Quick Building Blocks (QBB): An Innovative and Efficient Business Model To Speed Medicinal Chemistry Analog Synthesis.

Many pharmaceutical companies have invested millions of dollars in establishing internal chemical stores to provide reliable access to large numbers of building blocks (BB) for the synthesis of new molecules, especially for the timely design and execution of parallel (library) synthesis. Recognizing budget and logistical limitations, we required a more economically scalable process to provide diverse BB. We disclose a novel business partnership that achieves the goals of just-in-time, economical access to commercial BB that increases chemical space coverage and accelerates the synthesis of new drug candidates.

Novel 3-fluoro-6-methoxyquinoline derivatives as inhibitors of bacterial DNA gyrase and topoisomerase IV.

Novel (non-fluoroquinolone) inhibitors of bacterial type II topoisomerases (NBTIs) are an emerging class of antibacterial agents. We report an optimized series of cyclobutylaryl-substituted NBTIs. Compound 14 demonstrated excellent activity both in vitro (S.

Novel quinoline derivatives as inhibitors of bacterial DNA gyrase and topoisomerase IV.

A structurally novel set of inhibitors of bacterial type II topoisomerases with potent in vitro and in vivo antibacterial activity was developed. Dual-targeting ability, hERG inhibition, and pharmacokinetic properties were also assessed.

Inactivation of a class A and a class C β-lactamase by 6β-(hydroxymethyl)penicillanic acid sulfone.

β-Lactamase inhibitors (clavulanic acid, sulbactam, and tazobactam) contribute significantly to the longevity of the β-lactam antibiotics used to treat serious infections. In the quest to design more potent compounds and to understand the mechanism of action of known inhibitors, 6β-(hydroxymethyl)penicillanic acid sulfone (6β-HM-sulfone) was tested against isolates expressing the class A TEM-1 β-lactamase and a clinically important variant of the AmpC cephalosporinase of Pseudomonas aeruginosa, PDC-3. The addition of the 6β-HM-sulfone inhibitor to ampicillin was highly effective.

P(RNCH2CH2)3N: catalysts for the head-to-tail dimerization of methyl acrylate.

The dimerization of methyl acrylate to the head-to-tail 2-methylene-pentanedioic acid dimethyl ester product was realized in 82 and 85% yield in only 4 h at room temperature in THF in the presence of catalytic amounts of P(RNCH2CH2)3N (R = i-Bu and Bn, respectively). These phosphines are to our knowledge the best nonmetallic catalysts so far reported for this reaction. In contrast, less sterically hindered P(MeNCH2CH2)3N failed to catalyze this dimerization, giving oligomer or polymer instead.

In vitro metabolism studies on the isoxazole ring scission in the anti-inflammatory agent lefluonomide to its active alpha-cyanoenol metabolite A771726: mechanistic similarities with the cytochrome P450-catalyzed dehydration of aldoximes.

The 3-unsubstituted isoxazole ring in the anti-inflammatory drug leflunomide undergoes a unique N-O bond cleavage to the active alpha-cyanoenol metabolite A771726, which resides in the same oxidation state as the parent. In vitro studies were conducted to characterize drug-metabolizing enzyme(s) responsible for ring opening and to gain insight into the mechanism of ring opening. Under physiological conditions, leflunomide was converted to A771726 in rat and human plasma (rat plasma,t1/2 = 36 min; human plasma, t1/2 = 12 min) and whole blood (rat blood, t1/2 = 59 min; human blood, t1/2 = 43 min).

P(RNCH(2)CH(2))(3)N-Catalyzed Synthesis of beta-Hydroxy Nitriles.

We herein report the successful synthesis of beta-hydroxy nitriles in very good to excellent yields from aldehydes and ketones in a simple reaction that is promoted by strong nonionic bases of the title type. The reaction occurs in the presence of magnesium salts which activate the carbonyl group and stabilizes the enolate thus produced.