This agrees with the result from metabolism studies with compound 1 that the primary route of biotransformation is oxidation, mainly at the para position of the phenyl ring and the a 17-AAG CAS position of the sulfonyl group in the aliphatic side chain.
Isothermal titration calorimetry (ITC) was used to investigate the binding of six inhibitors to 1-deoxy-Dxylulose-5-phosphate reductoisomerase (DXR), a target for developing novel anti-infectives. The binding of hydroxamate inhibitors to Escherichia coli DXR is Mg2+-dependent, highly endothermic (Delta H, 22.7-24.3 kJ/mol), and entropy-driven, while that of nonhydroxamate compounds is metal ion-independent and exothermic (Delta H, -19.4 to -13.8 kJ/mol), showing that hydration/dehydration of the enzyme metal ion binding pocket account for the drastic Delta H change.

However, for DXRs from Plasmodium falciparum and Mycobacterium tuberculosis, the binding of all inhibitors is exothermic (Delta H, -24.9 to -9.2 kJ/mol), suggesting that the metal ion binding sites of these two enzymes are considerably less hydrated. The dissociation constants measured by ITC are well correlated with those obtained by enzyme inhibition assays (R-2 = 0.75). Given the rapid rise of antibiotic resistance, this work is of interest since it provides novel structural implications for rational development of potent DXR inhibitors.
Toll-like receptors (TLRs) are key targets in the design of immunomodulating agents for use as vaccine adjuvants and anticancer treatments. The imidazoquinolines, imiquimod and resiquimod, have been shown to activate TLR-7 and -8, which in turn induce cytokine production as part of the innate immune response.

Herein, we report the synthesis and discovery of a C7-methoxycarbonyl derivative of imiquimod that stimulates cytokine production but is devoid of TLR-7/8 activity. Data AV-951 are presented that shows that this analogue not only induces IL-12p40 and TNF production, similar to that of imiquimod and resiquimod, but greatly enhances the production of IL-1 beta, a key cytokine involved in the activation of CD4 T cells. It is further demonstrated that TLR-7/8 activation can be recovered by the addition of a C2-alkyl substituent to this newly discovered analogue. The results support the existence of an alternative mechanism of action by which imidazoquinolines can stimulate cytokine production.

Natural and synthetic histone deacetylase (HDAC) inhibitors generally derive their strong binding affinity and high potency from a key functional group that binds to the Zn2+ ion within the enzyme active site. However, this feature is also thought to carry the potential liability of undesirable off-target interactions with other metalloenzymes. As a step toward mitigating this issue, selleck here, we describe the design, synthesis, and structure-activity characterizations of cyclic alpha(3)beta-tetrapeptide HDAC inhibitors that lack the presumed indispensable Zn2+-binding group. The lead compounds (e.g.