Naphthylthiazoles: Targeting Multidrug-Resistant and Intracellular Staphylococcus aureus with Biofilm Disruption Activity

Abstract

Thirty-two new naphthylthiazole derivatives were synthesized with the aim of exploring their antimicrobial effect on multidrug-resistant Gram-positive bacteria. Compounds 25 and 32, with ethylenediamine and methylguanidine side chains, represent the most promising derivatives, as their antibacterial spectrum includes activity against multidrug-resistant staphylococcal and enterococcal strains. Moreover, the new derivatives are highly advantageous over the existing frontline therapeutics for the treatment of multidrug-resistant Gram-positive bacteria. In this vein, compound 25 possesses three attributes: no bacterial resistance was developed against it even after 15 passages, it was very efficient in targeting intracellular pathogens, and it exhibited a concentration-dependent ability to disrupt the preformed bacterial biofilm.

Identification of a Phenylthiazole Small Molecule with Dual Antifungal and Antibiofilm Activity Against Candida albicans and Candida auris

“…Compounds were synthesized and characterized as described in previous reports. The synthetic schemes for compounds 1 - 23 29,31,35,48,49 , compounds 24 - 31 28 , and compounds 32 - 85 30,34,50,51 are presented in the supplementary information file. Compounds were prepared as stock 10 mg/mL or 1 mg/mL solutions in dimethyl sulfoxide (DMSO).…”

From Phenylthiazoles to Phenylpyrazoles: Broadening the Antibacterial Spectrum toward Carbapenem-Resistant Bacteria

“…This work is built on the discovery of a lead compound, phenylthiazole, which bears an alkyl side chain on one side and a guanidine head on the other side; it possesses antimicrobial activity against Gram-positive pathogens . This initial discovery was followed by intensive structural optimization to improve its antimicrobial activity and metabolic stability. − The structural optimization focused on the nitrogenous part, the lipophilic tail, and the connection with the phenylthiazole scaffold. − Our structural optimization efforts with first generation compounds using different heterorings as a linker between the guanidine head and the main scaffold overcame its metabolic instability and improved its antibacterial activity (Figure ). ,,, Using an alkynyl lipophilic moiety blocked the metabolic soft spot, increased biological half-life, and enhanced the systemic efficiency …”

Evaluation of bisphenylthiazoles as a promising class for combating multidrug-resistant fungal infections

“…Methylsulfone, as a good leaving group, was used to access nucleophilic aromatic substitution on the oxadiazole ring. Compound 6 was prepared as previously reported [ 11 ], starting from the acid hydrazine (compound 4 ), and then the compound allowed to react with various amine-containing synthons to yield the desired final products, compounds 7–21 (Scheme 1).…”

“…Methylsulfone, as a good leaving group, was used to access nucleophilic aromatic substitution on the oxadiazole ring. Compound 6 was prepared as previously reported [11], starting from the acid hydrazine (compound 4), and then the compound allowed to react with various amine-containing synthons to yield the desired final products, compounds 7-21 (Scheme 1). The stereochemistry of the final products was derived from their corresponding starting materials because a one-step substitution reaction was not expected to affect the spatial configuration of the final compounds.…”

“…Our synthesized compounds were screened intuitively against bacterial and fungal species to assess their antimicrobial activity prior to further investigation. Through continuous modification, we discovered that the hydrazinyl cationic side chain provided the phenylthiazole core with potency against multidrug-resistant staphylococcal infections [ 11 ] ( Fig 1 ). Unfortunately, activation of hydrazine inside the body is presumed to generate aryl free radicals, which results in serious oxidative stress and induces acute liver injury in the case of isoniazid and iproniazid (the two known hydrazine-containing antitubercular therapeutics with black-box warnings) [ 12 – 15 ].…”