The United States of America, as Represented by the Secretary, Department of Health and Human Services

Xinhua Ji

Larry K Keefer

Genbin Shi

Gary X Shaw

Joseph E Saavedra

William G Rice

Aloka Srinivasan

Christian Bogdan

Joseph Saavedra

Anna E Maciag

Vandana Kumari

The disclosure provides linked purine pterin compounds of Formula I that are novel inhibitors of HPPK, a kinase responsible for an essential step in the biosynthesis of folic acid. (Formula I) The variables, e.g., A1-A3, R1-R4, B1-B2, and L1 are defined in the disclosure. These linked purine pterin inhibitors bind to HPPK with high affinity and specificity. Pharmaceutical compositions containing the HPPK inhibitors and methods of treating a bacterial infection in a patient with one or more of the HPPK inhibitors of the disclosure are also provided. 

HPPK inhibitors useful as antibacterial agents

The disclosure provides linked purine pterin compounds and analogs thereof that are novel HPPK inhibitors. The HPPK inhibitors described herein are compounds and the pharmaceutically acceptable salts thereof of general Formula I  The variables, e.g. Ato A, Rto R, L, L, B, and Bare described herein. Compounds and salts of Formula I bind to HPPK with high affinity and specificity. Pharmaceutical compositions containing an HPPK inhibitor of Formula I and methods of treating a bacterial infection in a patient by providing one or more HPPK inhibitors of Formula I to the patient are also provided. Processes and intermediates useful for preparing compounds of Formula I are also provided. Methods of using the disclosed compounds to guide the development of additional novel anti-bacterial agents are also provided.

Linked purine pterin HPPK inhibitors useful as antibacterial agents

Disclosed are hybrid compounds that release both nitric oxide and a moiety that inhibits poly (ADP-ribose) polymerase (PARP), e.g., a compound or a pharmaceutically acceptable salt thereof of formula (I), wherein Rand m-p are as described herein. Also disclosed are pharmaceutical compositions and methods of use including treating cancer and enhancing the chemotherapeutic treatment of chemotherapeutic agents and high energy radiation. 

Hybrid diazeniumdiolated compounds, pharmaceutical compositions, and method of treating cancer

The disclosure provides linked purine pterin compounds and analogs thereof that are novel HPPK inhibitors. The HPPK inhibitors described herein are compounds and the pharmaceutically acceptable salts thereof of general Formula I The variables, e.g. Ato A, Rto R, L, L, B, and Bare described herein. Compounds and salts of Formula I bind to HPPK with high affinity and specificity. Pharmaceutical compositions containing an HPPK inhibitor of Formula I and methods of treating a bacterial infection in a patient by providing one or more HPPK inhibitors of Formula I to the patient are also provided. Processes and intermediates useful for preparing compounds of Formula I are also provided. Methods of using the disclosed compounds to guide the development of additional novel anti-bacterial agents are also provided.

Provided are O-glycosylated 1-substituted diazen-1-ium-1,2-diolates (O-glycosylated diazeniumdiolates) having the formula:in which R is a saccharide, which is attached to the Oof the compound by the anomeric carbon of a pyranose ring or a furanose ring.

O2-glycosylated 1-substituted diazen-1-ium-1,2-diolates

Diazeniumdiolates, wherein the N position is substituted by an inorganic or organic moiety and the O -oxygen is bound to a substituted or unsubstituted aromatic group, are provided. Also provided are O -glycosylated 1-substituted diazen-1-ium-1,2-diolates (O -glycosylated diazeniumdiolates) and O -substituted 1-&lsqb;(2-carboxylato)pyrrolidin-1-yl&rsqb;diazen-1-ium-1,2-diolates (1-&lsqb;(2-carboxylato)pyrrolidin-1-yl&rsqb;diazeniumdiolates). The O -aryl diazeniumdiolates are stable with respect to the hydrolytic generation of nitric oxide in neutral to acidic solutions and generate nitric oxide in basic or nucleophilic environments or microenvironments. Also provided are compositions, including pharmaceutical compositions, comprising such compounds and methods of using such compounds.

O2-arylated or O2-glycosylated 1-substituted diazen-1-ium-1,2-diolates and O2-substituted 1-&lsqb;(2-carboxylato) pyrrolidin-1-yl&rsqb; diazen-1-ium-1,2-diolates

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Frederick, MD, United States of America

Xinhua Ji