tak-187 and albaconazole

The current situation regarding specific chemotherapy for Chagas disease (American trypanosomiasis), and new developments in this field, are reviewed. Despite previous controversy on the autoimmune origin of Chagas disease pathology, available knowledge supports the notion that this condition should be treated as a parasitic, not an autoimmune, disease. Currently available drugs (nitrofurans and nitroimidazoles) are active in acute or short-term chronic infections, but have very low antiparasitic activity against the prevalent chronic form of the disease, and toxic side-effects are frequently encountered. The nitroimidazole benznidazole has also shown significant activity in the treatment of reactivated Trypanosoma cruzi infections in patients with acquired immune deficiency syndrome and in other immunosuppressed patients with underlying chronic Chagas disease. Although the etiological agent, T. (Schizotrypanum) cruzi, requires specific endogenous sterols for cell viability and proliferation, the currently available antifungal sterol biosynthesis inhibitors are not powerful enough to induce parasitological cures of human or experimental infections. However, new triazole antifungal compounds, which are potent inhibitors of the sterol C14alpha demethylase of the parasite and have special pharmacokinetic properties, are capable of inducing parasitological cures in murine models of both acute and chronic Chagas disease. They are currently the most advanced candidates for clinical trials in patients with Chagas disease. Other potential chemotherapeutic agents against T. cruzi currently in development include antiproliferative lysophospholipid analogs (already in clinical trials as the first oral treatment for visceral leishmaniasis), cysteine proteinase (cruzipain) inhibitors, and compounds that interfere with purine salvage and inositol metabolism.

Topics: Chagas Disease; Cysteine Proteinase Inhibitors; Humans; Quinazolines; Triazoles

A series of azole antifungal agents featuring a quinazolinone nucleus have been subjected to studies of structure-activity relationships. In general, these compounds displayed higher in vitro activities against filamentous fungi and shorter half-lives than the structures described in our preceding paper. The most potent products in vitro carried a halogen (or an isostere) at the 7-position of the quinazolinone ring. Using a murine model of systemic candidosis, oral activity was found to be dependent on hydrophobicity, which, in turn, modulated the compound's half-life. The 7-Cl derivative, (1R,2R)-7-chloro-3-[2-(2, 4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2, 4-triazol-1-yl)propyl]quinazolin-4(3H)-one (20, UR-9825), was selected for further testing due to its high in vitro activity, low toxicity, good pharmacokinetic profile, and ease of obtention. Compound 20 is the (1R,2R) isomer of four possible stereoisomers. The other three isomers were also prepared and tested. The enantiomer (1S,2S) and the (1R,2S) epimer were inactive, whereas the (1S,2R) epimer retained some activity. In vitro 20 was superior to fluconazole, itraconazole, SCH-42427, and TAK-187 and roughly similar to voriconazole and ER-30346. In vivo, 20 was only moderately active in a mouse model of systemic candidosis when administration was limited to the first day. This was attributed to its short half-life in that species (t1/2 = 1 h po). Protection levels comparable to or higher than those of fluconazole, however, were observed in systemic candidosis models in rat and rabbit, where the half-life of the compound was found to be 6 and 9 h, respectively. Finally, 20 showed excellent protection levels in an immunocompromised rat model of disseminated aspergillosis. The compound showed low toxicity signs when administered to rats at 250 mg/kg qd or at 100 mg/kg bid during 28 days.

Topics: Animals; Antifungal Agents; Aspergillosis; Aspergillus fumigatus; Candidiasis; Colony Count, Microbial; Fungi; Male; Mice; Molecular Conformation; Quinazolines; Rabbits; Rats; Rats, Sprague-Dawley; Stereoisomerism; Structure-Activity Relationship; Triazoles