Quinolone Amides as Antitrypanosomal Lead Compounds with In Vivo Activity.

نویسندگان

  • Georg Hiltensperger
  • Nina Hecht
  • Marcel Kaiser
  • Jens-Christoph Rybak
  • Alexander Hoerst
  • Nicole Dannenbauer
  • Klaus Müller-Buschbaum
  • Heike Bruhn
  • Harald Esch
  • Leane Lehmann
  • Lorenz Meinel
  • Ulrike Holzgrabe
چکیده

Human African trypanosomiasis (HAT) is a major tropical disease for which few drugs for treatment are available, driving the need for novel active compounds. Recently, morpholino-substituted benzyl amides of the fluoroquinolone-type antibiotics were identified to be compounds highly active against Trypanosoma brucei brucei Since the lead compound GHQ168 was challenged by poor water solubility in previous trials, the aim of this study was to introduce structural variations to GHQ168 as well as to formulate GHQ168 with the ultimate goal to increase its aqueous solubility while maintaining its in vitro antitrypanosomal activity. The pharmacokinetic parameters of spray-dried GHQ168 and the newly synthesized compounds GHQ242 and GHQ243 in mice were characterized by elimination half-lives ranging from 1.5 to 3.5 h after intraperitoneal administration (4 mice/compound), moderate to strong human serum albumin binding for GHQ168 (80%) and GHQ243 (45%), and very high human serum albumin binding (>99%) for GHQ242. For the lead compound, GHQ168, the apparent clearance was 112 ml/h and the apparent volume of distribution was 14 liters/kg of body weight (BW). Mice infected with T. b. rhodesiense (STIB900) were treated in a stringent study scheme (2 daily applications between days 3 and 6 postinfection). Exposure to spray-dried GHQ168 in contrast to the control treatment resulted in mean survival durations of 17 versus 9 days, respectively, a difference that was statistically significant. Results that were statistically insignificantly different were obtained between the control and the GHQ242 and GHQ243 treatments. Therefore, GHQ168 was further profiled in an early-treatment scheme (2 daily applications at days 1 to 4 postinfection), and the results were compared with those obtained with a control treatment. The result was statistically significant mean survival times exceeding 32 days (end of the observation period) versus 7 days for the GHQ168 and control treatments, respectively. Spray-dried GHQ168 demonstrated exciting antitrypanosomal efficacy.

برای دانلود رایگان متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید

ثبت نام

اگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید

منابع مشابه

Novel 3-nitrotriazole-based amides and carbinols as bifunctional antichagasic agents.

3-Nitro-1H-1,2,4-triazole-based amides with a linear, rigid core and 3-nitrotriazole-based fluconazole analogues were synthesized as dual functioning antitrypanosomal agents. Such compounds are excellent substrates for type I nitroreductase (NTR) located in the mitochondrion of trypanosomatids and, at the same time, act as inhibitors of the sterol 14α-demethylase (T. cruzi CYP51) enzyme. Becaus...

متن کامل

Synthesis and Antimicrobial Activity of some Tetrahydro Quinolone Diones and Pyrano[2,3-d]pyrimidine Derivatives

There has been special interest in the chemistry of quinolone and pyrimidine derivatives due to their diverse biological activities such as anticonvulsant, anti-malarial agents, antibacterial, antiviral, cytostatic, antithelemintic, antigenotoxic, anti-cancer agents. These compounds are also used as targeting delayed-type hypersensivity and anti-convulsant agents. As a part of our research work...

متن کامل

Synthesis and Antimicrobial Activity of some Tetrahydro Quinolone Diones and Pyrano[2,3-d]pyrimidine Derivatives

There has been special interest in the chemistry of quinolone and pyrimidine derivatives due to their diverse biological activities such as anticonvulsant, anti-malarial agents, antibacterial, antiviral, cytostatic, antithelemintic, antigenotoxic, anti-cancer agents. These compounds are also used as targeting delayed-type hypersensivity and anti-convulsant agents. As a part of our research work...

متن کامل

Evaluation of antibacterial activity of new N-piperazinyl quinolone derivatives with 1,3,4.thiadiazole group

quinolones are broad-spectrum antibacterial agents.they have many clinical uses which are increasing.quinolones exert antibacterial activity primarily by inhibiting bacterial DNA gyrase.the inhibition of DNA gyrase by the quinolones are greatly influenced by the nature of the C-7 substituent on the quinolones molecule.substitution of bulky functional groupd is also possible in C-7 position.furt...

متن کامل

Evaluation of Medicinal Plants from Nupeland for Their in vivo Antitrypanosomal Activity

Over 25% of our common medicines contain at least some compounds obtained from plants. Nupeland located on the coastal basins of Rivers Niger and Kaduna in North Central Nigeria is greatly influenced by the savannah-forest vegetations with biodiversity rich in medicinal plants. This type of vegetation also harbours tsetsefly which are the vector of trypanosomes, thus making the area highly ende...

متن کامل

ذخیره در منابع من


  با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید

عنوان ژورنال:
  • Antimicrobial agents and chemotherapy

دوره 60 8  شماره 

صفحات  -

تاریخ انتشار 2016