Discovery and Optimization of DNA Gyrase and Topoisomerase IV Inhibitors with Potent Activity against Fluoroquinolone-Resistant Gram-Positive Bacteria.

Herein, we describe the discovery and optimization of a novel series that inhibits bacterial DNA gyrase and topoisomerase IV via binding to, and stabilization of, DNA cleavage complexes. Optimization of this series led to the identification of compound 25, which has potent activity against Gram-positive bacteria, a favorable in vitro safety profile, and excellent in vivo pharmacokinetic properties. Compound 25 was found to be efficacious against fluoroquinolone-sensitive Staphylococcus aureus infection in a mouse thigh model at lower doses than moxifloxacin. An X-ray crystal structure of the ternary complex formed by topoisomerase IV from Klebsiella pneumoniae, compound 25, and cleaved DNA indicates that this compound does not engage in a water-metal ion bridge interaction and forms no direct contacts with residues in the quinolone resistance determining region (QRDR). This suggests a structural basis for the reduced impact of QRDR mutations on antibacterial activity of 25 compared to fluoroquinolones.

Topoisomerase Inhibitors Addressing Fluoroquinolone Resistance in Gram-Negative Bacteria.

Since their discovery over 5 decades ago, quinolone antibiotics have found enormous success as broad spectrum agents that exert their activity through dual inhibition of bacterial DNA gyrase and topoisomerase IV. Increasing rates of resistance, driven largely by target-based mutations in the GyrA/ParC quinolone resistance determining region, have eroded the utility and threaten the future use of this vital class of antibiotics. Herein we describe the discovery and optimization of a series of 4-(aminomethyl)quinolin-2(1H)-ones, exemplified by 34, that inhibit bacterial DNA gyrase and topoisomerase IV and display potent activity against ciprofloxacin-resistant Gram-negative pathogens. X-ray crystallography reveals that 34 occupies the classical quinolone binding site in the topoisomerase IV-DNA cleavage complex but does not form significant contacts with residues in the quinolone resistance determining region.

Ultrasound-assisted one-pot four-component synthesis of novel 2-amino-3-cyanopyridine derivatives bearing 5-imidazopyrazole scaffold and their biological broadcast.

An alternative and environmentally caring way for the synthesis of novel 2-amino-3-cyanopyridine derivatives bearing 5-imidazopyrazole nucleus is reported by one-pot four-component cyclocondensation reaction of substituted 5-(1H-imidazol/4-methyl-1-yl)-3-methyl-1-phenyl-1H-pyrazole-4-carbaldehyde (3a-b), malononitrile (4), ammonium acetate (5) and aromatic (6a-f)/heterocyclic methyl ketones (7a-d) under ultrasonic irradiation. The newly synthesized compounds were evaluated for their in vitro antibacterial activity against a panel of pathogenic stains of bacteria and fungi, in vitro antitubercular activity against Mycobacterium tuberculosis H37Rv stain and in vitro antioxidant activity by ferric-reducing antioxidant power method. Compounds 8e, 8h, 8l, 9c, 9g and 9h exhibited excellent antibacterial activity and compounds 3a, 8k, 9a and 9bshowed moderate antituberculosis activity as compared with the first line drugs. Majority of the compounds showed excellent antioxidant activity. This approaches claimed to be an environment friendly protocol as it afforded numerous advantages i.e. excellent yields, cleaner reaction profile and shorter reaction time.

Synthesis, characterization and pharmacological screening of some novel 5-imidazopyrazole incorporated polyhydroquinoline derivatives.

A new category of polyhydroquinoline derivatives 8a-t were synthesized in moderate to good yield (64-85%) by one-pot three-component cyclocondensation reaction of 5-(1H-imidazol-1-yl)-3-methyl-1-phenyl-1H-pyrazole-4-carbaldehyde 3 with various enaminones 6a-h and different active methylene compounds (malononitrile 7a, ethylcaynoacetate 7b and caynoacetamide 7c) in absolute ethanol. The newly synthesized compounds were evaluated for their in vitro antimalarial activity against Plasmodium falciparum, in vitro antibacterial activity against a panel of pathogenic strains of bacteria and fungi and also for their antitubercular activity against Mycobacterium tuberculosis H37Rv strain. Two of them (8n, 8t) exhibited excellent antimalarial activity. Some of them exhibited excellent antibacterial activity and moderate antituberculosis activity compared with the first line drugs.

Catalytic regioselective synthesis of pyrazole based pyrido[2,3-d]pyrimidine-diones and their biological evaluation.

A new type of biopolymer-based heterogeneous catalyst, cellulose supported acidic ionic liquid (Cell-IL), which was developed earlier in our lab, has been found to be very effective for the regioselective synthesis of pyrazole based pyrido[2,3-d]pyrimidine-diones. Its regioselectivity was confirmed by (1)H NMR spectroscopy. All the newly synthesized compounds were characterized by LC-MS, (1)H NMR, (13)C NMR, IR spectroscopy and elemental analysis. The newly synthesized compounds were evaluated for their in vitro antimalarial activity against Plasmodium falciparum, in vitro antitubercular activity against Mycobacterium tuberculosis H37Rv strain and also for their antibacterial activity against a panel of pathogenic strains of bacteria and fungi. Some of them exhibited excellent activity when compared with first line drugs.