Biphenylthiazole antibiotics with an oxadiazole linker: An approach to improve physicochemical properties and oral bioavailability

Abstract

A new series of oxadiazolylbiphenylthiazoles was prepared with the objective of improving the limited solubility of first-generation derivatives while maintaining antibacterial activity against drug-resistant Staphylococcus aureus. Studying the structure-activity relationship at the cationic part provided the piperazine-1-carboximidamide derivative 27 with a MIC (MRSA) value of 1.1 μg/mL, bactericidal mode of action, and a 50-fold improvement in aqueous solubility. Additionally, 27 exhibited a wider safety margin against mammalian cells, and most importantly, a significant improvement in oral bioavailability.

Arylthiazole antibiotics targeting intracellular methicillin-resistant Staphylococcus aureus (MRSA) that interfere with bacterial cell wall synthesis

“…Using our previously defined structure-activity-relationships (SAR),[14, 15] amino, hydrazinyl and guanidinyl moieties were selected as the cationic part and connected to the thiazole linker to build a small focused library of nine final products 4a-4i . The minimum inhibitory concentration (MIC) and the minimum bactericidal concentration (MBC) of these final products, in addition to linezolid, and vancomycin were determined using the broth microdilution method (Table 1).…”

“…[14] Hence, the guanidine-containing derivatives 4g-4i demonstrated lower MIC values than their corresponding amine or hydrazine analogues (Table 1). The naphthyl derivative 4i showed antimicrobial potency comparable with two drugs of choices commonly used in treatment of invasive MRSA infections (vancomycin and linezolid).…”

“…Compound 4i retained its unique feature as a rapid bactericidal agent, compared to vancomycin, as it completely eliminated MRSA cells within four hours, while vancomycin required 24 hours to achieve the same effect (Figure 2), while the corresponding oxadiazole analogue behaves like vancomycin in its slow bactericidal action against MRSA.×. [14] The rapid killing kinetics of 4i is posited to be beneficial in helping to resolve an infection more rapidly and to limit the emergence of rapid resistance to the arylthiazoles. [17]…”

“…In order to improve the water solubility, the pyrimidine linker was replaced with an oxadiazole that has fewer carbons and a larger polar surface area. [14] Though the oxadiazole-containing phenylthiazoles exhibited a 50 to 65-fold improvement in aqueous solubility and high metabolic stability, their anti-MRSA activity, in general, was less potent than the corresponding pyrimidine-containing analogues (Figure 1). In this regard, the MIC value of the most potent oxadiazole analogue was three-times less active than the pyrimidine analogue (Figure 1).…”

Peptidoglycan pathways: there are still more!

“…109,110 This criteria is clinically important, as it would affect the size of the dosing regimen necessary for patients. 111,112 Through the more than 400 published phenylthiazole derivatives, 110,[113][114][115][116][117][118][119][120][121][122][123][124][125][126] the SAR of this class of compounds has become well dened (Fig. 4).…”