Synthesis of Novel Thiazole Derivatives Bearing β-Amino Acid and Aromatic Moieties as Promising Scaffolds for the Development of New Antibacterial and Antifungal Candidates Targeting Multidrug-Resistant Pathogens

Abstract

Rapidly growing antimicrobial resistance among clinically important bacterial and fungal pathogens accounts for high morbidity and mortality worldwide. Therefore, it is critical to look for new small molecules targeting multidrug-resistant pathogens. Herein, in this paper we report a synthesis, ADME properties, and in vitro antimicrobial activity characterization of novel thiazole derivatives bearing β-amino acid, azole, and aromatic moieties. The in silico ADME characterization revealed that compounds 1–9 meet at least 2 Lipinski drug-like properties while cytotoxicity studies demonstrated low cytotoxicity to Vero cells. Further in vitro antimicrobial activity characterization showed the selective and potent bactericidal activity of 2a–c against Gram-positive pathogens (MIC 1–64 µg/mL) with profound activity against S. aureus (MIC 1–2 µg/mL) harboring genetically defined resistance mechanisms. Furthermore, the compounds 2a–c exhibited antifungal activity against azole resistant A. fumigatus, while only 2b and 5a showed antifungal activity against multidrug resistant yeasts including Candida auris. Collectively, these results demonstrate that thiazole derivatives 2a–c and 5a could be further explored as a promising scaffold for future development of antifungal and antibacterial agents targeting highly resistant pathogenic microorganisms.

Liposomal formulation of a new antifungal hybrid compound provides protection against Candida auris in the ex vivo skin colonization model

“…However, the exhibited MIC values were, with one exception (B11211), higher than those found for rezafungin, which is a novel echinocandin being developed for the treatment and prevention of invasive fungal infections ( 43 ). It is also worth mentioning that the determined antifungal activity of PQA-Az-13 was much better than the recently published data for azobenzene ( 44 ) or thiazole derivatives ( 45 ), for Schiff bases of sulphonamides ( 46 ), for 4-dialkoxynaphthalen-2-acyl imidazolium salts ( 47 ), and for derivatives of the antimalarial drug mefloquine ( 48 ). Thus, our results are particularly interesting, especially in the context that, for the pan-resistant C. auris strain, B11211, a MIC value of 0.67 µg/mL was obtained for PQA-Az-13, whereas MIC values of >256 µg/mL for fluconazole and 1.5 µg/mL for amphotericin B were reported in reference ( 42 ) and a MIC of 2 µg/mL reported for rezafungin ( 43 ), confirming the superior antifungal properties of the synthesized structure and its potential application to drug-resistant fungi.…”

Synthesis and in vitro Antibacterial Evaluation of N‐(4‐methoxy‐2‐nitrophenyl)‐β‐alanine Derivatives

“…Our previous successful studies on the synthesis and biological evaluation of compounds using variously substituted anilines [35][36][37][38][39][40] motivated a new investigation with the parent compound having nitro group in the structure, namely 4methoxy-2-nitroaniline (1) (Scheme 1). With this aromatic amine in hand, the synthesis of compound 2 was first undertaken.…”

“…Variously substituted azole derivatives are frequently used as the fundamental pharmacophores in drug design due to their highly advantageable biological properties and also are used for the treatment of these infections mainly as antifungal, antimicrobial and antiparasitic agents. [33][34][35][36][37][38] For this moment, many drugs with azole moieties are approved for clinical use, including an anti-glaucoma and mild cardiac edema agent acetazolamide, [39] anti-HIV agents raltegravir and maraviroc [40,41] or nesapidil, a vasodilator, used in an antiarrhythmic and antihypertensive therapy. [38] Furthermore, our recent studies approved the importance of attaching azoles to scaffoldmolecules.…”

Synthesis, Characterization and Antibacterial Assays of Novel N,N1‐Disubstituted 2,2′‐Dithiodianiline Derivatives

“…[43] Previously, we have synthesized a library of N,N-disubstituted β-aminoacids derivatives containing hydrazone and azole fragments and have evaluated their biological properties, which appeared to possess the convincing anticancer effect against triple-negative breast cancer and glioblastoma cells in vitro. [44] They demonstrated promising antimicrobial, [45][46][47][48] significant antibacterial, [49][50][51][52] and in addition, antiviral and antioxidant [51,52] activities.…”