Improving Antimicrobial Activity and Physico-Chemical Properties by Isosteric Replacement of 2-Aminothiazole with 2-Aminooxazole

Abstract

Antimicrobial drug resistance is currently one of the most critical health issues. Pathogens resistant to last-resort antibiotics are increasing, and very few effective antibacterial agents have been introduced in recent years. The promising drug candidates are often discontinued in the primary stages of the drug discovery pipeline due to their unspecific reactivity (PAINS), toxicity, insufficient stability, or low water solubility. In this work, we investigated a series of substituted N-oxazolyl- and N-thiazolylcarboxamides of various pyridinecarboxylic acids. Final compounds were tested against several microbial species. In general, oxazole-containing compounds showed high activity against mycobacteria, especially Mycobacterium tuberculosis (best MICH37Ra = 3.13 µg/mL), including the multidrug-resistant strains. Promising activities against various bacterial and fungal strains were also observed. None of the compounds was significantly cytotoxic against the HepG2 cell line. Experimental measurement of lipophilicity parameter log k’w and water solubility (log S) confirmed significantly (typically two orders in logarithmic scale) increased hydrophilicity/water solubility of oxazole derivatives in comparison with their thiazole isosteres. Mycobacterial β-ketoacyl-acyl carrier protein synthase III (FabH) was suggested as a probable target by molecular docking and molecular dynamics simulations.

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“…For the synthesis of C 9 H 7 N 3 OS ( N -(thiazol-2-yl)­picolinamide; MW: 205.24), instead of utilizing the nongreen synthesis method that has been reported by Juhas et al, we chose the ionic liquid method, which is greener and more environmentally friendly. So, precise amounts of TBAB (10 mmol, 3.22 g), triphenylphosphite (20 mmol, 6.44 g), 2-aminothiazole (20 mmol, 2 g), and picolinic acid (20 mmol, 2.46 g) were mixed in a round-bottomed flask (50 mL) in an oil bath.…”

An efficient, catalyst-free and aqueous ethanol-mediated synthesis of 5-((2-aminothiazol-5-yl)(phenyl)methyl)-6-hydroxypyrimidine-2,4(1H,3H)-dione derivatives and their antioxidant activity

“…2-Aminothiazole has an important core structure that attracts researchers due to its extensive biological activity, such as antidiabetic, 24 antitubercular, 25 anticonvulsant, 26 antioxidant, 27 antimicrobial, 28 antiviral, 29 anticancer, 30 anti-inflammatory 31 and antifungal. 32 It is a natural product found in vitamin thiamine (B1) and other natural sources.…”

“…20 It has driven the synthetic community to look for better ecologically friendly syntheses and reactions to speed up preparation and use less energy and effort. [21][22][23] 2-Aminothiazole has an important core structure that attracts researchers due to its extensive biological activity, such as antidiabetic, 24 antitubercular, 25 anticonvulsant, 26 antioxidant, 27 antimicrobial, 28 antiviral, 29 anticancer, 30 anti-inammatory 31 and antifungal. 32 It is a natural product found in vitamin thiamine (B1) and other natural sources.…”

Correction: Juhás et al. Improving Antimicrobial Activity and Physico-Chemical Properties by Isosteric Replacement of 2-Aminothiazole with 2-Aminooxazole. Pharmaceuticals 2022, 15, 580

“…In the original publication [ 1 ], there was a mistake in assigning individual compounds to their structural subtype in Figure 2 and Table 1 . In correction, subtype I comprises compounds 1 – 10 , and subtype II comprises compounds 11 – 20 .…”