Arylpyrazole as selective anti‐enterococci; synthesis and biological evaluation of novel derivatives for their antimicrobial efficacy

Abstract

Exploring the structure–activity relationships (SAR) of a new set of phenylpyrazoles unveiled a potential anti‐enterococcus lead compound 12. The benzofuran moiety linked to the phenylpyrazole 12 was 32 times better than vancomycin against Enterococcus faecalis ATCC 51299. Besides, compound 12 is expected to have an excellent oral bioavailability according to the in silico studies. Of SAR analysis, we found that the benzofuran side chain was essential for the activity. Changing the benzofuran with either benzothiophene, phenyl, pyridinyl, tolyl, or naphthyl reduces/nullifies the pharmacological action. Besides the anti‐enterococcal activity, derivatives 4 and 6 can be used to develop new broad‐spectrum antibiotics as they exhibited activity against the wild‐type highly virulent Escherichia coli isolate. Moreover, compound 13 was proved to show antifungal activity (MIC = 4 μg/ml) against the Candida albicans SS5314 (wild type). Finally, the in silico analysis showed that those compounds have good profiles regarding the absorption, distribution, metabolism, and excretion studies, drug‐likeness and pharmacokinetics properties.

Exploring novel aryl/heteroaryl-isosteres of phenylthiazole against multidrug-resistant bacteria

“…The first one involved the direct reaction of boronic acid derivatives with p -iodophenylthiazole in one step. 22 The second method is an in situ borylation of p -chlorophenylthiazole, followed by reaction with the second aryl halide, which was suitable for a wide range of derivatives ( Table 1 ). 26 Thiophene sulfonamide derivatives 19–25 were synthesized via nucleophilic substitution reaction of the corresponding sulfonyl chloride with proper amines in the presence of triethylamine.…”

“…4.1.1. Preparation of sulfonamide intermediates (19)(20)(21)(22)(23)(24)(25). To a solution of 5-bromothiophene-2-sulfonyl chloride (0.13 g, 0.5 mmol) in dichloromethane (0.67 M), an appropriate amine (0.75 mmol) and triethylamine (0.1 g, 1 mmol) were added.…”

Substituted salicylic acid analogs offer improved potency against multidrug-resistant Neisseria gonorrhoeae and good selectivity against commensal vaginal bacteria

“…The in vitro cytotoxicity assessment for salicylic acid analogs was carried out against kidney fibroblast (Vero) cells as described elsewhere 43 – 48 . Briefly, compounds were incubated with Vero cells for 24 h and DMSO served as a negative control.…”

New Phenylthiazoles: Design, Synthesis, and Biological Evaluation as Antibacterial, Antifungal, and Anti‐COVID‐19 Candidates

“…One of the groups must possess lipophilic properties and the other has a cationic nature. [37,38] The microsomal oxidation suffered by the first-generation phenylthiazoles [23] was overcome by removing the benzylic CH 2 at the lipophilic end of the lead compound I and replacing it with an alkoxy group in compounds II and III or alkyne substituents in compounds IV and V thus rendering those derivatives with a longer half-life (Figure 1). [20,29] Phenylthiazole-based agents have recently shown promise in the treatment of COVID-19.…”

“…A study of the SAR of antibacterial phenylthiazoles uncovered that the thiazole ring should be enclosed within two major substituent groups. One of the groups must possess lipophilic properties and the other has a cationic nature [37,38] . The microsomal oxidation suffered by the first‐generation phenylthiazoles [23] was overcome by removing the benzylic CH 2 at the lipophilic end of the lead compound I and replacing it with an alkoxy group in compounds II and III or alkyne substituents in compounds IV and V thus rendering those derivatives with a longer half‐life (Figure 1).…”