Powerful Potential of Polyfluoroalkyl-Containing 4-Arylhydrazinylidenepyrazol-3-ones for Pharmaceuticals

Abstract

4-Arylhydrazinylidene-5-(polyfluoroalkyl)pyrazol-3-ones (4-AHPs) were found to be obtained by the regiospecific cyclization of 2-arylhydrazinylidene-3-(polyfluoroalkyl)-3-oxoesters with hydrazines, by the azo coupling of 4-nonsubstituted pyrazol-5-oles with aryldiazonium chlorides or by the firstly discovered acid-promoted self-condensation of 2-arylhydrazinylidene-3-oxoesters. All the 4-AHPs had an acceptable ADME profile. Varying the substituents in 4-AHPs promoted the switching or combining of their biological activity. The polyfluoroalkyl residue in 4-AHPs led to the appearance of an anticarboxylesterase action in the micromolar range. An NH-fragment and/or methyl group instead of the polyfluoroalkyl one in the 4-AHPs promoted antioxidant properties in the ABTS, FRAP and ORAC tests, as well as anti-cancer activity against HeLa that was at the Doxorubicin level coupled with lower cytotoxicity against normal human fibroblasts. Some Ph-N-substituted 4-AHPs could inhibit the growth of N. gonorrhoeae bacteria at MIC 0.9 μg/mL. The possibility of using 4-AHPs for cell visualization was shown. Most of the 4-AHPs exhibited a pronounced analgesic effect in a hot plate test in vivo at and above the diclofenac and metamizole levels except for the ones with two chlorine atoms in the aryl group. The methylsulfonyl residue was proved to raise the anti-inflammatory effect also. A mechanism of the antinociceptive action of the 4-AHPs through blocking the TRPV1 receptor was proposed and confirmed using in vitro experiment and molecular docking.

5‐Alkoxy‐1‐aryl‐3‐polyfluoroalkylpyrazoles with Antinociceptive Activity: Partial Agonists of TRPV1 Ion Channels

“…[25] We are also actively carrying out research on the development of analgesics based on fluorine-containing pyrazoles. [26][27][28][29][30][31][32] Recently, we have synthesized polyfluoroalkylcontaining MeN-and MeO-derivatives of pyrazol-5-ols as analogues of antipyrine and celecoxib, [33] which revealed the pronounced analgesic activity in the hot plate test. Among the obtained derivatives, 5-methoxy-3-(trifluoromethyl)-1phenylpyrazole was distinguished by a combination of high analgesic activity in the in vivo hot plate test with low acute toxicity, which is a very important point for the development of new analgesics.…”

“…We are also actively carrying out research on the development of analgesics based on fluorine‐containing pyrazoles [26–32] . Recently, we have synthesized polyfluoroalkyl‐containing MeN‐ and MeO‐derivatives of pyrazol‐5‐ols as analogues of antipyrine and celecoxib, [33] which revealed the pronounced analgesic activity in the hot plate test.…”

Deep Learning with Geometry-Enhanced Molecular Representation for Augmentation of Large-Scale Docking-Based Virtual Screening

“…Drug discovery is an extremely expensive, time-consuming, and interdisciplinary task due to the great efforts required to explore the chemical space of possible compounds and their corresponding activity, efficacy, and safety with various experiments in vivo and in vitro. − To this end, the computer-aided drug discovery (CADD) methods have significantly assisted the progress of modern drug discovery. − Among the diverse CADD techniques, structure-based virtual screening that relies on molecule docking and scoring has been a relatively mature technique. − Because of its efficiency and notable virtual-hits-enrichment effect, virtual screening has been routinely used to find hits that complement a biological target from large libraries of available, often purchasable, chemicals. − However, limited by the computational burden, at present, conventional structure-based virtual screening approaches can typically handle a scale of millions of chemical molecules, although recently a handful of billion-sized virtual screening campaigns have been carried out on elite supercomputing facilities. , …”