Synthesis and Optimization of Small Molecule Inhibitors of Prostate Specific Antigen.

Semen liquefaction is a postejaculation process that transforms semen from a gel-like (coagulated) form to a water-like consistency (liquefied). This process is primarily regulated by serine proteases from the prostate gland, most prominently, prostate-specific antigen (PSA; KLK3). Inhibiting PSA activity has the potential to impede liquefaction of human semen, presenting a promising target for nonhormonal contraception in the female reproductive tract.

Comparative molecular field analysis of fenoterol derivatives interacting with an agonist-stabilized form of the β₂-adrenergic receptor.

The β₂-adrenergic receptor (β₂-AR) agonist [(3)H]-(R,R')-methoxyfenoterol was employed as the marker ligand in displacement studies measuring the binding affinities (Ki values) of the stereoisomers of a series of 4'-methoxyfenoterol analogs in which the length of the alkyl substituent at α' position was varied from 0 to 3 carbon atoms. The binding affinities of the compounds were additionally determined using the inverse agonist [(3)H]-CGP-12177 as the marker ligand and the ability of the compounds to stimulate cAMP accumulation, measured as EC₅₀ values, were determined in HEK293 cells expressing the β₂-AR. The data indicate that the highest binding affinities and functional activities were produced by methyl and ethyl substituents at the α' position.

Discovery and optimization of benzotriazine di-N-oxides targeting replicating and nonreplicating Mycobacterium tuberculosis.

Compounds bactericidal against both replicating and nonreplicating Mtb may shorten the length of TB treatment regimens by eliminating infections more rapidly. Screening of a panel of antimicrobial and anticancer drug classes that are bioreduced into cytotoxic species revealed that 1,2,4-benzotriazine di-N-oxides (BTOs) are potently bactericidal against replicating and nonreplicating Mtb. Medicinal chemistry optimization, guided by semiempirical molecular orbital calculations, identified a new lead compound (20q) from this series with an MIC of 0.

Quaternary salts of 2-[(hydroxyimino)methyl]imidazole. 5. Structure-activity relationships for side-chain nitro-, sulfone-, amino-, and aminosulfonyl-substituted analogues for therapy against anticholinesterase intoxication.

Several quaternary imidazolium oxime derivatives incorporating side chains bearing nitro, sulfone, amino, and aminosulfonyl substituents were prepared and evaluated as treatment therapeutics for anti-AChE intoxication. In vivo test results in the mouse revealed that many of these compounds are highly effective in providing life-saving protection against the extremely toxic cholinesterase inhibitors soman and tabun. Several structure-activity relationships were noted that were characteristic of the side-chain substituent.

Quaternary salts of 2-[(hydroxyimino)methyl]imidazole. 4. Effect of various side-chain substituents on therapeutic activity against anticholinesterase intoxication.

A series of quaternary salt derivatives of 2-[(hydroxyimino)methyl]-1-methylimidazole incorporating various side chains bearing ether, silyl, nitrile, ester, halogen, nitro, sulfone, amino, or aminosulfonyl substituents was prepared and evaluated in vivo for the treatment of anticholinesterase intoxication. Test results in the mouse revealed that the type and location of the side-chain substituent both have a significant influence on the toxicity and antidotal effectiveness of the compounds. Some of the more active examples represent the most potent therapeutics to date against intoxication by the powerful cholinesterase inhibitors soman and tabun.