Curcuminoid analogs with potent activity against Trypanosoma and Leishmania species

Changtam, Chatchawan; Koning, Harry P. de; Ibrahim, Hasan M. S.; Sajid, Mohammed; Gould, Matthew K.; Suksamrarn, Apichart

doi:10.1016/j.ejmech.2009.11.035

Cited by 154 publications

(112 citation statements)

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“…Although anti-infective properties of curcumin have also been described, particularly with reference to parasitic disease (Haddad et al, 2011), the potential here is mostly in synthetic curcuminoids, as curcumin itself has insufficient antiparasitic activity. Efforts have been made to address the structureactivity relationships of these antiparasitic curcuminoids through the synthesis of small chemical libraries, but it is not clear whether the new curcumin analogs do in fact represent We recently described the synthesis and antitrypanosomal evaluation of a series of 57 curcumin analogs, all with a C7 linker between phenolic rings, of which the most active compound, AS-HK014, displayed an EC 50 value of 0.053 6 0.007 mM against T. b. brucei bloodstream forms (Changtam et al, 2010a), which is approximately 50-fold better than curcumin and 2-fold better than diminazene aceturate. AS-HK014 displayed an in vitro selectivity index of 221 versus human embryonic kidney cells compared with only 13.7 for curcumin itself.…”

Section: Discussionmentioning

confidence: 99%

“…The diamidine trypanocides pentamidine and diminazene (both from Sigma-Aldrich) were used as controls. Drug sensitivity assays with human embryonic kidney cells were performed similarly using a resazurin-based assay, exactly as described previously (Rodenko et al, 2007;Changtam et al, 2010a).…”

Section: Methodsmentioning

confidence: 99%

“…While the available evidence thus suggests predominantly indirect effects of curcumin against parasitic infections, curcuminoids with much improved activity against the human malaria parasite Plasmodium falciparum (Mishra et al, 2008;Manohar et al, 2013), Leishmania mexicana amastigotes, and Leishmania major promastigotes (Changtam et al, 2010a), experimental Leishmania amazonensis infections (Alves et al, 2003), and Trypanosoma brucei (Changtam et al, 2010a) have recently been reported. In particular, a series of monoketo enone curcuminoids displayed highly promising in vitro activity against T. brucei bloodstream forms (Changtam et al, 2010a).…”

Section: Introductionmentioning

confidence: 99%

“…In particular, a series of monoketo enone curcuminoids displayed highly promising in vitro activity against T. brucei bloodstream forms (Changtam et al, 2010a). In the current manuscript, we investigate the mode of action of these compounds and whether they act through a different mechanism than the parent compound curcumin.…”

Section: Introductionmentioning

confidence: 99%

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Potent Trypanocidal Curcumin Analogs Bearing a Monoenone Linker Motif Act on Trypanosoma brucei by Forming an Adduct with Trypanothione

et al. 2014

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We have previously reported that curcumin analogs with a C 7 linker bearing a C 4 -C 5 olefinic linker with a single keto group at C3 (enone linker) display midnanomolar activity against the bloodstream form of Trypanosoma brucei. However, no clear indication of their mechanism of action or superior antiparasitic activity relative to analogs with the original di-ketone curcumin linker was apparent. To further investigate their utility as antiparasitic agents, we compare the cellular effects of curcumin and the enone linker lead compound 1,7-bis(4-hydroxy-3-methoxyphenyl)hept-4-en-3-one (AS-HK014) here. An AS-HK014-resitant line, trypanosomes adapted to AS-HK014 (TA014), was developed by in vitro exposure to the drug. Metabolomic analysis revealed that exposure to AS-HK014, but not curcumin, rapidly depleted glutathione and trypanothione in the wild-type line, although almost all other metabolites were unchanged relative to control. In TA014 cells, thiol levels were similar to untreated wild-type cells and not significantly depleted by AS-HK014. Adducts of AS-HK014 with both glutathione and trypanothione were identified in AS-HK014-exposed wild-type cells and reproduced by chemical reaction. However, adduct accumulation in sensitive cells was much lower than in resistant cells. TA014 cells did not exhibit any changes in sequence or protein levels of glutathione synthetase and g-glutamylcysteine synthetase relative to wild-type cells. We conclude that monoenone curcuminoids have a different mode of action than curcumin, rapidly and specifically depleting thiol levels in trypanosomes by forming an adduct. This adduct may ultimately be responsible for the highly potent trypanocidal and antiparasitic activity of the monoenone curcuminoids.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Potent Trypanocidal Curcumin Analogs Bearing a Monoenone Linker Motif Act on Trypanosoma brucei by Forming an Adduct with Trypanothione

et al. 2014

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“…13 The resistance factor (RF) with respect to wild type trypanosomes was calculated for both resistant strains. Finally, the cytotoxicity against human endothelial kidney (HEK) cells was also determined, 15 and the selectivity indices were calculated ( Table 1).…”

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confidence: 99%

SAR Studies of Diphenyl Cationic Trypanocides: Superior Activity of Phosphonium over Ammonium Salts

Dardonville

Alkhaldi

Koning

2014

ACS Med. Chem. Lett.

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ABSTRACT:In previous studies, we have shown that phosphonium salt diphenyl derivatives are attractive antitrypanosomal hit compounds with EC 50 values against Trypanosoma brucei in the nanomolar range. To evaluate the role of the cationic center on the trypanocidal activity and extend the structure−activity relationship (SAR) of this series, trialkylammonium, pyridinium, and quinolinium salt analogues were synthesized and evaluated in vitro against T. b. brucei. Similar SARs were observed with ammonium and phosphonium salts showing that charge dispersion and lipophilic groups around the cationic center are crucial to obtain submicromolar activities. The new compounds were equally effective against wild type (T. b. brucei s427) and resistant strains (TbAT1-KO and TbB48) of trypanosomes indicating that the P2 and high affinity pentamidine transporters (HAPT) are not essential to their trypanocidal action. Similarly to phosphonium salt derivatives, diffusion seems to be the main route of entry into trypanosomes. KEYWORDS: Trypanosoma brucei, ammonium salt, quinolinium salt, pyridinium salt, P2-transporter, high affinity pentamidine transporter (HAPT) P arasitic protozoa of the genus Trypanosoma cause human and animal trypanosomiases in Africa. Two subspecies of T. brucei (T. b. gambiense and T. b. rhodesiense) are pathogenic to man and cause human African trypanosomiasis (HAT) in sub-Saharan Africa. In contrast, T. b. brucei, T. congolense, and T. vivax cause veterinary diseases in domestic and wild animals. 1,2 African trypanosomiasis is one of the most neglected tropical diseases as shown by the lack of safe drugs to treat both (early and late) stages of the illness. These drugs, which have been used for decades, are subject to treatment failure (drug resistance) and have severe drawbacks such as unacceptable toxicity and parenteral administration. 3 Cationic drugs are an important class of trypanocides used for the treatment of human and veterinary trypanosomiasis (e.g., pentamidine, diminazene, homidium, and isomethamidium). 4,5 In previous studies we have shown that a new class of cationic compounds, mono-and bisphosphonium salt derivatives with a diphenyl scaffold, have submicromolar activities against T. brucei and Leishmania parasites. 6,7 These compounds display a good selectivity index relative to human cell lines, are not cross-resistant with existing trypanocides, and require only a short exposure time for trypanocidal activity. 6 Like other dicationic trypanocides, 8,9 the bisphosphonium salts are expected to accumulate in the mitochondria. Indeed, a mitochondrial target for these compounds was demonstrated in Leishmania. 7 Structure−activity relationship (SAR) studies revealed that bulky substituents on the phosphorus atoms are required to achieve submicromolar EC 50 values within this series. In the present work, we wanted to learn whether the nature of the cationic center was important for the observed trypanocidal activity of these hit compounds. Thus, new cationic analogues of the hits with a nitr...

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Diterpenoids and a Diarylheptanoid from Hedychium coronarium with Significant Anti‐Angiogenic and Cytotoxic Activities

Zhan

Wen

Ren

et al. 2012

Chemistry & Biodiversity

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Two new labdane diterpenoids, namely hedycoronals A and B (1 and 2, resp.), were isolated from the rhizomes of Hedychium coronarium, together with eight known diterpenoids, 4-11, and a known diarylheptanoid, 3. The structures of 1 and 2 were established by detailed interpretation of their 1D- and 2D-NMR spectra and HR-ESI-MS data. Inhibitory activities against human umbilical vein endothelial cells (HUMECs) proliferation and cytotoxic activities against four cancer cell lines were assessed for all the isolates. Most of these metabolites showed moderate or potent cytotoxic activities against four cancer cell lines. Moreover, compounds 3 and 8 exhibited promising inhibitory activities against HUMECs with the IC(50) values of 6.4 to 3.3 μM.

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Curcuminoid analogs with potent activity against Trypanosoma and Leishmania species

Cited by 154 publications

References 56 publications

Potent Trypanocidal Curcumin Analogs Bearing a Monoenone Linker Motif Act on Trypanosoma brucei by Forming an Adduct with Trypanothione

Potent Trypanocidal Curcumin Analogs Bearing a Monoenone Linker Motif Act on Trypanosoma brucei by Forming an Adduct with Trypanothione

SAR Studies of Diphenyl Cationic Trypanocides: Superior Activity of Phosphonium over Ammonium Salts

Diterpenoids and a Diarylheptanoid from Hedychium coronarium with Significant Anti‐Angiogenic and Cytotoxic Activities

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