , 35 , 36 ], pyrimidinediones [ 37 ], and benzimidazoles [ 38 , 39 ]. Inhibition of cell proliferation of colorectal cancer cell HCT116 was screened at a compound concentration of 5 μM; compounds that reproducibly inhibited growth by over 100% were selected.…”