Structure-Activity Relationship Studies on Highly Functionalized Pyrazole Hydrazones and Amides as Antiproliferative and Antioxidant Agents

Abstract

Aminopyrazoles represent interesting structures in medicinal chemistry, and several derivatives showed biological activity in different therapeutic areas. Previously reported 5-aminopyrazolyl acylhydrazones and amides showed relevant antioxidant and anti-inflammatory activities. To further extend the structure-activity relationships in this class of derivatives, a novel series of pyrazolyl acylhydrazones and amides was designed and prepared through a divergent approach. The novel compounds shared the phenylamino pyrazole nucleus that was differently decorated at positions 1, 3, and 4. The antiproliferative, antiaggregating, and antioxidant properties of the obtained derivatives 10-22 were evaluated in in vitro assays. Derivative 11a showed relevant antitumor properties against selected tumor cell lines (namely, HeLa, MCF7, SKOV3, and SKMEL28) with micromolar IC₅₀ values. In the platelet assay, selected pyrazoles showed higher antioxidant and ROS formation inhibition activity than the reference drugs acetylsalicylic acid and N-acetylcysteine. Furthermore, in vitro radical scavenging screening confirmed the good antioxidant properties of acylhydrazone molecules. Overall, the collected data allowed us to extend the structure-activity relationships of the previously reported compounds and confirmed the pharmaceutical attractiveness of this class of aminopyrazole derivatives.

Keywords: ROS production inhibition; antioxidant activity; antiproliferative agents; platelet aggregation; pyrazole synthesis.

Figure 1

Selected examples of pyrazole compounds with relevant pharamacological activity. The pyrazole and aminopyrazole substructures are colored blue and red, respectively.

Figure 2

Developed SARs around pyrazolyl hydrazones IV.

Scheme 1

Synthesis of pyrazole acylhydrazones 10–13 and pyrazolyl amides 14–22. Reaction conditions: (a) hydrazine monohydrate, EtOH_abs, reflux, 4–6 h; (b) aldehyde a–d, EtOH_abs, reflux, 16 h; (c) acyl chloride, TEA or TMEDA, DMF or ACN or DCM, various temperatures and times.

Figure 3

Bidimensional plot of ROS formation inhibition and antiaggregant activity of derivatives 10–22. Pyrazolyl amides are colored red, and acylhydrazones are reported as green dots. The dashed red line indicates the antiaggregant IC₅₀ value of the reference drug ASA (IC₅₀ = 438 µM). All compounds were found to be more effective ROS formation inhibitors than NAC (IC₅₀ = 872 µM).

Figure 4

SARs developed for acylhydrazones 10–13 and pyrazolyl amides 14–22.