70458-93-4Relevant articles and documents
Quinolone amides as antitrypanosomal lead compounds with In Vivo activity
Hiltensperger, Georg,Hecht, Nina,Kaiser, Marcel,Rybak, Jens-Christoph,Hoerst, Alexander,Dannenbauer, Nicole,Müller-Buschbaum, Klaus,Bruhn, Heike,Esch, Harald,Lehmann, Leane,Meinel, Lorenz,Holzgrabe, Ulrike
supporting information, p. 4442 - 4452 (2016/08/02)
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.
Identification and characterisation of small-molecule inhibitors of Rv3097c-encoded lipase (LipY) of Mycobacterium tuberculosis that selectively inhibit growth of bacilli in hypoxia
Saxena, Anil K.,Roy, Kuldeep K.,Singh, Supriya,Vishnoi,Kumar, Anil,Kashyap, Vivek Kr.,Kremer, Laurent,Srivastava, Ranjana,Srivastava, Brahm S.
, p. 27 - 35 (2013/07/26)
The mycobacterial Rv3097c-encoded lipase LipY is considered as a true lipase involved in the hydrolysis of triacylglycerol stored in lipid inclusion bodies for the survival of dormant mycobacteria. To date, orlistat is the only known LipY inhibitor. In view of the important emerging role of this enzyme, a search for small-molecule inhibitors of LipY was made, leading to the identification of some new compounds (8a-8d, 8f, 8h and 8i) with potent inhibitory activities against recombinant LipY, with no cytotoxicity [50% inhibitory concentration (CC50) ≥500 μg/mL]. The compounds 6a, 8c and 8f potently inhibited (>90%) the growth of Mycobacterium tuberculosis H37Rv grown under hypoxia (oxygen-depleted condition) but had no effect on aerobically grown bacilli, suggesting that these new small molecules are highly selective towards the growth inhibition of hypoxic cultures of M. tuberculosis and hence provide new leads for combating latent tuberculosis.
Synthesis of novel α-amino acid functionalized 6-fluoro quinolones, their antibacterial activity and molecular docking studies
Venkat Lingaiah,Yakaiah,Chandra Shekhar,Ravi Kumar,Sathaiah,Raju,Shanthan Rao,Narsaiah,Pranay Kumar,Murthy,Purushotham,Narahari Sastry
experimental part, p. 969 - 980 (2012/10/08)
A series of novel α-amino acid functionalized 6-fluoro quinolone derivatives have been synthesized from quinoline ester 2 in series of steps with good yields. The compounds have been screened against gram-positive and gram-negative bacteria in-vitro. Some compounds show promising activity against all species of gram-positive and gram-negative bacteria, with reference to standard Norfloxacin as well as Ciprofloxacin. The activity data is validated by molecular docking studies and are in good co-relation with observed trends.
