Novel 2-methoxyacylhydrazones as potent, selective PDE10A inhibitors with activity in animal models of schizophrenia.

A series of 2-methoxyacylhydrazones were optimized to yield compounds with high affinity for PDE10A. Several compounds demonstrated efficacy in animal models of schizophrenia, including conditioned avoidance response and a pro-psychotic phencyclidine hyperactivity model.

N-Acylhydrazones as inhibitors of PDE10A.

Cyclic nucleotide phosphodiesterases (PDEs) are represented by a large superfamily of enzymes. A series of hydrazone-based inhibitors was synthesized and shown to be novel, potent, and selective against PDE10A. Optimized compounds of this class were efficacious in animal models of schizophrenia and may be useful for the treatment of this disease.

Identification of antimicrobial compounds active against intracellular Staphylococcus aureus.

Small-colony variants (SCVs) of Staphylococcus aureus exhibit characteristics of bacteria that can penetrate mammalian cells and remain intracellular and innocuous for indefinite periods. These properties make SCVs a convenient tool that can be used to identify new antibacterial agents having activity against intracellular, quiescent bacteria. Agents active against SCVs could be useful in the treatment of chronic staphylococcal infections such as bovine mastitis. An hemB deletion mutant of S. aureus Newbould, a bovine mastitis isolate, having a stable, genetically defined SCV phenotype, was used in a screening program to identify compounds active against intracellular, gram-positive bacteria. Out of more than 260,000 compounds screened, nine compounds having the desired properties were identified. The range of MICs against gram-positive bacteria was < or = 0.12-32 microg ml-1. One of the compounds (no. 8) showed excellent activity against gram-positive (MICs < or = 0.12 microg ml-1) and gram-negative (MICs < or = 0.12-4 microg ml-1) bacteria. Each of the nine compounds demonstrated efficacy in a neutropenic mouse thigh infection model. Two compounds, including compound no. 8, reduced numbers of bacteria in a mouse mastitis model of infection. Application of a stepwise screening process has identified lead compounds that may be useful for treating persistent, intracellular infections.

Substrate-dependent dihydroxylation of substituted cyclopentenes: toward the syntheses of carbocyclic sinefungin and noraristeromycin.

Carbocyclic nucleosides are of considerable interest for the development of new therapeutic agents. A key reaction in the preparation of many such nucleoside analogues is dihydroxylation of appropriately substituted cyclopentenes. Although often considered a routine reaction, in this paper, we report the dramatic influence of substituents on the facial selectivity of dihydroxylations. The substituted cyclopentene substrates are derived from acylnitroso cycloaddition reactions of cyclopentadiene, followed by N-O reduction and efficient enzymatic resolution. The results are directly utilized in a very efficient asymmetric synthesis of an antiviral carbocyclic nucleoside, noraristeromycin 5. Extensions toward the synthesis of carbocyclic sinefungin 7 document the importance of realizing the substituent dependence of the dihydroxylation reaction.

Chemoenzymatic synthesis and synthetic application of enantiopure aminocyclopentenols: total synthesis of carbocyclic (+)-uracil polyoxin C and its alpha-epimer.

Carbocyclic uracil polyoxin C (+)-2 and its alpha-epimer (-)-3 were synthesized in an efficient fashion from cis-4-(N-tert-butylcarbamoyl)cyclopent-2-en-1-ol (+/-)-7. The synthesis incorporates a concise, inexpensive chemoenzymatic synthesis of enantiopure aminocyclopentenols, a Pd(0)-catalyzed substitution reaction, and a mild reduction of an alpha-nitro ester by TiCl(3)/sodium borohydride. Significantly, this process demonstrates the synthetic utility of the versatile enantiopure aminocyclopentenol building block (-)-4.

Synthesis and evaluation of a series of 1,4-diarylbutadienes for anticoccidial activity.

During the course of a collaborative screening program, a set of 1-phenyl-4-pyridyl-butadienes was found to exhibit in vitro activity against Eimeria tenella in a cell-based assay. Activity was dependent on the chain length and degree of unsaturation of the linker between the two aryl groups as well as substitution of the pyridine moiety. Structure-activity relationship studies were subsequently conducted over a larger range of 1,4-diarylbutadienes in order to determine the scope of active compounds, to identify structural patterns governing activity and to enhance in vitro potency against E. tenella. In addition, the efficacy of many compounds for treating coccidiosis in chickens was measured by testing the ability of the compound to prevent or reduce intestinal and cecal lesions when administered by oral gavage. A few compounds in the series were identified that exhibited a moderate degree of in vitro and in vivo activity.