Second-Generation Phenylthiazole Antibiotics with Enhanced Pharmacokinetic Properties

Abstract

A series of second-generation analogues for 2-(1-(2-(4-butylphenyl)-4-methylthiazol-5-yl)ethylidene)aminoguanidine (1) have been synthesized and tested against methicillin-resistant Staphylococcus aureus (MRSA). The compounds were designed with the objective of improving pharmacokinetic properties. This main aim has been accomplished by replacing the rapidly hydrolyzable Schiff-base moiety of first-generation members with a cyclic, unhydrolyzable pyrimidine ring. The hydrazide-containing analogue 17 was identified as the most potent analogue constructed thus far. The corresponding amine 8 was 8 times less active. Finally, incorporating the nitrogenous side chain within an aromatic system completely abolished the antibacterial character. Replacement of the n-butyl group with cyclic bioisosteres revealed cyclohexenyl analogue 29, which showed significant improvement in in vitro anti-MRSA potency. Increasing or decreasing the ring size deteriorated the antibacterial activity. Compound 17 demonstrated a superior in vitro and in vivo pharmacokinetic profile, providing compelling evidence that this particular analogue is a good drug candidate worthy of further analysis.

Phenylthiazole Antibacterial Agents Targeting Cell Wall Synthesis Exhibit Potent Activity in Vitro and in Vivo against Vancomycin-Resistant Enterococci

“…Additionally, designing new analogues focused on improving the limitations of compounds 1 – 3 (namely improving permeability and metabolic stability) while maintaining their potent anti-VRE activity will be pursued. This approach was successful in discovering second-generation phenylthiazoles with an enhanced pharmacokinetic profile that were potent inhibitors of MRSA growth 40 . However, most of the second-generation phenylthiazoles were not active against VRE (MIC > 64 μg/mL) or were significantly less potent than the first-generation compounds.…”

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).…”

Investigating the Antibacterial Activity of Biphenylthiazoles against Methicillin- and Vancomycin-Resistant Staphylococcus aureus (MRSA and VRSA)

“…[11][12][13][14][15] The first-generation phenylthiazoles were characterized by two structural groups: a nitrogenous head and a lipophilic side chain linked to the phenyl ring. Subsequent optimization of the lipophilic side chain afforded the biphenylthiazole 1b with improved activity against MRSA ( Figure 1).…”

“…However, increasing the carbon chain from methyl to ethyl (compound 17) improved the activity by one-fold (Table 1, entry 14); further lengthening of the carbon chain led to a series of derivatives (compounds 18-22) without antibacterial activity, irrespective of the alky side chain (Table 1, entries [15][16][17][18][19]. Furthermore, a second alkylation with dimethyl or diethyl groups (compounds 23 and 24) or incorporation of the nitrogen atom within cyclic structures (compounds 8, 9 and 25) furnished inactive derivatives (Table 1, entries 7, 8 and 22).…”