A pyrazole nucleus is an easy-to-prepare scaffold with large therapeutic potential. Consequently, the search for new pyrazole-based compounds is of great interest to the academic community as well as industry. In the last ten years, a large number of papers and reviews on the design, synthesis, and biological evaluation of different classes of pyrazoles and many pyrazole-containing compounds have been published. However, an overview of pyrazole derivatives bearing a free amino group at the 3, 4, or 5 position (namely, 3-aminopyrazoles, 4-aminopyrazoles, and 5-aminopyrazoles, respectively) and their biological properties is still missing, despite the fact that aminopyrazoles are advantageous frameworks able to provide useful ligands for receptors or enzymes, such as p38MAPK, and different kinases, COX and others, as well as targets important for bacterial and virus infections. With the aim to fill this gap, the present review focuses on aminopyrazole-based compounds studied as active agents in different therapeutic areas, with particular attention on the design and structure-activity relationships defined by each class of compounds. In particular, the most relevant results have been obtained for anticancer/anti-inflammatory compounds, as the recent approval of Pirtobrutinib demonstrates. The data reported here are collected from different databases (Scifinder, Web of Science, Scopus, Google Scholar, and Pubmed) using “aminopyrazole” as the keyword.

Phosphodiesterase 4 (PDE4) enzymes catalyze cyclic adenosine monophosphate (cAMP) hydrolysis and are involved in a variety of physiological processes, including brain function, monocyte and macrophage activation, and neutrophil infiltration. Among different PDE4 isoforms, Phosphodiesterases 4D (PDE4Ds) play a fundamental role in cognitive, learning and memory consolidation processes and cancer development. Selective PDE4D inhibitors (PDE4Dis) could represent an innovative and valid therapeutic strategy for the treatment of various neurodegenerative diseases, such as Alzheimer’s, Parkinson’s, Huntington’s, and Lou Gehrig’s diseases, but also for stroke, traumatic brain and spinal cord injury, mild cognitive impairment, and all demyelinating diseases such as multiple sclerosis. In addition, small molecules able to block PDE4D isoforms have been recently studied for the treatment of specific cancer types, particularly hepatocellular carcinoma and breast cancer. This review overviews the PDE4DIsso far identified and provides useful information, from a medicinal chemistry point of view, for the development of a novel series of compounds with improved pharmacological properties.

Water-soluble formulations of the pyrazole derivative 3-(4-chlorophenyl)-5-(4-nitrophenylamino)-1H-pyrazole-4-carbonitrile (CR232), which were proven to have in vitro antiproliferative effects on different cancer cell lines, were prepared by two diverse nanotechnological approaches. Importantly, without using harmful organic solvents or additives potentially toxic to humans, CR232 was firstly entrapped in a biodegradable fifth-generation dendrimer containing lysine (G5K). CR232-G5K nanoparticles (CR232-G5K NPs) were obtained with high loading (DL%) and encapsulation efficiency (EE%), which showed a complex but quantitative release profile governed by Weibull kinetics. Secondly, starting from hydrogenated soy phosphatidylcholine and cholesterol, we prepared biocompatible CR232-loaded liposomes (CR232-SUVs), which displayed DL% and EE% values increasing with the increase in the lipids/CR232 ratio initially adopted and showed a constant prolonged release profile ruled by zero-order kinetics. When relevant, attenuated total reflectance Fourier transformed infrared spectroscopy (ATR-FTIR) and nuclear magnetic resonance (NMR) spectroscopy, scanning electron microscopy (SEM) and dynamic light scattering (DLS) experiments, as well as potentiometric titrations completed the characterization of the prepared NPs. CR232-G5K NPs were 2311-fold more water-soluble than the pristine CR232, and the CR232-SUVs with the highest DL% were 1764-fold more soluble than the untreated CR232, thus establishing the success of both our strategies.

A series of highly functionalized pyrazole derivatives has been prepared by a one‐pot, versatile and regioselective procedure. Pyrazoles 1–29 were tested in cell‐based assay to assess their antiproliferative activity against a panel of tumour cells. Additionally, the cytotoxicity of prepared compounds was evaluated against normal human fibroblasts. The antiproliferative activity of the synthesized molecules emerged to be affected by the nature of the substituents of the pyrazole scaffold and derivatives 21–23 proved to inhibit the growth of melanoma and cervical cancer cells. Compound 23 was identified as the most active derivative and docking simulations predicted its ability to interact with estrogen receptors.

The antimicrobial potency of the pyrazole nucleus is widely reported these days, and pyrazole derivatives represent excellent candidates for meeting the worldwide need for new antimicrobial compounds against multidrug-resistant (MDR) bacteria. Consequently, 3-(4-chlorophenyl)-5-(4-nitrophenylamino)-1H-pyrazole-4-carbonitrile (CR232), recently reported as a weak antiproliferative agent, was considered to this end. To overcome the CR232 water solubility issue and allow for the determination of reliable minimum inhibitory concentration values (MICs), we initially prepared water-soluble and clinically applicable CR232-loaded nanoparticles (CR232-G5K NPs), as previously reported. Here, CR232-G5K NPs have been tested on several clinically isolates of Gram-positive and Gram-negative species, including MDR strains. While for CR232 MICs ≥ 128 µg/mL (376.8 µM) were obtained, very low MICs (0.36–2.89 µM) were observed for CR232-G5K NPs against all of the considered isolates, including colistin-resistant isolates of MDR Pseudomonas aeruginosa and Klebsiella pneumoniae carbapenemases (KPCs)-producing K. pneumoniae (0.72 µM). Additionally, in time–kill experiments, CR232-G5K NPs displayed a rapid bactericidal activity with no significant regrowth after 24 h on all isolates tested, regardless of their difficult-to-treat resistance. Conjecturing a clinical use of CR232-G5K NPs, cytotoxicity experiments on human keratinocytes were performed, determining very favorable selectivity indices. Collectively, due to its physicochemical and biological properties, CR232-G5K NPs could represent a new potent weapon to treat infections sustained by broad spectrum MDR bacteria.

A small library of highly functionalized phenylaminopyrazoles, bearing different substituents at position 1, 3, and 4 of the pyrazole ring, was prepared by the one-pot condensation of active methylene reagents, phenylisothiocyanate, and substituted hydrazine (namely, methyl- and benzyl-hydrazine). The identified reaction conditions proved to be versatile and efficient. Furthermore, the evaluation of alternative stepwise protocols affected the chemo- and regio-selectivity outcome of the one-pot procedure. The chemical identities of two N-methyl pyrazole isomers, selected as prototypes of the whole series, were unambiguously identified by means of NMR and mass spectrometry studies. Additionally, semiempirical calculations provided a structural rationale for the different chromatographic behavior of the two isomers. The prepared tetra-substituted phenylaminopyrazoles were tested in cell-based assays on a panel of cancer and normal cell lines. The tested compounds did not show any cytotoxic effect on the selected cell lines, thus supporting their pharmaceutical potentials.