Balancing Physicochemical Properties of Phenylthiazole Compounds with Antibacterial Potency by Modifying the Lipophilic Side Chain

Abstract

Bacterial resistance to antibiotics is presently one of the most pressing healthcare challenges and necessitates the discovery of new antibacterials with unique chemical scaffolds. However, the determination of the optimal balance between structural requirements for pharmacological action and pharmacokinetic properties of novel antibacterial compounds is a significant challenge in drug development. The incorporation of lipophilic moieties within a compound’s core structure can enhance biological activity but have a deleterious effect on drug-like properties. In this Article, the lipophilicity of alkynylphenylthiazoles, previously identified as novel antibacterial agents, was reduced by introducing cyclic amines to the lipophilic side chain. In this regard, substitution with methylpiperidine (compounds 14–16) and thiomorpholine (compound 19) substituents significantly enhanced the aqueous solubility profile of the new compounds more than 150-fold compared to the first-generation lead compound 1b. Consequently, the pharmacokinetic profile of compound 15 was significantly enhanced with a notable improvement in both half-life and the time the compound’s plasma concentration remained above its minimum inhibitory concentration (MIC) against methicillin-resistant Staphylococcus aureus (MRSA). In addition, compounds 14–16 and 19 were found to exert a bactericidal mode of action against MRSA and were not susceptible to resistance formation after 14 serial passages. Moreover, these compounds (at 2× MIC) were superior to the antibiotic vancomycin in the disruption of the mature MRSA biofilm. The modifications to the alkynylphenylthiazoles reported herein successfully improved the pharmacokinetic profile of this new series while maintaining the compounds’ biological activity against MRSA.

Lipophilic Ga Complex with Broad-Spectrum Antimicrobial Activity and the Ability to Overcome Gallium Resistance in both Pseudomonas aeruginosa and Staphylococcus aureus

“…To prevent the formation of the suspected coordination polymer, we added an additional bidentate ligand (2,2′-bipyridine) to the synthesis and obtained the new dimeric complex, [Ga 2 L 3 (bpy) 2 ] (hereafter abbreviated as 1 ). The use of this aromatic co-ligand also significantly increased the lipophilicity of the complex, which has been previously correlated with antimicrobial potency. − …”

A New Discovery of Unique 13-(Benzimidazolylmethyl)berberines as Promising Broad-Spectrum Antibacterial Agents

“…It was notable that OBMB- 6f exhibited a lower hemolytic rate (>512 μg/mL) than decyl derivative 6g (413.2 μg/mL). Moreover, it was reported that excessive lipid solubility was detrimental to the preparation of compounds into suitable dosage forms . Therefore, OBMB- 6f with a moderate C log P value (4.21) was selected as a representative compound for subsequent studies including cytotoxicity, bactericidal performance, antibiofilm activity, and drug-resistance development, as well as antibacterial mechanism.…”

Development of Biphenylthiazoles Exhibiting Improved Pharmacokinetics and Potent Activity Against Intracellular Staphylococcus aureus

“…1 H NMR (DMSO-d 6 ) δ: 8.38 (d, J = 4.8 Hz, 1H), 8.02 (d, J = 8.4 Hz, 2H), 7.78 (d, J = 8.4 Hz, 2H), 7.72 (d, = 7.2 Hz, 2H), 7.47 (t, J = 7.6 Hz, 2H), 7.39 (t, J = 6.8 Hz, 1H), 6.87 (d, J = 4.8 Hz, 1H), 3.80−3.68 (m, 3H), 3.41−3.37 (m, 2H), 3.18−3.14 (m, 1H), 2.73 (s, 3H), 2.18 (s, 6H), 1.81−1.75 (m, 1H). 13 (23). After we followed the general procedure, using (S)-(−)-3-(dimethylamino)pyrrolidine (42 μL, 0.4 mmol), compound 23 was obtained as a yellow solid (0.07 g, 64%) with mp = 136 °C.…”

“…One of our successfully discovered new antibacterial scaffolds is arylthiazole which demonstrated confirmed activity against a large panel of multidrug-resistant (MDR) Gram-positive pathogens. − These compounds outperformed vancomycin in terms of their rapid bactericidal mode of action. , The structure–activity relationships (SARs) of the arylthiazole antibacterial core were studied from three different perspectives. Briefly, the biphenyl side chain revealed notable improvement in the antibacterial effect, while the short half-life of the first discovered lead compound was remarkably enhanced by inserting the CN linker within pyrimidine structure (Figure ).…”