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1.
Med Res Rev ; 44(1): 66-137, 2024 Jan.
Article in English | MEDLINE | ID: mdl-37222435

ABSTRACT

The demand for novel, fast-acting, and effective antimalarial medications is increasing exponentially. Multidrug resistant forms of malarial parasites, which are rapidly spreading, pose a serious threat to global health. Drug resistance has been addressed using a variety of strategies, such as targeted therapies, the hybrid drug idea, the development of advanced analogues of pre-existing drugs, and the hybrid model of resistant strains control mechanisms. Additionally, the demand for discovering new potent drugs grows due to the prolonged life cycle of conventional therapy brought on by the emergence of resistant strains and ongoing changes in existing therapies. The 1,2,4-trioxane ring system in artemisinin (ART) is the most significant endoperoxide structural scaffold and is thought to be the key pharmacophoric moiety required for the pharmacodynamic potential of endoperoxide-based antimalarials. Several derivatives of artemisinin have also been found as potential treatments for multidrug-resistant strain in this area. Many 1,2,4-trioxanes, 1,2,4-trioxolanes, and 1,2,4,5-tetraoxanes derivatives have been synthesised as a result, and many of these have shown promise antimalarial activity both in vivo and in vitro against Plasmodium parasites. As a consequence, efforts to develop a functionally straight-forward, less expensive, and vastly more effective synthetic pathway to trioxanes continue. This study aims to give a thorough examination of the biological properties and mode of action of endoperoxide compounds derived from 1,2,4-trioxane-based functional scaffolds. The present system of 1,2,4-trioxane, 1,2,4-trioxolane, and 1,2,4,5-tetraoxane compounds and dimers with potentially antimalarial activity will be highlighted in this systematic review (January 1963-December 2022).


Subject(s)
Antimalarials , Artemisinins , Tetraoxanes , Humans , Antimalarials/chemistry , Artemisinins/pharmacology , Artemisinins/chemistry , Plasmodium falciparum , Systematic Reviews as Topic , Tetraoxanes/pharmacology , Tetraoxanes/chemistry
2.
Molecules ; 27(17)2022 Aug 24.
Article in English | MEDLINE | ID: mdl-36080174

ABSTRACT

Leishmaniases are among the most impacting neglected tropical diseases. In attempts to repurpose antimalarial drugs or candidates, it was found that selected 1,2,4-trioxanes, 1,2,4,5-tetraoxanes, and pyrazole-containing chemotypes demonstrated activity against Leishmania parasites. This study reports the synthesis and structure of trioxolane-pyrazole (OZ1, OZ2) and tetraoxane-pyrazole (T1, T2) hybrids obtained from the reaction of 3(5)-aminopyrazole with endoperoxide-containing building blocks. Interestingly, only the endocyclic amine of 3(5)-aminopyrazole was found to act as nucleophile for amide coupling. However, the fate of the reaction was influenced by prototropic tautomerism of the pyrazole heterocycle, yielding 3- and 5-aminopyrazole containing hybrids which were characterized by different techniques, including X-ray crystallography. The compounds were evaluated for in vitro antileishmanial activity against promastigotes of L. tropica and L. infantum, and for cytotoxicity against THP-1 cells. Selected compounds were also evaluated against intramacrophage amastigote forms of L. infantum. Trioxolane-pyrazole hybrids OZ1 and OZ2 exhibited some activity against Leishmania promastigotes, while tetraoxane-pyrazole hybrids proved inactive, most likely due to solubility issues. Eight salt forms, specifically tosylate, mesylate, and hydrochloride salts, were then prepared to improve the solubility of the corresponding peroxide hybrids and were uniformly tested. Biological evaluations in promastigotes showed that the compound OZ1•HCl was the most active against both strains of Leishmania. Such finding was corroborated by the results obtained in assessments of the L. infantum amastigote susceptibility. It is noteworthy that the salt forms of the endoperoxide-pyrazole hybrids displayed a broader spectrum of action, showing activity in both strains of Leishmania. Our preliminary biological findings encourage further optimization of peroxide-pyrazole hybrids to identify a promising antileishmanial lead.


Subject(s)
Antiprotozoal Agents , Leishmania infantum , Leishmania , Leishmaniasis , Tetraoxanes , Antiprotozoal Agents/chemistry , Humans , Leishmaniasis/drug therapy , Pyrazoles/chemistry , Tetraoxanes/pharmacology , Tetraoxanes/therapeutic use
3.
Chempluschem ; 87(8): e202200207, 2022 08.
Article in English | MEDLINE | ID: mdl-36000152

ABSTRACT

Plasmodium falciparum artemisinin-resistance boosted the quest for novel plasmodial "fast killers," uncovering antimalarial candidates OZ439 and E209, whose peroxide precursors are 1,2,4-trioxolane (1) and 1,2,4,5-tetraoxane (2), differing solely in the pharmacophore (trioxolane or tetraoxane). Combining X-ray crystallography and vibrational spectroscopy, along with Hirshfeld surface analysis and calculations (CE-B3LYP/6-31G(d,p)) of pairwise interaction energies of intermolecular contacts existing in the crystal structure, may deepen the understanding of relative reactivity and properties of these endoperoxides classes. In the crystal, the tetraoxane ring in 2 and the trioxolane-adamantyl fragment in 1 are disordered, with molecules 1 and 2 existing as two distinct, stable conformations. Whereas the dominant C-H⋅⋅⋅O H-bonds in 1 connect an adamantyl C-H and O1 or O2 of the trioxolane ring, in 2 they involve the carbonyl oxygen, acting as a double acceptor from phenyl ring C-H groups. C-H⋅⋅⋅O and C-H⋅⋅⋅π H-bonds define the molecular packing of 2, while C-H⋅⋅⋅H-C van der Waals interactions determine the packing of 1. The dispersive component dominates the interaction energies calculated for the most representative molecular pairs.


Subject(s)
Antimalarials , Tetraoxanes , Antimalarials/chemistry , Antimalarials/pharmacology , Antiparasitic Agents , Molecular Structure , Peroxides/chemistry , Tetraoxanes/chemistry , Tetraoxanes/pharmacology
4.
Int J Mol Sci ; 23(3)2022 Feb 04.
Article in English | MEDLINE | ID: mdl-35163703

ABSTRACT

This study aimed to identify potential inhibitors and investigate the mechanism of action on SARS-CoV-2 ACE2 receptors using a molecular modeling study and theoretical determination of biological activity. Hydroxychloroquine was used as a pivot structure and antimalarial analogues of 1,2,4,5 tetraoxanes were used for the construction and evaluation of pharmacophoric models. The pharmacophore-based virtual screening was performed on the Molport® database (~7.9 million compounds) and obtained 313 structures. Additionally, a pharmacokinetic study was developed, obtaining 174 structures with 99% confidence for human intestinal absorption and penetration into the blood-brain barrier (BBB); posteriorly, a study of toxicological properties was realized. Toxicological predictions showed that the selected molecules do not present a risk of hepatotoxicity, carcinogenicity, mutagenicity, and skin irritation. Only 54 structures were selected for molecular docking studies, and five structures showed binding affinity (ΔG) values satisfactory for ACE2 receptors (PDB 6M0J), in which the molecule MolPort-007-913-111 had the best ΔG value of -8.540 Kcal/mol, followed by MolPort-002-693-933 with ΔG = -8.440 Kcal/mol. Theoretical determination of biological activity was realized for 54 structures, and five molecules showed potential protease inhibitors. Additionally, we investigated the Mpro receptor (6M0K) for the five structures via molecular docking, and we confirmed the possible interaction with the target. In parallel, we selected the TopsHits 9 with antiviral potential that evaluated synthetic accessibility for future synthesis studies and in vivo and in vitro tests.


Subject(s)
Hydroxychloroquine/pharmacology , SARS-CoV-2/drug effects , Tetraoxanes/pharmacology , Antiviral Agents/pharmacology , Binding Sites , Computational Biology/methods , Drug Evaluation, Preclinical/methods , Humans , Hydroxychloroquine/analogs & derivatives , Molecular Docking Simulation/methods , Molecular Dynamics Simulation , Protease Inhibitors/pharmacology , Protein Binding/drug effects , SARS-CoV-2/pathogenicity , Spike Glycoprotein, Coronavirus/metabolism , COVID-19 Drug Treatment
5.
Molecules ; 26(13)2021 Jun 30.
Article in English | MEDLINE | ID: mdl-34208832

ABSTRACT

The rapid emergence of drug resistance to the current antimalarial agents has led to the urgent need for the discovery of new and effective compounds. In this work, a series of 5-phenoxy primaquine analogs with 8-aminoquinoline core (7a-7h) was synthesized and investigated for their antimalarial activity against Plasmodium falciparum. Most analogs showed improved blood antimalarial activity compared to the original primaquine. To further explore a drug hybrid strategy, a conjugate compound between tetraoxane and the representative 5-phenoxy-primaquine analog 7a was synthesized. In our work, the hybrid compound 12 exhibited almost a 30-fold increase in the blood antimalarial activity (IC50 = 0.38 ± 0.11 µM) compared to that of primaquine, with relatively low toxicity against mammalian cells (SI = 45.61). Furthermore, we found that these 5-phenoxy primaquine analogs and the hybrid exhibit significant heme polymerization inhibition, an activity similar to that of chloroquine, which could contribute to their improved antimalarial activity. The 5-phenoxy primaquine analogs and the tetraoxane hybrid could serve as promising candidates for the further development of antimalarial agents.


Subject(s)
Antimalarials , Erythrocytes/parasitology , Malaria, Falciparum/drug therapy , Plasmodium falciparum/growth & development , Primaquine , Tetraoxanes , Adult , Antimalarials/chemical synthesis , Antimalarials/chemistry , Antimalarials/pharmacology , Erythrocytes/metabolism , Erythrocytes/pathology , Female , Humans , Malaria, Falciparum/metabolism , Malaria, Falciparum/pathology , Male , Middle Aged , Primaquine/analogs & derivatives , Primaquine/chemical synthesis , Primaquine/chemistry , Primaquine/pharmacology , Tetraoxanes/chemical synthesis , Tetraoxanes/chemistry , Tetraoxanes/pharmacology
6.
Chem Biodivers ; 17(6): e2000142, 2020 Jun.
Article in English | MEDLINE | ID: mdl-32294320

ABSTRACT

Leishmaniasis is a neglected disease, caused by a parasite of Leishmania genus and widespread in the tropical and subtropical areas of the world. Currents drugs are limited due to their toxicity and parasite resistance. Therefore, the discovery of new treatment, more effective and less toxic, is urgent. In this study, we report the synthesis of six gem-dihydroperoxides (2a-2f), with yields ranging from 10 % to 90 %, utilizing a new methodology. The dihydroperoxides were converted into ten tetroxanes (3a-3j), among which six (3b, 3c, 3d, 3g, 3h and 3j) showed activity against intracellular amastigotes of Leishmania amazonensis. The cytotoxicity of all compounds was also evaluated against canine macrophages (DH82), human hepatoma (HepG2) and monkey renal cells (BGM). Most compounds were more active and less toxic than potassium antimonyl tartrate trihydrate, used as positive control. Amongst all tetroxanes, 3b (IC50 =0.64 µm) was the most active, being more selective than positive control in relation to DH82, HepG2 and BGM cells. In summary, the results revealed a hit compound for the development of new drugs to treat leishmaniasis.


Subject(s)
Antiprotozoal Agents/pharmacology , Leishmania/drug effects , Tetraoxanes/chemistry , Animals , Antiprotozoal Agents/chemical synthesis , Antiprotozoal Agents/chemistry , Cell Line , Cell Survival/drug effects , Dogs , Haplorhini , Humans , Macrophages/cytology , Macrophages/metabolism , Tetraoxanes/chemical synthesis , Tetraoxanes/pharmacology
7.
Med Chem ; 16(3): 392-402, 2020.
Article in English | MEDLINE | ID: mdl-31208310

ABSTRACT

BACKGROUND: With few exceptions, existing tuberculosis drugs were developed many years ago and resistance profiles have emerged. This has created a need for new drugs with discrete modes of action. There is evidence that tuberculosis (like other bacteria) is susceptible to oxidative pressure and this has yet to be properly utilised as a therapeutic approach in a manner similar to that which has proven highly successful in malaria therapy. OBJECTIVE: To develop an alternative approach to the incorporation of bacterial siderophores that results in the creation of antitubercular peroxidic leads for subsequent development as novel agents against tuberculosis. METHODS: Eight novel peroxides were prepared and the antitubercular activity (H37Rv) was compared to existing artemisinin derivatives in vitro. The potential for toxicity was evaluated against the L6 rat skeletal myoblast and HeLa cervical cancer lines in vitro. RESULTS: The addition of a pyrimidinyl residue to an artemisinin or, preferably, a tetraoxane peroxidic structure results in antitubercular activity in vitro. The same effect is not observed in the absence of the pyrimidine or with other heteroaromatic substituents. CONCLUSION: The incorporation of a pyrimidinyl residue adjacent to the peroxidic function in an organic peroxide results in anti-tubercular activity in an otherwise inactive peroxidic compound. This will be a useful approach for creating oxidative drugs to target tuberculosis.


Subject(s)
Antitubercular Agents/pharmacology , Artemisinins/pharmacology , Tetraoxanes/pharmacology , Animals , Antitubercular Agents/chemical synthesis , Artemisinins/chemical synthesis , HeLa Cells , Humans , Microbial Sensitivity Tests , Mycobacterium tuberculosis/drug effects , Rats , Tetraoxanes/chemical synthesis
8.
PLoS Negl Trop Dis ; 13(3): e0007235, 2019 03.
Article in English | MEDLINE | ID: mdl-30908481

ABSTRACT

Visceral leishmaniasis (VL) is a major problem worldwide and causes significant morbidity and mortality. Existing drugs against VL have limitations, including their invasive means of administration long duration of treatment regimens. There are also concerns regarding increasing treatment relapses as well as the identification of resistant clinical strains with the use of miltefosine, the sole oral drug for VL. There is, therefore, an urgent need for new alternative oral drugs for VL. In the present study, we show the leishmanicidal effect of a novel, oral antimalarial endoperoxide N-251. In our In vitro studies, N-251 selectively and specifically killed Leishmania donovani D10 amastigotes with no accompanying toxicity toward the host cells. In addition, N-251 exhibited comparable activities against promastigotes of L. donovani D10, as well as other L. donovani complex parasites, suggesting a wide spectrum of activity. Furthermore, even after a progressive infection was established in mice, N-251 significantly eliminated amastigotes when administered orally. Finally, N-251 suppressed granuloma formation in mice liver through parasite death. These findings indicate the therapeutic effect of N-251 as an oral drug, hence suggest N-251 to be a promising lead compound for the development of a new oral chemotherapy against VL.


Subject(s)
Antimalarials/administration & dosage , Antiprotozoal Agents/administration & dosage , Leishmania donovani/drug effects , Leishmaniasis, Visceral/drug therapy , Spiro Compounds/administration & dosage , Tetraoxanes/administration & dosage , Animals , Antimalarials/pharmacology , Antiprotozoal Agents/pharmacology , Cell Survival/drug effects , Disease Models, Animal , Leishmania donovani/physiology , Leishmaniasis, Visceral/pathology , Liver/pathology , Mice, Inbred BALB C , Spiro Compounds/pharmacology , Tetraoxanes/pharmacology , Treatment Outcome
9.
Steroids ; 129: 17-23, 2018 01.
Article in English | MEDLINE | ID: mdl-29180289

ABSTRACT

A series of new steroidal peroxides - 3'-trifluoromethylated 1,2,4-trioxolanes and 1,2,4,5-tetraoxanes based on deoxycholic acid were prepared via the reactions of the Griesbaum coozonolysis and peroxycondensation, respectively. 1,2,4-Trioxolanes were synthesized by the interaction of methyl O-methyl-3-oximino-12α-acetoxy-deoxycholate with CF3C(O)CH3 or CF3C(O)Ph and O3 as the mixtures of four possible stereoisomers at ratios of 1:2:2:1 and in yields of 50% and 38%, respectively. The major diastereomer of methyl 12α-acetoxy-5ß-cholan-24-oate-3-spiro-5'-(3'-methyl-3'-trifluoromethyl-1',2',4'-trioxolane) was isolated via crystallization of a mixture of stereoisomers from hexane and its (3S,3'R)-configuration was determined using X-ray crystallographic analysis. Peroxycondensation of methyl 3-bishydroperoxy-12α-acetoxy-deoxycholate with CF3C(O)CH3 or acetone led to 1,2,4,5-tetraoxanes in yields of 44% and 37%, respectively. Antimalarial activity of these new steroidal peroxides was evaluated in vitro against the chloroquine-sensitive (CQS) T96 and chloroquine-resistant (CQR) K1 strains of Plasmodium falciparum. Deoxycholic acid 3'-trifluoromethylated 1,2,4,5-tetraoxane demonstrated a good IC50 value against CQR-strain (IC50 (K1) = 7.6 nM) of P. falciparum. Tetraoxane with the acetone subunit demonstrated the best results among all tested peroxides with an IC50 value of 3 nM against the CQ-resistant K1 strain. In general, 1,2,4-trioxolanes of deoxycholic acid are less active than 1,2,4,5-tetraoxanes.


Subject(s)
Antimalarials/chemical synthesis , Antimalarials/pharmacology , Deoxycholic Acid/chemistry , Furans/chemical synthesis , Furans/pharmacology , Tetraoxanes/chemical synthesis , Tetraoxanes/pharmacology , Antimalarials/chemistry , Chemistry Techniques, Synthetic , Furans/chemistry , Methylation , Models, Molecular , Molecular Conformation , Plasmodium falciparum/drug effects , Stereoisomerism , Structure-Activity Relationship , Tetraoxanes/chemistry
10.
Parasitol Int ; 66(5): 619-621, 2017 Oct.
Article in English | MEDLINE | ID: mdl-28571765

ABSTRACT

Metronidazole is well known for medicine against Trichomonas vaginalis infection, but it has side effects though it is effective, and especially because reports of metronidazole-tolerant species are increasing, the development of new medicine is being required. Here, we noticed the killing effects of endoperoxide compounds, N-89 and N-251 as new antimalarial drug candidates, on T. vaginalis and searched the possibility of development of new medicine. We added each of metronidazole, artemisinin, and two of new endoperoxides (N-89 and N-251) to metronidazole-resistant and -sensitive species and compared its anti-trichomonal efficacy. For metronidazole, IC50 value, 50% of killing concentration for T. vaginalis, was very low for metronidazole-sensitive isolates (11.7 to 22.8µM), but was high for metronidazole-resistant ones (182.9 to 730.4µM). The IC50 values of N-89 and N-251 were 41.0 to 60.0µM, and 82.0 to 300.0µM for metronidazole-sensitive and -resistant isolates, respectively. In conclusion, we found the endoperoxides, N-89 and N-251, have anti-trichomonal effect against metronidazole-resistant T. vaginalis as well as metronidazole-sensitive ones. These results indicate that the anti-trichomonal effects for our endoperoxides are equivalent or better in metronidazole-resistant T. vaginalis in comparison to metronidazole.


Subject(s)
Antiprotozoal Agents/pharmacology , Heterocyclic Compounds, 2-Ring/pharmacology , Spiro Compounds/pharmacology , Tetraoxanes/pharmacology , Trichomonas vaginalis/drug effects , Artemisinins/pharmacology , Drug Resistance , Heterocyclic Compounds, 2-Ring/chemical synthesis , Inhibitory Concentration 50 , Metronidazole/pharmacology , Spiro Compounds/chemical synthesis , Tetraoxanes/chemical synthesis
11.
Nat Commun ; 8: 15159, 2017 05 24.
Article in English | MEDLINE | ID: mdl-28537265

ABSTRACT

K13 gene mutations are a primary marker of artemisinin resistance in Plasmodium falciparum malaria that threatens the long-term clinical utility of artemisinin-based combination therapies, the cornerstone of modern day malaria treatment. Here we describe a multinational drug discovery programme that has delivered a synthetic tetraoxane-based molecule, E209, which meets key requirements of the Medicines for Malaria Venture drug candidate profiles. E209 has potent nanomolar inhibitory activity against multiple strains of P. falciparum and P. vivax in vitro, is efficacious against P. falciparum in in vivo rodent models, produces parasite reduction ratios equivalent to dihydroartemisinin and has pharmacokinetic and pharmacodynamic characteristics compatible with a single-dose cure. In vitro studies with transgenic parasites expressing variant forms of K13 show no cross-resistance with the C580Y mutation, the primary variant observed in Southeast Asia. E209 is a superior next generation endoperoxide with combined pharmacokinetic and pharmacodynamic features that overcome the liabilities of artemisinin derivatives.


Subject(s)
Antimalarials/pharmacology , Artemisinins/pharmacology , Drug Resistance/drug effects , Plasmodium falciparum/drug effects , Plasmodium vivax/drug effects , Protozoan Proteins/metabolism , Tetraoxanes/chemistry , Tetraoxanes/pharmacology , Animals , Antimalarials/chemistry , Dogs , Dose-Response Relationship, Drug , Drug Resistance/genetics , Erythrocytes/parasitology , Female , Half-Life , Humans , Male , Mice , Mice, Inbred NOD , Mice, SCID , Mutation , Plasmodium falciparum/genetics , Plasmodium vivax/genetics , Rats , Rats, Sprague-Dawley , Tetraoxanes/pharmacokinetics , Transgenes
12.
Parasitol Int ; 66(1): 917-924, 2017 Feb.
Article in English | MEDLINE | ID: mdl-27771462

ABSTRACT

The new synthetic compound 1,2,6,7-tetraoxaspiro[7.11]nonadecan (N-89), a novel anti-malaria drug candidate, is also a promising drug candidate against schistosomiasis with killing effects against juvenile stage of S. mansoni. In order to investigate how N-89 kills schistosomes, we used a derivative of N-89, 6-(1,2,6,7-tetraoxaspiro[7.11] nonadec-4-yl)hexan-1-ol (N-251), which enables us to conjugate with fluorescent reagents. Firstly, N-251 showed strong killing effects to larvae of S. mansoni in vitro. Ultrastructural analysis showed the disruptions of the lysosome-like organelles or the acetabular glands, followed by cytoplasmic lysis inside the worm body in N-251-treated group under electron microscopy. For rhodamine-conjugated N-251 and organelle markers, we observed that N-251 accumulated in acidic organelle. In addition, LysoTracker signals in these acidic organelles disappeared in N-251-treated group over time. Finally, we observed that the activity of cathepsin B, a lysosome-specific enzyme, was also decreased together with alternation of acidic organelle marker signal by N-251-treated group. These results suggested that our synthesized compounds induced the dysfunction or the disruption of acidic lysosome-like organelles and finally led to worm death.


Subject(s)
Lysosomes/drug effects , Organelles/drug effects , Schistosoma mansoni/drug effects , Schistosoma mansoni/growth & development , Schistosomicides/pharmacology , Spiro Compounds/pharmacology , Tetraoxanes/pharmacology , Animals , Cathepsin B/metabolism , Drug Discovery , Heterocyclic Compounds, 2-Ring/pharmacology , Larva/drug effects , Life Cycle Stages/drug effects , Lysosomes/pathology , Lysosomes/ultrastructure , Microscopy, Electron, Transmission , Organelles/chemistry , Organelles/ultrastructure , Rhodamines/chemistry , Schistosoma mansoni/ultrastructure , Spiro Compounds/metabolism , Tetraoxanes/metabolism
13.
Parasitol Int ; 65(5 Pt A): 494-9, 2016 Oct.
Article in English | MEDLINE | ID: mdl-27380994

ABSTRACT

An anti-malarial candidate, 6-(1,2,6,7-tetraoxaspiro[7.11]nonadec-4-yl)hexan-1-ol (N-251), was studied to characterize its potential as a novel anti-Toxoplasma gondii drug. In the present study, IC50 and LC50 of N-251 on host cells and T. gondii were compared to those of artemisinin and sulfadiazine. The IC50 on Huh-7 cells was 10.19µg/ml, 67.69µg/ml and 310.17µg/ml for N-251, artemisinin, and sulfadiazine, respectively. The LC50 for anti-T. gondii effect was shown to be 1.11µg/ml, 5.79µg/ml, and 5.45µg/ml for N-251, artemisinin and sulfadiazine, respectively. N-251 concentration causing complete parasiticidal effect with minimal cytotoxicity on host cells was determined to be 5µg/ml. Additionally, the anti-T. gondii effect of N-251 was confirmed by ultrastructural changes, loss of organelles, degenerated morphology and the increase of amylopectin as detected by transmission electron microscope (TEM). Accordingly, the present study suggests that the anti-malarial synthetic endoperoxide, N-251, is an emerging drug candidate more effective than artemisinin and sulfadiazine.


Subject(s)
Antimalarials/pharmacology , Spiro Compounds/pharmacology , Tetraoxanes/pharmacology , Toxoplasma/drug effects , Artemisinins/pharmacology , Cell Line , Humans , Parasitic Sensitivity Tests , Sulfadiazine/pharmacology
14.
J Med Chem ; 59(1): 264-81, 2016 Jan 14.
Article in English | MEDLINE | ID: mdl-26640981

ABSTRACT

The syntheses and antiplasmodial activities of various substituted aminoquinolines coupled to an adamantane carrier are described. The compounds exhibited pronounced in vitro and in vivo activity against Plasmodium berghei in the Thompson test. Tethering a fluorine atom to the aminoquinoline C(3) position afforded fluoroaminoquinolines that act as intrahepatocytic parasite inhibitors, with compound 25 having an IC50 = 0.31 µM and reducing the liver load in mice by up to 92% at 80 mg/kg dose. Screening our peroxides as inhibitors of liver stage infection revealed that the tetraoxane pharmacophore itself is also an excellent liver stage P. berghei inhibitor (78: IC50 = 0.33 µM). Up to 91% reduction of the parasite liver load in mice was achieved at 100 mg/kg. Examination of tetraoxane 78 against the transgenic 3D7 strain expressing luciferase under a gametocyte-specific promoter revealed its activity against stage IV-V Plasmodium falciparum gametocytes (IC50 = 1.16 ± 0.37 µM). To the best of our knowledge, compounds 25 and 78 are the first examples of either an 4-aminoquinoline or a tetraoxane liver stage inhibitors.


Subject(s)
Aminoquinolines/chemical synthesis , Aminoquinolines/pharmacology , Antimalarials/chemical synthesis , Antimalarials/pharmacology , Tetraoxanes/chemical synthesis , Tetraoxanes/pharmacology , Aminoquinolines/metabolism , Animals , Antimalarials/metabolism , Drug Evaluation, Preclinical , Ether-A-Go-Go Potassium Channels/drug effects , Hemin/antagonists & inhibitors , Hepatocytes/metabolism , Humans , In Vitro Techniques , Liver/parasitology , Mice , Microsomes, Liver/metabolism , Parasite Load , Plasmodium berghei/drug effects , Plasmodium falciparum/drug effects , Structure-Activity Relationship , Tetraoxanes/metabolism
15.
Bioorg Med Chem ; 23(16): 5175-81, 2015 Aug 15.
Article in English | MEDLINE | ID: mdl-25744189

ABSTRACT

Praziquantel is currently the only drug available to treat schistosomiasis. Since drug resistance would be a major barrier for the increasing global attempts to eliminate schistosomiasis as a public health problem, efforts should go hand in hand with the discovery of novel treatment options. Synthetic peroxides might offer a good direction since their antischistosomal activity has been demonstrated in the laboratory. We studied 19 bridged 1,2,4,5-tetraoxanes, 2 tricyclic monoperoxides, 11 bridged 1,2,4-trioxolanes, 12 silyl peroxides, and 4 hydroxylamine derivatives against newly transformed schistosomula (NTS) and adult Schistosoma mansoni in vitro. Schistosomicidal compounds were tested for cytotoxicity followed by in vivo studies of the most promising compounds. Tricyclic monoperoxides, trioxolanes, and tetraoxanes revealed the highest in vitro activity against NTS (IC50s 0.4-20.2 µM) and adult schistosomes (IC50s 1.8-22.8 µM). Tetraoxanes showed higher cytotoxicity than antischistosomal activity. Selected trioxolane and tricyclic monoperoxides were tested in mice harboring an adult S. mansoni infection. The highest activity was observed for two trioxolanes, which showed moderate worm burden reductions (WBR) of 44.3% and 42.9% (p>0.05). Complexation of the compounds with ß-cyclodextrin with the aim to improve solubility and gastrointestinal absorption did not increase in vivo antischistosomal efficacy. The high in vitro antischistosomal activity of trioxolanes and tricyclic monoperoxides is a promising basis for future investigations, with the focus on improving in vivo efficacy.


Subject(s)
Drug Discovery , Schistosoma mansoni/drug effects , Schistosomiasis mansoni/drug therapy , Schistosomicides/chemistry , Schistosomicides/therapeutic use , Animals , Female , Humans , Hydroxylamine/chemistry , Hydroxylamine/pharmacology , Hydroxylamine/therapeutic use , Mice , Peroxides/chemistry , Peroxides/pharmacology , Peroxides/therapeutic use , Schistosomicides/pharmacology , Tetraoxanes/chemistry , Tetraoxanes/pharmacology , Tetraoxanes/therapeutic use
16.
Pest Manag Sci ; 71(7): 1037-48, 2015 Jul.
Article in English | MEDLINE | ID: mdl-25157959

ABSTRACT

BACKGROUND: Several 1,2,4,5-tetraoxanes were synthesised, and their herbicidal activity was tested against weeds and compared with the activity of commercial herbicides glyphosate and imazethapyr. RESULTS: The compounds were prepared by reacting carbonyl compounds with hydrogen peroxide under acid catalysis, affording 1,1-dihydroperoxides (36-91%) that were further converted into 1,2,4,5-tetraoxanes (10-52%) under similar reaction conditions. All products were evaluated against Sorghum bicolor and Cucumis sativus at 0.0125-1.0 mM, and several tetraoxanes caused >70% inhibition of the growth of roots and aerial parts. The most active products were evaluated against the weeds Sorghum arundinaceum, Euphorbia heterophylla, Brachiaria brizantha and Bidens pilosa. Some compounds were highly effective (>80% inhibition at 1.0 mM) against the weeds, showing activity comparable with that of glyphosate or imazethapyr. One of the tetraoxanes was selective, being inactive against dicotyledonous species while inhibiting the roots and aerial parts of monocotyledonous species by 92.9-97.5%, which is comparable with the effect of glyphosate. CONCLUSIONS: Tetraoxanes constitute a new class of effective herbicides with great potential for commercial development.


Subject(s)
Herbicides/chemical synthesis , Plant Weeds/drug effects , Tetraoxanes/chemical synthesis , Cucumis sativus/drug effects , Glycine/analogs & derivatives , Glycine/pharmacology , Herbicides/pharmacology , Nicotinic Acids/pharmacology , Plant Development/drug effects , Sorghum/drug effects , Tetraoxanes/pharmacology , Glyphosate
17.
Parasitol Int ; 64(1): 113-7, 2015 Feb.
Article in English | MEDLINE | ID: mdl-25449979

ABSTRACT

We have reported that two endoperoxides, N-89 and N-251, synthesized in 2001, possess potent antimalarial activities. Aiming at their eventual use for curing malaria in humans, we have been investigating various aspects of their antimalarial actions. Here we show that N-89 and N-251 inhibit the growth of Plasmodium falciparum within human erythrocytes in vitro at its lifecycle stage 'trophozoite' specifically. It is known that artemisinin compounds, which are currently used for curing malaria, have other stage-specificities. Therefore, it is likely that the antimalarial mechanism of N-89 and N-251 differs from those of artemisinin compounds. As malaria parasites resistant to artemisinin-based combination therapy are currently emerging in some tropical regions, N-89 and N-251 are candidates for overcoming these new problems.


Subject(s)
Antimalarials/pharmacology , Heterocyclic Compounds, 2-Ring/pharmacology , Plasmodium falciparum/drug effects , Spiro Compounds/pharmacology , Tetraoxanes/pharmacology , Animals , Antimalarials/chemical synthesis , Artemisinins/pharmacology , Drug Resistance, Multiple , Erythrocytes/parasitology , Humans , Malaria/parasitology , Parasitic Sensitivity Tests , Plasmodium falciparum/growth & development , Trophozoites/drug effects , Trophozoites/ultrastructure
18.
J Pharm Biomed Anal ; 97: 178-83, 2014 Aug.
Article in English | MEDLINE | ID: mdl-24876068

ABSTRACT

The chromatographic behavior of mixed 1,2,4,5-tetraoxanes, cholic and deoxycholic acid derivatives with distinct biological activity, was examined by high-performance thin-layer chromatography in order to correlate their structure and retention. Chromatographic systems were consisted of RP-18 or CN-silica as stationary phase, and binary mixtures of water with methanol, dioxane or acetone as mobile phase. Based on the respective retentions, the lipophilicity of the investigated compounds was determined. Multiple linear regression and partial least squares have been used to select variables that best describe the behavior of the investigated compounds in chromatographic systems and to quantify influences of most important parameters. The validation and cross-validation of the QSRR model suggest its applicability for prediction and understanding of retention of congeners. The models indicate the importance of nonpolar properties of the solutes and their ability for hydrophobic interactions, as well as the importance of proton donating abilities, hydrophilic and π interactions pointing out on that way the possible separation mechanism in the studied chromatographic systems. Observed correlations between structure and biological activity of mixed 1,2,4,5-tetraoxanes, indicate that the antimalarial activity against W2 and D6 Plasmodium falciparum strains, is governed by hydrophobic feature (measured with lipophilicity parameter), hydrophilic feature (measured with HLB, %HS, HB and HBA descriptors), and electronic feature (HOMO).


Subject(s)
Antimalarials/chemistry , Antimalarials/pharmacology , Hydrophobic and Hydrophilic Interactions , Plasmodium falciparum/drug effects , Tetraoxanes/chemistry , Tetraoxanes/pharmacology , Chromatography, Thin Layer , Models, Chemical , Molecular Structure , Quantitative Structure-Activity Relationship
19.
J Med Chem ; 57(11): 4916-23, 2014 Jun 12.
Article in English | MEDLINE | ID: mdl-24824551

ABSTRACT

The use of artemisinin or other endoperoxides in combination with other drugs is a strategy to prevent development of resistant strains of Plasmodium parasites. Our previous work demonstrated that hybrid compounds, comprising endoperoxides and vinyl sulfones, were capable of high activity profiles comparable to artemisinin and chloroquine while acting through two distinct mechanisms of action: oxidative stress and falcipain inhibition. In this study, we adapted this approach to a novel class of falcipain inhibitors: peptidomimetic pyrimidine nitriles. Pyrimidine tetraoxane hybrids displayed potent nanomolar activity against three strains of Plasmodium falciparum and falcipain-2, combined with low cytotoxicity. In vivo, a decrease in parasitemia and an increase in survival of mice infected with Plasmodium berghei was observed when compared to control. All tested compounds combined good blood stage activity with significant effects on liver stage parasitemia, a most welcome feature for any new class of antimalarial drug.


Subject(s)
Antimalarials/chemical synthesis , Nitriles/chemical synthesis , Peptidomimetics/chemical synthesis , Pyrimidines/chemical synthesis , Tetraoxanes/chemical synthesis , Animals , Antimalarials/chemistry , Antimalarials/pharmacology , Cell Line , Cysteine Endopeptidases/metabolism , Cysteine Proteinase Inhibitors/chemical synthesis , Cysteine Proteinase Inhibitors/chemistry , Cysteine Proteinase Inhibitors/pharmacology , Humans , Malaria/drug therapy , Mice, Inbred C57BL , Molecular Docking Simulation , Nitriles/chemistry , Nitriles/pharmacology , Oxidative Stress , Peptidomimetics/chemistry , Peptidomimetics/pharmacology , Plasmodium berghei , Plasmodium falciparum/drug effects , Pyrimidines/chemistry , Pyrimidines/pharmacology , Structure-Activity Relationship , Tetraoxanes/chemistry , Tetraoxanes/pharmacology
20.
Mini Rev Med Chem ; 14(2): 123-35, 2014 Feb.
Article in English | MEDLINE | ID: mdl-24456270

ABSTRACT

With the emergence of resistance to artemesinin, the need for new antimalarial compounds is pressing. Several research groups have made significant contributions to the exploration of the use of 1,2,4,5-tetraoxanes and 1,2,4- trioxanes as synthetic analogues of artemesinin. This short review highlights the recent developments in this field detailing both biological results and useful synthetic methodology. In addition, the current understanding of the mode of action of this class of compounds has been described.


Subject(s)
Antimalarials/chemistry , Antimalarials/pharmacology , Malaria/drug therapy , Peroxides/chemistry , Plasmodium falciparum/drug effects , Plasmodium vivax/drug effects , Tetraoxanes/pharmacology , Antimalarials/chemical synthesis , Humans , Molecular Structure , Parasitic Sensitivity Tests , Structure-Activity Relationship , Tetraoxanes/chemical synthesis , Tetraoxanes/chemistry
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