**1. Introduction**

Antimicrobial resistance represents a significant threat to global health and development today. Without effective antimicrobials (e.g., antibiotics, antifungals, and antiparasitics) and antiviral drugs, the success of modern medicine in preventing and treating infections would be at increased risk [1]. The discovery and development of new antimicrobial agents are therefore of considerable importance and one of the main focuses of today's scientific community is the synthesis and identification of potent active substances.

An exhaustive survey of the literature on natural and synthetic oxazole-based molecules shows that they have numerous biological properties, which include antibacterial, antifungal, anti-inflammatory, antioxidant, and cytotoxic activities [2–11]. For example, a physiologically important active cyclic peptide with a 1,3-oxazole ring is dalfopristin, a semi-synthetic streptogramin A antibiotic analog marketed under the trade name Synercid in the combination with quinupristin, a streptogramin B derivative. The structures of some representative antimicrobial agents containing the 1,3-oxazole skeleton are shown in Figure 1.

**Citation:** Apostol, T.-V.; Chifiriuc, M.C.; Socea, L.-I.; Draghici, C.; Olaru, O.T.; Nitulescu, G.M.; Visan, D.-C.; Marutescu, L.G.; Pahontu, E.M.; Saramet, G.; et al. Synthesis, Characterization, and Biological Evaluation of Novel *N*-{4-[(4- Bromophenyl)sulfonyl]benzoyl}-*L*valine Derivatives. *Processes* **2022**, *10*, 1800. https://doi.org/10.3390/ pr10091800

Academic Editors: Iliyan Ivanov and Stanimir Manolov

Received: 17 August 2022 Accepted: 3 September 2022 Published: 7 September 2022

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**Copyright:** © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

**Figure 1.** Structures of some representative bioactive compounds sharing the 1,3-oxazole scaffold as antimicrobial agents: (**a**) Natural or semi-synthetic products; (**b**) Synthetic compounds.

The isolable 5-keto-tautomers of 1,3-oxazol-5-ols are 5-oxo-4,5-dihydro-1,3-oxazoles, known as 4*H*-1,3-oxazol-5-ones or 2-oxazolin-5-ones, which are also mentioned for their antimicrobial, cytotoxic, antiprotozoal, and antiviral properties [12–15]. Moreover, the *N*-acylated α-amino acids are reported to display many pharmaceutical activities, such as antimicrobial, antiviral, anticancer, mucolytic, antioxidant, and antihypertensive effects [16–22], and the 2-acylamino ketones present antiviral, anti-inflammatory, antithrombotic, and antihypertensive actions [23–28].

Furthermore, diaryl sulfones represent an important class of bioactive compounds with diverse biological properties, including antimicrobial and antioxidant actions [29–37]. The structural prototype of this class is dapsone (4,4 -sulfonyldianiline, 4,4 -diaminodiphenyl sulfone, DDS), which is used alone or as part of a multi-drug regimen in the treatment or prophylaxis of certain infectious diseases, such as leprosy (also known as Hansen's disease). Currently, the therapeutic potential of organic compounds with a sulfonyl group in their molecules is being studied extensively [38,39]. In this regard, a new drug candidate from the organosulfones class is masupirdine (SUVN-502), a 1-[(2-bromophenyl)sulfonyl]- 1*H*-indole derivative with a selective 5-HT6 receptor antagonist effect, developed for the symptomatic treatment of Alzheimer's disease [40].

Based on the promising therapeutic potential of these scaffolds and in the continuation of our research [41–46], we designed, obtained, and characterized novel *L*-valine-derived analogs with a 4-[(4-bromophenyl)sulfonyl]phenyl fragment and also evaluated their in silico and in vitro antimicrobial, antioxidant, and toxicity properties with the aim of identifying new biologically active compounds. The used synthesis methodology enables synthetic chemical diversification with the potential to prepare drug-like compounds.

The in silico approach to the biological activity of the new bromine compounds allowed the assessment of their toxicity and potential antimicrobial effect.

The in vitro antimicrobial testing of the new compounds included both qualitative screening (measuring the diameters of the zones of inhibition of microbial growth) and quantitative analysis (determining the values of minimal inhibitory concentration), as well as the assay of the antibiofilm action (determining the values of minimal biofilm inhibitory concentration). Particular emphasis was placed on evaluating the inhibition of microbial adhesion to surfaces as a possible means of reducing the burden of biofilm-associated infections.

The in vitro antioxidant activity of newly obtained compounds was investigated colorimetrically according to three electron transfer-based methods, namely 2,2-diphenyl-1 picrylhydrazyl (DPPH) assay, 2,2 -azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) radical cation test, and ferric reducing power assay.

The compounds' toxicity was assessed on *Daphnia magna*. This bioassay is a widely used method for the toxicity evaluation of natural and synthetic compounds, and it is in accordance with the "3 R's" (reduction, refinement, and replacement) concept regarding experiments on vertebrates. It can be used as a prescreening method for rats and other mammals' acute toxicity tests. The main advantage of this method is the crustacean reproduction mode by parthenogenesis, which leads to populations with lower variability than other invertebrate species [47,48].
