Search

The current Letter describes the synthesis and biological evaluation of dihydrophthalazine-appended 2,4-diaminopyrimidine (DAP) inhibitors (1) oxidized at the methylene bridge linking the DAP ring to the central aromatic ring and (2) modified at the central ring ether groups. Structures 4a – b incorporating an oxidized methylene bridge showed a decrease in activity, while slightly larger alkyl groups (CH 2 CH 3 vs CH 3 ) on the central ring oxygen atoms (R 2 and R 3 ) had a minimal impact on the inhibition. Comparison of the potency data for previously reported RAB1 and BN-53 with the most potent of the new derivatives ( 19b and 20a – b ) showed similar values for inhibition of cellular growth and direct enzymatic inhibition (MICs 0.5–2 μg/mL). Compounds 29 – 34 with larger ester and ether groups containing substituted aromatic rings at R 3 exhibited slightly reduced activity (MICs 2–16 μg/mL). One explanation for this attenuated activity could be encroachment of the extended R 3 into the neighboring NADPH co-factor. These results indicate that modest additions to the central ring oxygen atoms are well tolerated, while larger modifications have the potential to act as dual-site inhibitors of dihydrofolate reductase (DHFR). [ABSTRACT FROM AUTHOR]

The article offers information on the comparative study of the frech catalyst with two conventional catalysts in the Heck synthesis of 2,4-diaminopyrimidine-based antibiotics. It states that nano palladium complexes are reported to be very competent catalysts for cross-coupling reactions which give exceptional yields with low catalyst loading. It also states that the absence of thermal stability and functional group tolerance of many palladium complexes as well as the condition for relatively high catalyst loadings results in the serious limitation on the use of the reactions. It further notes that decomposition of catalysts at normal reaction temperatures can result in extremely contaminated products that need purification.

The article discusses the synthesis of substituted 2,4-diaminopyrimidine-based antibiotics through microwave-assisted Heck reaction. It says that the use of N-ethylpiperidine and bis(triphenylphosphine)palladium(II) dichloride catalyst have established a low yield in the coupled product with substantial side-product formation. It mentions that microwave-assisted reactions have given superior conversions to products with low impurities and decrease the required catalyst loading by 20% and the amount of solvent needed by 25% as well. It states that the method is considered as superior to reactions under conventional or sealed tube conditions.

The Frech catalyst proves to be superior to conventional palladium-based Heck catalysts, giving the desired products (III) and (V) in higher yields with fewer contaminants. [ABSTRACT FROM AUTHOR]

Racemic diaminopyrimidine derivatives (VI) are synthesized via a novel Heck coupling reaction and evaluated for activity against Bacillus anthracis. [ABSTRACT FROM AUTHOR]

We are addressing bacterial resistance to antibiotics by repurposing a well-established classic antimicrobial target, the dihydrofolate reductase (DHFR) enzyme. In this work, we have focused on Enterococcus faecalis, nosocomial pathogen that frequently harbors antibiotic resistance determinants leading to complicated and difficult- to-treat infections. An inhibitor series with a hydrophobic dihydrophthalazine heterocycle was designed from the antifolate trimethoprim. We have examined the potency of this inhibitor series based on inhibition of DHFR enzyme activity and bacterial growth, including in the presence of the exogenous product analogue folinic acid. The resulting preferences were rationalized using a cocrystal structure of the DHFR from this organism with a propyl-bearing series member (RAB-propyl). In a companion apo structure, we identify four buried waters that act as placeholders for a conserved hydrogen-bonding network to the substrate and indicate an important role in protein stability during catalytic cycling. In these structures, the nicotinamide of the nicotinamide adenine dinucleotide phosphate cofactor is visualized outside of its binding pocket, which is exacerbated by RAB-propyl binding. Finally, homology models of the TMPR sequences dfrK and dfrF were constructed. While the dfrK-encoded protein shows clear sequence changes that would be detrimental to inhibitor binding, the dfrF-encoded protein model suggests the protein would be relatively unstable. These data suggest a utility for anti-DHFR compounds for treating infections arising from E, faecalis. They also highlight a role for water in stabilizing the DHFR substrate pocket and for competitive substrate inhibitors that may gain advantages in potency by the perturbation of cofactor dynamics. [ABSTRACT FROM AUTHOR]