Chloramphenicol-borate/boronate complex for controlling infections by chloramphenicol-resistant bacteria.

Increasing bacterial resistance to antibiotics is a pressing problem worldwide, with many health organisations prioritizing this issue. Whilst there is a desperate need for new effective antimicrobials, it is also important to understand the mechanisms and epidemiology of the resistant pathogens currently present in the community. Chloramphenicol is one such well known antibiotic which had lost its efficacy due to bacterial resistance. In this paper, we report the design, synthesis, and bio-studies of novel chloramphenicol-borate/boronate derivatives which showed the ability to control the infections caused by chloramphenicol-resistant bacteria. Activity profiling against P. aeruginosa strain EXR1 with catB gene indicated the inability of acetyl transferase to acetylate the chloramphenicol-borate/boronate complex, unlike chloramphenicol. Results obtained from the antimicrobial assays were further rationalized by molecular docking studies. The latter revealed that the probable reason for the enhanced antibacterial activity may be attributed to the change in the binding site of chloramphenicol-borate/boronate with chloramphenicol acetyl transferase (CAT) with respect to chloramphenicol itself. Hemolytic and genotoxic studies established the reduced toxicity of these synthetic derivatives with respect to chloramphenicol.

Inhibition of M. tuberculosis ß-ketoacyl CoA reductase FabG4 (Rv0242c) by triazole linked polyphenol-aminobenzene hybrids: comparison with the corresponding gallate counterparts.

Herein we report six novel triazole linked polyphenol-aminobenzene hybrids (3-8) as inhibitors of Mycobacterium tuberculosis FabG4 (Rv0242c), a less explored ß-ketoacyl CoA reductase that has immense potential to be the future anti-tuberculosis drug target due to its possible involvement in drug resistance and latent infection. Novel triazole linked polyphenol-aminobenzene hybrids have been synthesized, characterized and evaluated for their inhibitory activity against FabG4. All of them inhibit FabG4 at low micromolar concentrations. In silico docking study has been carried out to explain the experimental findings. A comparative study of these new inhibitors with previously reported gallate counterparts leads to structure-activity relations (SAR) of substituent linked to N-1 of triazole ring.

Design, synthesis and characterization of novel inhibitors against mycobacterial ß-ketoacyl CoA reductase FabG4.

We report the design and synthesis of triazole-polyphenol hybrid compounds 1 and 2 as inhibitors of the FabG4 (Rv0242c) enzyme of Mycobacterium tuberculosis for the first time. A major advance in this field occurred only a couple of years ago with the X-ray crystal structure of FabG4, which has helped us to design these inhibitors by the computational fragment-based drug design (FBDD) approach. Compound 1 has shown competitive inhibition with an inhibition constant (Ki) value of 3.97 ± 0.02 µM. On the other hand, compound 2 has been found to be a mixed type inhibitor with a Ki value of 0.88 ± 0.01 µM. Thermodynamic analysis using isothermal titration calorimetry (ITC) reveals that both inhibitors bind at the NADH co-factor binding domain. Their MIC values, as determined by resazurin assay against M. smegmatis, indicated their good anti-mycobacterial properties. A preliminary structure-activity relationship (SAR) study supports the design of these inhibitors. These compounds may be possible candidates as lead compounds for alternate anti-tubercular drugs. All of the reductase enzymes of the Mycobacterium family have a similar ketoacyl reductase (KAR) domain. Hence, this work may be extrapolated to find structure-based inhibitors of other reductase enzymes.

Twist does a twist to the reactivity: stoichiometric and catalytic oxidations with twisted tetramethyl-IBX.

The methyl groups in TetMe-IBX lower the activation energy corresponding to the rate-determining hypervalent twisting (theoretical calculations), and the steric relay between successive methyl groups twists the structure, which manifests in significant solubility in common organic solvents. Consequently, oxidations of alcohols and sulfides occur at room temperature in common organic solvents. In situ generation of the reactive TetMe-IBX from its precursor iodo-acid, i.e., 3,4,5,6-tetramethyl-2-iodobenzoic acid, in the presence of oxone as a co-oxidant facilitates the oxidation of diverse alcohols at room temperature.

6-Membered pseudocyclic IBX acids: syntheses, X-ray structural characterizations, and oxidation reactivities in common organic solvents.

We designed and synthesized λ(5)-cyclic periodinanes 1 and 2, which are homologous to IBX (1-hydroxy-1-oxo-1H-1λ(5)-benzo[d][1,2]iodoxol-3-one) by one carbon, to thwart close packing of molecules in the crystal lattice to permit solubility in common organic solvents and to facilitate oxidations with enhanced reactivity. The X-ray crystal structures revealed that both 1 and 2 exist in the solid state as pseudocyclic (PC) acids, i.e., 1PC and 2PC, and that the molecules in the lattice are less weakly associated as compared to those in the parent IBX due to the twisting introduced via the sp(3) benzylic carbon. Both 1PC and 2PC are found to dissolve in palpable amounts in DCM and acetonitrile to allow oxidation of a variety of alcohols and sulfides to carbonyl compounds and sulfoxides in a facile manner. The subtle differences in the sterics due to methyl and ethyl substituents in 1PC and 2PC are found to manifest in contrasting reactivities in that the oxidations of alcohols occur faster with 2PC, while those of sulfides to sulfoxides occur more rapidly with 1PC.

IBX-I2 redox couple for facile generation of IOH and I+: expedient protocol for iodohydroxylation of olefins and iodination of aromatics.

IBX is readily reduced to IBA in the presence of molecular iodine in DMSO to generate hypoiodous acid (IOH), which reacts with a variety of olefins as well as alpha,beta-unsaturated ketones leading to their respective iodohydrins with anti stereochemistry. The same redox chemistry in acetonitrile containing TFA produces iodonium ions for facile iodination of a variety of aromatic compounds in respectable isolated yields.

Oxidative cleavage of vicinal diols: IBX can do what Dess-Martin periodinane (DMP) can.

The fact that IBX exhibits reactivity akin to DMP is demonstrated from the results observed with strained and sterically hindered syn 1,2-diols, which undergo oxidative cleavage via a 12-I-5 spirobicyclic periodinane. The use of TFA, a protonating solvent, promotes the formation of the 12-I-5 intermediate for 1,2-diols of all types (sec,sec, sec,tert and tert,tert), leading to efficient oxidative fragmentation.