Abstract:Bis(indazol-3-ol) derivatives (5, 30-38) were prepared by alkylation of 3-alkoxyindazoles with alpha,omega-dibromides, followed by removal of the O-protecting groups. These compounds were subsequently evaluated as inhibitors of biocrystallization of ferriprotoporphyrin IX (heme) to hemozoin, a Plasmodium detoxification specific process. Most bis(5-nitroindazol-3-ols) were good inhibitors, however, a denitro analogue (38), the intermediate bis(3-alkoxyindazoles) (15-29) as well as bis(indazolin-3-ones) (39-42) … Show more
“…3 and Table 1). Indazole compounds (DIM 5 and DIM 32) gave IC 50 values comparable to chloroquine in agreement with former results 45 . However, these drugs behaved differently to quinolines as they precipitated hemin which redissolved during assay of absorbance contributing to hemin.Figure 2Increase of free hemin (inhibition of β-hematin) in presence of chloroquine.…”
Section: Resultssupporting
confidence: 91%
“…The current work determines the actions of quinoline drugs and related compounds (e.g. β-carbolines and nitroindazoles) having antimalarial activity 44,45 on the synthesis of hemozoin and free hemin build-up. We have developed an assay to determinate the conversion of hemin into hemozoin, and subsequently it is used to investigate the activity of quinoline drugs.…”
Malaria caused by Plasmodium affects millions people worldwide. Plasmodium consumes hemoglobin during its intraerythrocytic stage leaving toxic heme. Parasite detoxifies free heme through formation of hemozoin (β-hematin) pigment. Proteolysis of hemoglobin and formation of hemozoin are two main targets for antimalarial drugs. Quinoline antimarial drugs and analogs (β-carbolines or nitroindazoles) were studied as inhibitors of β-hematin formation. The most potent inhibitors were quinacrine, chloroquine, and amodiaquine followed by quinidine, mefloquine and quinine whereas 8-hydroxyquinoline and β-carbolines had no effect. Compounds that inhibited β-hematin increased free hemin that promoted peroxidative reactions as determined with TMB and ABTS substrates. Hemin-catalyzed peroxidative reactions were potentiated in presence of proteins (i.e. globin or BSA) while antioxidants and peroxidase inhibitors decreased peroxidation. Free hemin increased by chloroquine action promoted oxidative reactions resulting in inhibition of proteolysis by three cysteine proteases: papain, ficin and cathepsin B. Glutathione reversed inhibition of proteolysis. These results show that active quinolines inhibit hemozoin and increase free hemin which in presence of H2O2 that abounds in parasite digestive vacuole catalyzes peroxidative reactions and inhibition of cysteine proteases. This work suggests a link between the action of quinoline drugs with biochemical processes of peroxidation and inhibition of proteolysis.
“…3 and Table 1). Indazole compounds (DIM 5 and DIM 32) gave IC 50 values comparable to chloroquine in agreement with former results 45 . However, these drugs behaved differently to quinolines as they precipitated hemin which redissolved during assay of absorbance contributing to hemin.Figure 2Increase of free hemin (inhibition of β-hematin) in presence of chloroquine.…”
Section: Resultssupporting
confidence: 91%
“…The current work determines the actions of quinoline drugs and related compounds (e.g. β-carbolines and nitroindazoles) having antimalarial activity 44,45 on the synthesis of hemozoin and free hemin build-up. We have developed an assay to determinate the conversion of hemin into hemozoin, and subsequently it is used to investigate the activity of quinoline drugs.…”
Malaria caused by Plasmodium affects millions people worldwide. Plasmodium consumes hemoglobin during its intraerythrocytic stage leaving toxic heme. Parasite detoxifies free heme through formation of hemozoin (β-hematin) pigment. Proteolysis of hemoglobin and formation of hemozoin are two main targets for antimalarial drugs. Quinoline antimarial drugs and analogs (β-carbolines or nitroindazoles) were studied as inhibitors of β-hematin formation. The most potent inhibitors were quinacrine, chloroquine, and amodiaquine followed by quinidine, mefloquine and quinine whereas 8-hydroxyquinoline and β-carbolines had no effect. Compounds that inhibited β-hematin increased free hemin that promoted peroxidative reactions as determined with TMB and ABTS substrates. Hemin-catalyzed peroxidative reactions were potentiated in presence of proteins (i.e. globin or BSA) while antioxidants and peroxidase inhibitors decreased peroxidation. Free hemin increased by chloroquine action promoted oxidative reactions resulting in inhibition of proteolysis by three cysteine proteases: papain, ficin and cathepsin B. Glutathione reversed inhibition of proteolysis. These results show that active quinolines inhibit hemozoin and increase free hemin which in presence of H2O2 that abounds in parasite digestive vacuole catalyzes peroxidative reactions and inhibition of cysteine proteases. This work suggests a link between the action of quinoline drugs with biochemical processes of peroxidation and inhibition of proteolysis.
“…This allowed the calculation of a selectivity index Compounds from the hydrazide series (Table 1) had IC 50 values against T. brucei in the range 5.5 to > 400 µM. Seven compounds showed IC 50 < 50 µM (3,11,16,(17)(18)(19)(20) but only three of those (3, 11, and 20) were selective for the parasite with SI of 8.3, 13.7, and 13, respectively. Of note is the effect of replacing the 6-halogen atom (Cl, F) by an ethoxy group in 20; this reduced significantly the cytotoxicity (13-to 57-fold) with only a two-fold decrease in antitrypanosomal activity with respect to 18 and 19.…”
Section: Introductionmentioning
confidence: 99%
“…Other authors have reviewed the shortcomings of those drugs especially regarding toxicity, lack of oral bioavailability or lack of efficiency. 3 Apart from the recent inclusion of the nifurtimox-eflornithine combination therapy (NECT) 19,20 Besides, it should be kept in mind that the nitroheterocycles benznidazole and nifurtimox ( Fig. 1) are currently the only drugs available for the treatment of American trypanosomiasis which emphasizes the importance of this class of chemical structures as antiprotozoal agents.…”
mentioning
confidence: 99%
“…We report here the in vitro screening against T. b. rhodesiense (strain STIB900) of a selection of 76 nitro-derivatives of nitrogenated heterocycles (e.g., nitrocinnolines, nitroindoles, nitroindazoles and nitroquinoxalinones) and related compounds 13,19,[21][22][23][24][25][26][27][28][29][30]31 using the Alamar blue growth inhibition assay. 32 Their cytotoxicity against mammalian L6-cells was also determined in vitro.…”
A selection of 76 nitroheterocycles and related compounds from our in-house compound library was screened in vitro against the parasite Trypanosoma brucei rhodesiense, causative agent of human African trypanosomiasis (HAT). The unspecific cytotoxicity of the compounds was also evaluated against rat myoblast L6-cells to measure the selectivity of the compounds towards the parasite. This screening revealed some preliminary structure-activity relationships (SAR) among the series, and six hit compounds showing interesting activity (IC 50 ≤ 10 µM) and fair selectivity (SI > 17).The 7-nitroquinoxalin-2-one and 5-nitroindazole scaffold derivatives 58 and 35, respectively, are particularly interesting because of their established oral bioavailability in mice. These hits represent interesting starting points for a medicinal project aimed at identifying the SAR behind this class of compounds. The NTD status of sleeping sickness is highlighted by the fact that 3 out of the 4 drugs approved for its treatment (i.e., pentamidine, melarsoprol, suramin) were discovered more that 60 years ago. The other drug, eflornithine, was approved in 1990 for the We report here the in vitro screening against T. b. rhodesiense (strain STIB900) of a selection of 76 nitro-derivatives of nitrogenated heterocycles (e.g., nitrocinnolines, nitroindoles, nitroindazoles and nitroquinoxalinones) and related compounds 13,19,[21][22][23][24][25][26][27][28][29][30] 31 using the Alamar blue growth inhibition assay. 32 Their cytotoxicity against mammalian L6-cells was also determined in vitro. This allowed the calculation of a selectivity index Compounds from the hydrazide series (Table 1) had IC 50 values against T. brucei in the range 5.5 to > 400 µM. Seven compounds showed IC 50 < 50 µM (3,11,16,(17)(18)(19)(20) but only three of those (3, 11, and 20) were selective for the parasite with SI of 8.3, 13.7, and 13, respectively. Of note is the effect of replacing the 6-halogen atom (Cl, F) by an ethoxy group in 20; this reduced significantly the cytotoxicity (13-to 57-fold) with only a two-fold decrease in antitrypanosomal activity with respect to 18 and 19.[insert Table 1 here] 5-Nitroindazolols derivatives with free OH group (Table 2) [insert Table 2 here]Among indazolinone derivatives (Table 3) [insert Table 3 here]The quinoxalin-2-one scaffold gave the best antitrypanosomal compounds with 6 molecules (57, 58, 59, 60, 62, 65) having IC 50 values < 15 µM and SI values in the range 3.6-39.7 (Table 4). The N1,N4-dimethyl compound 58 and the fused pyrrolidine derivative 65 were the most active compounds of this screening (IC 50 = 3.6 and 2.7 µM, respectively The bisnitroindazole derivatives were poorly active against T. brucei (Table 5). The sole compound with interesting activity was the urea 76 which was one of the best hits of this study with IC 50 = 7.1 µM and SI > 23.6.[insert Tables 4 and 5 here]The discovery of fexinidazole as a potential clinical candidate for the oral treatment of both stages of sleeping sickness has led, in the last ...
A new and efficient cascade synthesis of indazolo[2,1-a]indazole-6,12-diones has been developed. This protocol includes an intermolecular N-acylation followed by a copper-catalyzed intramolecular C-N coupling reaction. The methodology is applied to a wide range of 2-bromo and 2-chloro benzoyl chlorides to yield the indazolo-[2,1-a]indazole-6,12-diones in good to excellent yields with high regioselectivities.
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