Exploration of the Activity of 7-Pyrrolidino-8-methoxyisothiazoloquinolones against Methicillin-Resistant Staphylococcus aureus (MRSA)

Abstract

A series of 7-(3'-substituted)pyrrolidino-8-methoxyisothiazoloquinolone (ITQ) analogues were prepared, and their antibacterial potency against methicillin-sensitive Staphylococcus aureus (MSSA), methicillin-resistant Staphylococcus aureus (MRSA), and Escherichia coli were compared. Many of these analogues had MIC ≤ 0.25 μg/mL against quinolone-resistant MRSA strains. The stereochemical preference was explored for a series of 1''-methyl-3'-aminomethylpyrrolidine analogues. Antibacterial activity was generally more favorable with 3'-R, 1''-S configuration. Substitution on the 3'-aminomethyl nitrogen tended to decrease activity, while potency was maintained with disubstitution or aryl substitution at the 1''-carbon. The 7-[(R)-3-((S)-1-aminoethyl)pyrrolidin-1-yl] analogue (6a(R,S)) and the (R)-7-[3-(2-aminopropan-2-yl)pyrrolidin-1-yl] analogue (7a(R)) were found to be the ITQs with the most promising antibacterial profiles. The MICs of these select ITQs versus a panel of clinical MRSA strains were determined, and the ITQs were found to have 8- to 16-fold greater potency than linezolid. These analogues were also evaluated for inhibition of the target enzymes, topoisomerase IV and DNA gyrase, from both wild-type and multidrug resistant strains. The ITQs were up to >30 times more inhibitory against these targets than the fluoroquinolone moxifloxacin.

Synthesis and Evaluation of Thiazolidine Amide and N‐Thiazolyl Amide Fluoroquinolone Derivatives

“…The corresponding acid chloride was treated with thiazolidine in the presence of Et 3 N to yield 42% of compound 2 [11]. Synthesis of 7-amino-substituted thiazolidine amide (8)(9)(10) and N-thiazolyl amide fluoroquinolone derivatives (11)(12)(13)(14) involved a two-step reaction sequence of nucleophilic aromatic substitution followed by acid derivatization to amides (Scheme 1). 7-Amino-substituted fluoroquinolone intermediates (3-7) were obtained by refluxing 1 in CH 3 CN, Et 3 N with piperidine, octahydro-1H-isoindole, perhydroisoquinoline, pyrrolidine, and morpholine in 48-89% yields [12].…”

“…7-Amino-substituted fluoroquinolone intermediates (3-7) were obtained by refluxing 1 in CH 3 CN, Et 3 N with piperidine, octahydro-1H-isoindole, perhydroisoquinoline, pyrrolidine, and morpholine in 48-89% yields [12]. Subsequently, intermediates 3-5 in DMF, DIPEA were coupled with thiazolidine in the presence of HATU at 70°C for 20-24 h to yield corresponding amides (8)(9)(10) in 54-60% yields [13] (Fig. 2).…”

A practical and catalyst-free trifluoroethylation reaction of amines using trifluoroacetic acid

“…The most widely used method involves LiAlH 4 or borane reduction of trifluoromethylamides generated using trifluoroacetic anhydride (Fig. 1a)4142. The use of pyrophoric reductants requires special precautions, limits applicability on-scale and precludes substrates that contain other reducible functional groups.…”

A “Double-Edged” Scaffold: Antitumor Power within the Antibacterial Quinolone

“…Achillion Pharmaceuticals determined that isothiazoloquinolone analogs had good potency against MRSA as well as against other quinolone-resistant pathogens, and therefore established a program to search for a clinical candidate from this scaffold series [188-194]. Mindful of the inherent risk of unwanted eukaryotic cytotoxicity in this class, Achillion counterscreened their antibacterial analogs in a Hep2 (human laryngeal carcinoma) cytotoxicity assay.…”