**1. Introduction**

Pyrazoles are nitrogen-containing aromatic heterocycles possessing a five-membered ring in their structure, with two nitrogen atoms in an adjacent position [1]. Catalytic hydrogenation of pyrazoles yields 4,5-dihydro-1 *<sup>H</sup>*-pyrazoles or 2-pyrazoline (Figure 1) [2].

**Figure 1.** Structure of pyrazole and 4,5-dihydro-1 *<sup>H</sup>*-pyrazole.

4,5-Dihydro-1*<sup>H</sup>*-pyrazoles are often synthesized in cyclocondensation of chalcones with hydrazine hydrate, while chalcones are formed in the reaction between aldehydes and acetophenones in the presence of NaOH [3], KOH [4,5]. Zhou et al. [6] synthesized chalcones in the presence of neutral Al2O3 and KOH under microwave irradiation, which in reaction with the hydrazine hydrate yielded *<sup>N</sup>*-4,5-dihydro-1*<sup>H</sup>*-pyrazoles with tyrosinase inhibiting activity.

In general, pyrazoline derivatives exhibit a variety of biological activities, depending on the substituents, which can be placed at a different position of the ring [2]. The accumulation of the fluorine on the carbon atom causes increased oxidative and thermal stability of the drugs as well as increased lipid solubility, which accelerates the drug absorption and transport in vivo [7]. Introduction of fluorine to the drug molecules can reduce their in vivo metabolic turnover by blocking potential reactive positions with fluorine and improving the stability of the molecule toward acid hydrolysis [8]. The biological activity of pyrazoline derivatives includes anticancer activity, especially fluorinated derivatives [9], anti-inflammatory activity [10,11], and anticonvulsant activity [12]. Antifertility, antibacterial, and antifungal agents are frequently fluorinated pyrazolines and pyrazoles [13]. They have also been investigated in inhibitory nNOS activity in rat brains and proven very effective [14]. Fused 4,5-dihydro-1*<sup>H</sup>*-pyrazoles were found to be an excellent antibacterial agen<sup>t</sup> against *Staphylococcus aureus* and *Corynebacterium diphtheriae* [15], while 5-aryl-1-carboxamidino-3-styryl-4,5-dihydro-1*<sup>H</sup>*-pyrazoles were found to be potent antioxidants and antimicrobial agents against *Salmonella typhi, Staphylococcus aureus,* and *Streptococcus pneumoniae* [16]. An excellent antibacterial activity of 4,5-dihydro-1*<sup>H</sup>*-pyrazole derivatives was also proven against *Pseudomonas aeruginosa, Escherichia coli*, *Bacillus subtilis,* and *Staphylococcus aureus*, showing a potent DNA gyrase inhibitory activity as well [17]. All the described above indicates that 4,5-dihydro-1*<sup>H</sup>*-pyrazoles are very potent bioactive compounds and their structural modifications, especially the introduction of a fluorine atom on a phenyl ring, could lead to their increased bioactivity.

The growing necessity for new and potent antibiotics, due to the microorganism resistance to the existing antibiotics, has led us to synthesize pyrazole derivatives as potential antimicrobials. Thus, the aim of this work was to synthesize fluorinated 4,5-dihydro-1*<sup>H</sup>*-pyrazole derivatives in order to examine their antibacterial activity. Since 4,5-dihydro-1*<sup>H</sup>*-pyrazoles have already proven to inhibit tyrosinase activity [6], and this enzyme is responsible for human hyperpigmentation as well as browning reactions, we also investigated the compound's tyrosinase inhibiting activity. In order to indicate the other biological activity of synthesized compounds, in silico prediction according to the structural formulas was performed, as well as molecular docking to evaluated interactions of the ligand with the compatible enzyme.

### **2. Materials and Methods**
