Synthesis, thermal stability, antimalarial activity of symmetrically and asymmetrically substituted tetraoxanes

Symmetrically and asymmetrically substituted 1,2,4,5-tetraoxanes were synthesized by the oxidative system H(2)O(2)/TFE in presence of MeReO(3) as a catalyst. All of the synthesized compounds were characterized spectroscopically, and evaluated for cytotoxicity, and antimalarial activity. Several of these tetraoxanes exhibited in vitro antimalarial activity without showing any cytotoxicity. Thermal stability of these compounds was studied by differential scanning calorimetry.     

An efficient route into synthetically challenging bridged achiral 1,2,4,5-tetraoxanes with antimalarial activity

Here we present an efficient route into synthetically challenging bridged 1,2,4,5-tetraoxanes. The key to the success of this route is the use of H(2)O(2) and catalytic I(2) to form the gem-dihydroperoxide followed by a Ag(2)O mediated alkylation using 1,3-diiodopropane. Using this methodology a range of bridged tetraoxanes which display good in vitro antimalarial activity were synthesized.     

Antimalarial and antiproliferative evaluation of bis-steroidal tetraoxanes

Several cis and trans bis-steroidal 1,2,4,5-tetraoxanes possessing amide terminus were synthesised and evaluated as antimalarials and antiproliferatives. The compounds exhibited submicromolar antimalarial activity against Plasmodium falciparum D6 and W2 strains. The existence of HN-C(O) moiety was found necessary for pronounced antimalarial and antiproliferative activity. In antiproliferative screen, the trans tetraoxane 6 was found to exhibit a pronounced cytotoxicity on 14 cancer cell lines. In addition, tetraoxanes 11 and 12 exhibited significant cytotoxic activity too; microscopic examination of treated HeLa cells showed morphological appearance reminiscent for apoptosis (condensed and/or fragmented nuclei).     

The activity of dispiro peroxides against Fasciola hepatica

Dispiro 1,2,4-trioxanes and 1,2,4,5-tetraoxanes had superior efficacy against Fasciola hepatica than the corresponding ozonides (1,2,4-trioxolanes). For highest efficacy, spiroadamantane and carboxymethyl substructures were required. Three compounds completely cured F. hepatica-infected mice at single oral doses of 50mg/kg and two were partially curative at single doses of 25mg/kg.     

Influence of stereoisomer of dispiro-1,2,4,5-tetraoxanes on their binding mode with heme and on antimalarial activity: molecular docking studies

Based on the fact that different isomers may exhibit substantial distinct activities, quantum chemical calculations and automated molecular docking simulations were carried out for 13 dispiro-1,2,4,5-tetraoxane compounds, which experimentally exist as a mixture of several isomers, to elucidate the most probable isomer(s) responsible for their antimalarial activity. The results indicate significant effects of stereoisomer on the binding mode and the activity. Moreover, the antimalarial potency of each compound can be described by the docking results. Compounds 1, 2, 4, 5, 7, and 9 have the most probable isomers coordinate suitably with heme iron and hence they have high activities while the most probable isomer in compounds 3 and 8 could not bind appropriately to heme yielding only moderate activities. On the other hand, the steric hindrance in compounds 11-13 prevents an approach of heme iron to peroxide bonds resulting in a devoid of antimalarial activity. However, compounds 6 and 10 with isopropyl substituents exhibit a different docking character, which is possibly caused by a limitation in molecular flexibility of the available docking technique. Our results can be used as a guideline for stereochemical control in synthesis process to improve drug's potency.     

Synthesis and evaluation of the antimalarial,anticancer, and caspase 3 activities of tetraoxane dimers

The synthesis of a range of mono spiro and dispiro 1,2,4,5-tetraoxane dimers is described. Selected molecules were examined in in vitro assays to determine their antimalarial and anticancer potential. Our studies reveal that several molecules possess potent nanomolar antimalarial and single digit micromolar antiproliferative IC₅₀s versus colon (HT29-AK and leukemia (HL60) cell lines.     

Antiprotozoal and antimicrobial activities of O-alkylated and formylated acylphloroglucinols

In the present article, we examined the antileishmanial, antimalarial, antibacterial, and antifungal activities of several newly synthesized O-alkylated phloroglucinol compounds (11-19) which are analogues of the naturally occurring antimalarial compound 1. Analogues 12 and 16 exhibited antileishmanial activity against, Leishmania donovani promastigotes with IC(50)s of 5.3 and 4.2microg/mL, respectively. Naturally occurring monomeric formylated acylphloroglucinol compounds, grandinol (2), jensenone (3), and their analogues (29-37), were also synthesized and evaluated for antileishmanial, antimalarial, antibacterial, and antifungal activities. Amongst these, both grandinol and jensenone showed mild to moderate antibacterial, antifungal, and antileishmanial activities. Jensenone (3) was effective against Candida albicans with an IC(50) of 5.5microg/mL but was ineffective against Cryptococcus neoformans and methicillin-resistant Staphylococcus aureus. Among the analogues, 34 was the most active against C. albicans and C. neoformans with IC(50)s of 2.0 and 2.5microg/mL, respectively, and was fungicidal toward Candida albicans.     

Synthesis and blood-schizontocidal antimalarial activities of 2-substituted/2,5-disubstituted-8-quinolinamines and some of their amino acid conjugates

Thirteen new analogues (32-40, 45-48) of recently discovered potent blood-schizontocidal antimalarial agent, 2-tert-butylprimaquine (2) are synthesized and evaluated for in vivo antimalarial activities against drug-sensitive P. berghei strain and multi-drug resistant P. yoelii nigeriensis strain. Two of the amino acid conjugates (47-48) have exhibited potent antimalarial activities similar to that of 2 against both drug-sensitive and multi-drug resistant strains.     

Bioactive deoxypreussomerins and dimeric naphthoquinones from Diospyros ehretioides fruits: deoxypreussomerins may not be plant metabolites but may be from fungal epiphytes or endophytes

Deoxypreussomerin derivatives, palmarumycins JC1 (1) and JC2 (2), and two dimeric naphthoquinones, isodiospyrin (3) and its new derivative isodiospyrol A (4), were isolated from dried fruits of Diospyros ehretioides. Structures of the isolated compounds were elucidated by spectroscopic analyses. Palmarumycins were not found in the extract of freshly collected fruits; however, they were present in dried fruit extract. The absence of palmarumycins in fresh fruits of D. ehretioides, together with the chemotaxonomic point of view, we proposed that palmarumycins JC1 (1) and JC2 (2) are more likely to be fungal metabolites, i.e., endophytes or epiphytes. The isolation of palmarumycins 1 and 2 from dried D. ehretioides fruits could be reproducible; both plant samples collected in the years 2002 and 2004 provided the same result, and, therefore, symbiont fungal strains should be specific to the plant host, D. ehretioides, and they can grow on the fruits during drying the sample. Palmarumycin JC1 (1) did not exhibit antimalarial, antifungal, antimycobacterial, and cytotoxic activities. Palmarumycin JC2 (2) exhibited antimalarial (IC50 4.5 microg/ml), antifungal (IC50 12.5 microg/ml), antimycobacterial (MIC 6.25 microg/ml), and cytotoxic (IC50 11.0 microg/ml for NCI-H187 cell line) activities. In our bioassay systems, isodiospyrin (3) did not exhibit antimycobacterial, antifungal, antimalarial, and cytotoxic activities. Isodiospyrol A (4) exhibited antimalarial (IC50 2.7 microg/ml) and antimycobacterial (MIC 50 microg/ml) activities, but was inactive towards Candida albicans. Compound 4 also exhibited cytotoxicity against BC cells (IC50 12.3 microg/ml), but not towards KB and Vero cell lines.     

Iodine-catalyzed one-pot synthesis and antimalarial activity evaluation of symmetrically and asymmetrically substituted 3,6-diphenyl[1,2,4,5]tetraoxanes

A novel iodine-catalyzed one-pot synthesis of symmetrically and asymmetrically substituted 3,6-diphenyl-[1,2,4,5]tetraoxanes is described. The synthetic protocol is general with substituted benzaldehydes and proceeds well under acidic conditions. Total 17 tetraoxanes have been prepared during this study and some of these compounds exhibit promising antimalarial activity. None of the compounds shows any toxicity against vero cells.     

Biologically active alkylated coumarins from Kayea assamica

Four coumarin derivatives, theraphins A (1), B (2), C (3), and D (4), along with three known xanthones, 2-hydroxyxanthone, 1,7-dihydroxyxanthone, and 5-hydroxy-1-methoxyxanthone, were isolated from the bark of Kayea assamica (Clusiaceae) native to Myanmar. Their structures were determined using spectroscopic and chemical techniques. The absolute configuration of 1 was established by the modified Mosher ester method. Theraphins A (1), B (2), and C (3) exhibited good cytotoxicity against Col2, KB, and LNCaP human cancer cell lines. Theraphin D (4) showed mild activity only against the KB cell line. The coumarins also exhibited mild antimalarial activities.     

Synthesis, antimalarial, antileishmanial, antimicrobial, cytotoxicity, and methemoglobin (MetHB) formation activities of new 8-quinolinamines

We report the synthesis, in vitro antiprotozoal (against Plasmodium and Leishmania), antimicrobial, cytotoxicity (Vero and MetHb-producing properties), and in vivo antimalarial activities of two series of 8-quinolinamines. N1-{4-[2-(tert-Butyl)-6-methoxy-8-quinolylamino]pentyl}-(2S/2R)-2-aminosubstitutedamides (21-33) and N1-[4-(4-ethyl-6-methoxy-5-pentyloxy-8-quinolylamino)pentyl]-(2S/2R)-2-aminosubstitutedamides (51-63) were synthesized in six steps from 6-methoxy-8-nitroquinoline and 4-methoxy-2-nitro-5-pentyloxyaniline, respectively. Several analogs displayed promising antimalarial activity in vitro against Plasmodium falciparum D6 (chloroquine-sensitive) and W2 (chloroquine-resistant) clones with high selectivity indices versus mammalian cells. The most promising analogs (21-24) also displayed potent antimalarial activity in vivo in a Plasmodium berghei-infected mouse model. Most interestingly, many analogs exhibited promising in vitro antileishmanial activity against Leishmania donovani promastigotes, and antimicrobial activities against a panel of pathogenic bacteria and fungi. Several analogs, notably 21-24, 26-32, and 60, showed less MetHb formation compared to primaquine indicating the potential of these compounds in 8-quinolinamine-based antimalarial drug development.     

Synthesis, antimalarial, antileishmanial, and antimicrobial activities of some 8-quinolinamine analogues

In the present communication, newly synthesized 8-quinolinamines (25-27) related to previously reported 2-tert-butylprimaquine (2) were evaluated for their in vitro antimalarial activity against chloroquine sensitive and resistant Plasmodium falciparum strains, in vivo antimalarial activity against P. berghei infected mice, in vitro antileishmanial activity against Leishmania donovani, in vitro antimicrobial activity against various fungi and bacteria, and cytotoxicity in a panel of mammalian cell lines. No promising cytotoxicities were observed for compounds reported herein. Analogue 25 was found to exhibit curative antimalarial activity at a dose of 25 mg/kg/dayx4 in a P. berghei infected mice model, and produced suppressive activity at a lower dose of 10 mg/kg/dayx4. In vitro antileishmanial activities (IC50 and IC90) comparable to standard drug pentamidine were exhibited by all synthesized 8-quinolinamines 25-27. At the same time, promising antibacterial and antifungal activities were also observed for synthesized compounds against a panel consisting of several bacteria and fungi.     

Antimalarial activity enhancement in hydroxymethylcarbonyl (HMC) isostere-based dipeptidomimetics targeting malarial aspartic protease plasmepsin

Plasmepsin (Plm) is a potential target for new antimalarial drugs, but most reported Plm inhibitors have relatively low antimalarial activities. We synthesized a series of dipeptide-type HIV protease inhibitors, which contain an allophenylnorstatine-dimethylthioproline scaffold to exhibit potent inhibitory activities against Plm II. Their activities against Plasmodium falciparum in the infected erythrocyte assay were largely different from those against the target enzyme. To improve the antimalarial activity of peptidomimetic Plm inhibitors, we attached substituents on a structure of the highly potent Plm inhibitor KNI-10006. Among the derivatives, we identified alkylamino compounds such as 44 (KNI-10283) and 47 (KNI-10538) with more than 15-fold enhanced antimalarial activity, to the sub-micromolar level, maintaining their potent Plm II inhibitory activity and low cytotoxicity. These results suggest that auxiliary substituents on a specific basic group contribute to deliver the inhibitors to the target Plm.     

A small library of trisubstituted pyrimidines as antimalarial and antitubercular agents

A small library of 20 trisubstituted pyrimidines were synthesized and evaluated for their in vitro antimalarial and antitubercular activities. Out of the total screened compounds, 16 compounds have shown in vitro antimalarial activity against Plasmodium falciparum in the range of 0.25-2microg/mL and 8 compounds have shown antitubercular activity against Mycobacterium tuberculosis H(37)Ra, at a concentration of 12.5microg/mL.     

Structure-activity relationships of antileishmanial and antimalarial chalcones

A series of oxygenated chalcones which have been evaluated earlier for antimalarial activity (Plasmodium falciparum K1) were tested for antileishmanial activity against Leishmania donovani amastigotes. A comparison of structure-activity relationships reveal that different physicochemical and structural requirements exist for these two activities. Antileishmanial activity is associated with less lipophilic chalcones, in particular those with 4'-hydroxyl-substituted B rings and hetero/polyaromatic A rings. In contrast, chalcones with good antimalarial activity have alkoxylated B rings and electron-deficient A rings. Visualization of the steric and electrostatic fields generated from comparative molecular field analysis (CoMFA) indicate that the ring A of chalcones make a more significant contribution to antileishmanial activity while both rings A and B are important for antimalarial activity. Despite different requirements, two alkoxylated chalcones (8, 19) were identified which combined good antimalarial and antileishmanial activities.     

1,2,4-Triazino-[5,6b]indole derivatives: effects of the trifluoromethyl group on in vitro antimalarial activity

In an attempt to search for new and alternative antimalarial agents, a series of unsubstituted and 6-trifluoromethyl-1,2,4-triazino[5,6b]indole and 5H-1,2,4-triazolo[1',5',2,3]-1,2,4-triazino[5,6b]indole derivatives were synthesized and their chemical structures confirmed by 1H NMR and 13C NMR, elemental, IR and mass spectrophotometric analyses. The in vitro antimalarial activities of these compounds were evaluated against the chloroquine-sensitive (D10) and the chloroquine-resistant (RSA11) strains of Plasmodium falciparum. The 1,2,4-triazino[5,6b]indole derivatives (4, 6 and 8) with a trifluoromethyl group at position 6 exhibit increased in vitro activity when compared to the unsubstituted analogues, which are all devoid of activity. The presence of the trifluoromethyl group in the 5H-1,2,4-triazolo[1',5',2,3]-1,2,4-triazino[5,6b]indole ring system leads to compounds with diminished antimalarial activity when compared to the corresponding unsubstituted analogues. The compounds associate with ferriprotoporphyrin IX and interact with DNA to more or less the same extent.     

In vitro antimalarial activity of ICL670: a further proof of the correlation between inhibition of β-hematin formation and of peroxidative degradation of hemin

Iron chelators such as deferiprone, deferoxamine (DFO) and ICL670 (deferasirox) have previously been shown to display in vitro and/or in vivo antimalarial activities. To gain further insight in their antimalarial mechanism of action, their activities on inhibition of β-hematin formation and on both peroxidative and glutathione (GSH)-mediated degradation of hemin were investigated. Neither deferiprone nor DFO were able to inhibit β-hematin formation while ICL670 activity nearly matched that of chloroquine (CQ). Peroxidative degradation of hemin was also only strongly inhibited by both CQ and ICL670, the latter being significantly more efficient at pH 5.2. All iron chelators displayed minor, if any, inhibitory activity on GSH-mediated degradation of hemin. Discrepancies in the results obtained for the three iron chelators show that iron chelation is not the main driving force behind interference with heme degradation. Deferiprone, DFO and ICL670 share little structural community but both ICL670 and antimalarial ursolic acid derivatives (previously shown to block β-hematin formation and the peroxidative degradation of hemin) have hydrophobic groups and hydroxyphenyl moieties. These similarities in structures and activities further back up a possible two-step mechanism of action previously proposed for ursolic acid derivatives (Mullié et al., 2010) implying (1) stacking of an hydrophobic structure to hemin and (2) additive protection of hemin ferric iron from H₂O₂ by hydroxyphenyl groups through steric hindrance and/or trapping of oxygen reactive species in the direct neighborhood of ferric iron. These peculiar antimalarial mechanisms of action for ICL670 warrant further investigations and development.     

Effect of functional group polarity on the antimalarial activity of spiro and dispiro-1,2,4-trioxolanes

Based on the structures of several lipophilic trioxolane antimalarial prototypes, we set out to determine which functional groups were associated with good antimalarial profiles and identify more polar (lower LogP/LogD) lead compounds with good physicochemical properties. More lipophilic trioxolanes tended to have better oral activities than their more polar counterparts. Trioxolanes with a wide range of neutral and basic, but not acidic, functional groups had good antimalarial profiles.