98318-77-5Relevant articles and documents
Imidazolium salts as small-molecule urinary bladder exfoliants in a murine model
Wagers, Patrick O.,Tiemann, Kristin M.,Shelton, Kerri L.,Kofron, William G.,Panzner, Matthew J.,Wooley, Karen L.,Youngs, Wiley J.,Hunstad, David A.
, p. 5494 - 5502 (2015)
We present a novel family of small-molecule urinary bladder exfoliants that are expected to be of great value in preclinical studies of urologic conditions and have improved potential for translation compared with prior agents. There is broad urologic interest in the therapeutic potential of such exfoliating agents. The primary agent used in preclinical models, the cationic peptide protamine sulfate (PS), has limited translational potential due to concerns including systemic adverse reactions and bladder tissue injury. Intravesical application of a safe, systemically nontoxic exfoliant would have potential utility in the eradication of Escherichia coli and other uropathogens that reside in the bladder epithelium following cystitis, as well as in chronic bladder pain and bladder cancer. Here, we introduce a family of imidazolium salts with potent and focused exfoliating activity on the bladder epithelium. Synthesis and purification were straightforward and scalable, and the compounds exhibited prolonged stability in lyophilized form. Most members of the compound family were cytotoxic to cultured uroepithelial cells, with > 10-fold differences in potency across the series. Upon topical (intravesical) administration of selected compounds to the murine bladder, complete epithelial exfoliation was achieved with physiologically relevant imidazolium concentrations and brief contact times. The exfoliative activity of these compounds was markedly improved in comparison to PS, as assessed by microscopy, immunofluorescence, and immunoblotting for uroplakins. Bladder uroepithelium regenerated within days to yield a histologically normal appearance, and no toxicity was observed. Finally, the chemical scaffold offers an opportunity for inclusion of antimicrobials or conjugation with chemotherapeutic or other moieties.
Synthesis and Antibacterial Evaluation of Bis-thiazolium, Bis-imidazolium, and Bis-triazolium Derivatives
Thomas, Beno?t,Duval, Rapha?l E.,Fontanay, Stéphane,Varbanov, Mihayl,Boisbrun, Michel
supporting information, p. 1232 - 1237 (2019/06/13)
Given the worldwide spread of bacterial drug resistance, there is an urgent need to develop new compounds that exhibit potent antibacterial activity and that are unimpaired by this phenomenon. Quaternary ammonium compounds have been used for many years as disinfectants, but recent advances have shown that polycationic derivatives exhibit much stronger activity and are less prone to bacterial resistance than commonly used monocationic compounds. In this sense, we prepared three series of new bis-cationic compounds: bis-thiazoliums, bis-imidazoliums, and bis-1,2,4-triazoliums. If some compounds of the first series showed fair antibacterial activity, most of those belonging to the two other series were highly potent, with minimum inhibitory concentrations close to 1 μg mL?1. Some of them also exhibited low toxicity toward eukaryotic MRC-5 lung fibroblasts, and we showed that this toxicity is clearly correlated with clogP. Finally, four selected compounds were found to exhibit a clear bactericidal effect.
C17,20-lyase inhibitors I. Structure-based de novo design and SAR study of C17,20-lyase inhibitors.
Matsunaga, Nobuyuki,Kaku, Tomohiro,Itoh, Fumio,Tanaka, Toshimasa,Hara, Takahito,Miki, Hiroshi,Iwasaki, Masahiko,Aono, Tetsuya,Yamaoka, Masuo,Kusaka, Masami,Tasaka, Akihiro
, p. 2251 - 2273 (2007/10/03)
Novel nonsteroidal C(17,20)-lyase inhibitors were synthesized using de novo design based on its substrate, 17 alpha-hydroxypregnenolone, and several compounds exhibited potent C(17,20)-lyase inhibition. However, in vivo activities were found to be short-lasting, and in order to improve the duration of action, a series of benzothiophene derivatives were evaluated. As a result, compounds 9h, (S)-9i, and 9k with nanomolar enzyme inhibition (IC(50)=4-9 nM) and 9e (IC(50)=27 nM) were identified to have powerful in vivo efficacy with extended duration of action. The key structural determinants for the in vivo efficacy were demonstrated to be the 5-fluoro group on the benzothiophene ring and the 4-imidazolyl moiety. Superimposition of 9k and 17 alpha-hydroxypregnenolone demonstrated their structural similarity and enabled rationalization of the pharmacological results. In addition, selected compounds were also identified to be potent inhibitors of human enzyme with IC(50) values of 20-30 nM.
