3 research outputs found
Nicotinamide Phosphoribosyltransferase Inhibitors, Design, Preparation, and Structure–Activity Relationship
Existing pharmacological
inhibitors for nicotinamide phosphoribosyltransferase
(NAMPT) are promising therapeutics for treating cancer. By using medicinal
and computational chemistry methods, the structure–activity
relationship for novel classes of NAMPT inhibitors is described, and
the compounds are optimized. Compounds are designed inspired by the
NAMPT inhibitor APO866 and cyanoguanidine inhibitor scaffolds. In
comparison with recently published derivatives, the new analogues
exhibit an equally potent antiproliferative activity in vitro and
comparable activity in vivo. The best performing compounds from these
series showed subnanomolar antiproliferative activity toward a series
of cancer cell lines (compound <b>15</b>: IC<sub>50</sub> 0.025
and 0.33 nM, in A2780 (ovarian carcinoma) and MCF-7 (breast), respectively)
and potent antitumor in vivo activity in well-tolerated doses in a
xenograft model. In an A2780 xenograft mouse model with large tumors
(500 mm<sup>3</sup>), compound <b>15</b> reduced the tumor volume
to one-fifth of the starting volume at a dose of 3 mg/kg administered
ip, bid, days 1–9. Thus, compounds found in this study compared
favorably with compounds already in the clinic and warrant further
investigation as promising lead molecules for the inhibition of NAMPT
Targeting Carnitine Biosynthesis: Discovery of New Inhibitors against γ‑Butyrobetaine Hydroxylase
γ-Butyrobetaine
hydroxylase (BBOX) catalyzes the conversion
of gamma butyrobetaine (GBB) to l-carnitine, which is involved
in the generation of metabolic energy from long-chain fatty acids.
BBOX inhibitor 3-(1,1,1-trimethylhydrazin-1-ium-2-yl)propanoate (mildronate),
which is an approved, clinically used cardioprotective drug, is a
relatively poor BBOX inhibitor and requires high daily doses. In this
paper we describe the design, synthesis, and properties of 51 compounds,
which include both GBB and mildronate analogues. We have discovered
novel BBOX inhibitors with improved IC<sub>50</sub> values; the best
examples are in the nanomolar range and about 2 orders of magnitude
better when compared to mildronate. For six inhibitors, crystal structures
in complex with BBOX have been solved to explain their activities
and pave the way for further inhibitor design
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<i>N</i>-Leucinyl benzenesulfonamides have been discovered
as a novel class of potent inhibitors of <i>E. coli</i> leucyl-tRNA
synthetase. The binding of inhibitors to the enzyme was measured by
using isothermal titration calorimetry. This provided information
on enthalpy and entropy contributions to binding, which, together
with docking studies, were used for structure–activity relationship
analysis. Enzymatic assays revealed that <i>N</i>-leucinyl
benzenesulfonamides display remarkable selectivity for <i>E.
coli</i> leucyl-tRNA synthetase compared to <i>S. aureus</i> and human orthologues. The simplest analogue of the series, <i>N</i>-leucinyl benzenesulfonamide (R = H), showed the highest
affinity against <i>E. coli</i> leucyl-tRNA synthetase and
also exhibited antibacterial activity against Gram-negative pathogens
(the best MIC = 8 μg/mL, <i>E. coli</i> ATCC 25922),
which renders it as a promising template for antibacterial drug discovery