The reaction of polyfluomalkyl-containing 2-tolylhydrazinylidene-1,3-diketones with 3-aminopyrazoles depending on their structure can proceed as N,N-cyclization to form 5-R-F- and 7-R-F-regioisomeric pyrazolo [1,5-a]pyrimidines (at that haloform cleavage to non-fluorinated pyrazolo[1,5-a]pyrimidine-7-ones is typical of 7-polyfluoroalkyl-containing isomers) or as C,N-cyclization to give 4-polyfluoroalkylpyrazolo [3,4-b]pyridines. The analogous transformations of non-fluorinated 3-tolylhydrazinylidenepentane-2,4-dione led to pyrazolo [1,5-a] pyrimidines only. Antiviral effect against influenza and Coxsackie viruses, analgesic activity and acute toxicity of some synthesized pyrazoloazines were evaluated.

4-Nitroso-3-trifluoromethyl-5-alkyl[(het)aryl]pyrazoles were synthesized via one-pot nitrosation of 1,3-diketones or their lithium salts followed by treatment of hydrazines. Reduction of nitroso-derivatives made it possible to obtain 4-amino-3-trifluoromethylpyrazoles chlorides. According to computer-aided calculations, all synthesized compounds are expected to have acceptable ADME profile for drug design. Tuberculostatic, antibacterial, antimycotic, antioxidant and cytotoxic activities of the compounds were evaluated in vitro, while their analgesic and anti-inflammatory action was tested in vivo along with acute toxicity studies. N-Unsubstituted 4-nitrosopyrazoles were the most effective tuberculostatics (MIC to 0.36 μg/ml) and antibacterial agents against Streptococcus pyogenes (MIC to 7.8 μg/ml), Staphylococcus aureus,S. aureus MRSA and Neisseria gonorrhoeae (MIC to 15.6 μg/ml). 4-Nitroso-1-methyl-5-phenylpyrazole had the pronounced antimycotic action against a wide range of fungi (Trichophytonrubrum, T. tonsurans, T. violaceum, T. interdigitale, Epidermophytonfloccosum, Microsporumcanis with MIC 0.38-12.5 μg/ml). N-Unsubstituted 4-aminopyrazoles shown high radical-scavenging activity in ABTS test, ORAC/AAPH and oxidative erythrocyte hemolysis assays. 1-Methyl-5-phenyl-3-trifluoromethylpyrazol-4-aminium chloride revealed potential anticancer activity against HeLa cells (SI > 1351). The pronounced analgesic activity was found for 4-nitroso- and 4-aminopyrazoles having phenyl fragment at the position 5 in "hot plate" test. The most of the obtained pyrazoles had a moderate acute toxicity.

New pyrazolo[1,5-a]pyrimidinones functionalized with the tolylhydrazone fragment were obtained as a result of cyclization of 3-oxo-2-(tolylhydrazinylidene) esters with 3-aminopyrazoles. In this case, methyl- and trifluoromethyl-containing derivatives regioselectively form pyrazolo[1,5-a]pyrimidin-7-ones, while cyclization of polyfluoroalkyl-substituted analogs can take place competitively with the formation of dihydropyrazolo[1,5-a]pyrimidin-5-ones, for which ring-chain isomerism is characteristic in solution. It was found that 6-(tolylhydrazinylidene)pyrazolo[1,5-a]pyrimidin-7-ones have a pronounced analgesic activity. The trifluoromethyl-containing analog selectively inhibits carboxylesterase in micromolar concentration.

A series of novel 4-cycloamino-substituted polyfluorosalicylic acids, their esters and amides have been synthesized by the reactions of alkyl polyfluorosalicylates with morpholine, N-methylpiperazine, pyrrolidine and proline. It was observed that esters of polyfluorosalicylic acids under prolonged heating with amines could undergo one pot nucleophilic substitution of fluorine and intramolecular acidic hydrolysis owing to catalysis by the neighboring hydroxyl group. According to ADME calculations, the synthesized compounds are suitable for drug-design. 4-(N-Methylpiperazinyl)-substituted polylfluorosalicylic acids were found to have good analgesic activity while 4-morphonyl-containing analogs revealed moderate anti-inflammatory action. In addition, the presence of amine fragment in polyfluorosalicylates reduced acute toxicity comparing to non-substituted polyfluorosalicylic acids. The molecular docking of the most active compounds was carried out into the tyrosine site of cyclooxygenase-1.

Background: Formally belonging to the non-steroidal anti-inflammatory drug class pyrazolones have long been used in medical practices. Objective: Our goal is to synthesize N-methylated 1-aryl-3-polyfluoroalkylpyrazolones as fluorinated analogs of antipyrine, their isomeric O-methylated derivatives resembling celecoxib structure and evaluate biological activities of obtained compounds. Methods: In vitro (permeability) and in vivo (anti-inflammatory and analgesic activities, acute toxicity, hyperalgesia, antipyretic activity, “open field” test) experiments. To suggest the mechanism of biological activity, molecular docking of the synthesized compounds was carried out into the tyrosine site of COX-1/2. Conclusion: The trifluoromethyl antipyrine represents a valuable starting point in design of the lead series for discovery new antipyretic analgesics with anti-inflammatory properties.

We propose different methods for the synthesis of 4-hydroxyimino-5-polyfluoroalkylpyrazol-3-ones. The simplest and most convenient procedure relies on sequential one-pot treatment of polyfluoroalkyl-3-oxoesters with hydrazine and sodium nitrite in acetic acid. It was established that 4-hydroxyimino-5-polyfluoroalkylpyrazol-3-ones exist in solid state and in solutions as mixtures of Z , Е -isomers of the hydroxyimine tautomer. The synthesized compounds were characterized with respect to in vivo analgesic activity and acute toxicity.