Periphery Exploration around 2,6-Diazaspiro[3.4]octane Core Identifies a Potent Nitrofuran Antitubercular Lead.

A small set of twelve compounds of a nitrofuran carboxamide chemotype was elaborated from a readily available 2,6-diazaspiro[3.4]octane building block, exploring diverse variants of the molecular periphery, including various azole substituents. The in vitro inhibitory activities of the synthesized compounds were assessed against H37Rv.

Synthesis and Antibacterial Evaluation of Ciprofloxacin Congeners with Spirocyclic Amine Periphery.

The synthesis of novel fluoroquinolones, congeners of ciprofloxacin, which was inspired by earlier work on spirocyclic ciprofloxacin, is described. An antibacterial evaluation of the 11 fluoroquinolone compounds synthesized against the ESKAPE panel of pathogens in comparison with ciprofloxacin revealed that the more compact spirocycles in the fluoroquinolone periphery resulted in active compounds, while larger congeners gave compounds that displayed no activity at all. In the active cohort, the level of potency was comparable to that of ciprofloxacin.

Exploration of Spirocyclic Derivatives of Ciprofloxacin as Antibacterial Agents.

The previously reported as well as newly synthesized derivatives of the 1-oxa-9-azaspiro[5.5]undecane were employed in the synthesis of thirty-six derivatives of ciprofloxacin using commercially available 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid and the literature protocol involving the preparation of boron chelate complex to facilitate nucleophilic aromatic substitution. All new fluoroquinolone derivatives were tested against two gram-positive as well as three gram-negative strains of bacteria.

A three-component, Zn(OTf)-mediated entry into trisubstituted 2-aminoimidazoles.

A three-component reaction involving in situ generation of propargylureas and subsequent Zn(OTf)-mediated cyclocondensation with a primary amine yielded trisubstituted 2-aminoimidazoles. These findings are in contrast to the previously reported base-promoted unimolecular cyclization of propargylureas (leading to 2-imidazolones) and extend the range of Lewis acid-catalyzed azole syntheses based on -carbonyl propargylamines.

Attachment of a 5-nitrofuroyl moiety to spirocyclic piperidines produces non-toxic nitrofurans that are efficacious in vitro against multidrug-resistant Mycobacterium tuberculosis.

A selectively antimycobacterial compound belonging to the nitrofuran class of antimicrobials has been developed via conjugation of the nitrofuran moiety to a series of spirocyclic piperidines through an amide linkage. It proved to have comparable activity against drug-sensitive (H37Rv) strain as well as multidrug-resistant, patient-derived strains of Mycobacterium tuberculosis. The compound is druglike, showed no appreciable cytotoxicity toward human retinal pigment epithelial cell line ARPE-19 in concentrations up to 100 μM and displayed low toxicity when evaluated in mice.

Conjugation of a 5-nitrofuran-2-oyl moiety to aminoalkylimidazoles produces non-toxic nitrofurans that are efficacious in vitro and in vivo against multidrug-resistant Mycobacterium tuberculosis.

Within the general nitrofuran carboxamide chemotype, chimera derivatives incorporating diversely substituted imidazoles attached via an alkylamino linker were synthesized. Antimycobacterial evaluation against drug-sensitive M. tuberculosis H37Rv strain identified five active druglike compounds which were further profiled against patient-derived M.

Continued SAR exploration of 1,2,4-thiadiazole-containing scaffolds in the design of free fatty acid receptor 1 (GPR40) agonists.

An earlier reported series of 1,2,4-thiadiazole-based agonists of FFA1 (GPR40) was evolved into two structurally distinct series of compounds. One of the series (structurally related to known FFA1 agonist GW9508) displayed low micromolar potency while the other (representing a truncated version of the earlier reported potent FFA1 agonists) was, surprisingly, found to be devoid of agonist potency. In silico docking of representative compounds into the crystal structure of FFA1 revealed possible structural grounds for the observed SAR.