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.     

Synthesis of symmetrically and asymmetrically branched pegylating reagents.

A solution-phase procedure using an orthogonal protection scheme was developed for the synthesis of a novel family of multi-pegylating reagents. The procedure was exemplified by the synthesis of bis- and tris-pegylating reagents prepared by stepwise insertion of the poly(ethylene glycol) units thereby enabling the preparation of both symmetrical and asymmetrical pegylating reagents. Asymmetrical pegylation and tris-pegylation of peptides and proteins introduces new variables for use in the optimization of pegylated peptides and proteins. These reagents are ideally suited for conjugation to peptides and proteins as they possess a required functional group and will be useful intermediates for the synthesis of a new generation of pegylated products. Tris-pegylation can also provide more effective protection from proteolysis by shielding the protein surface from approaching macromolecules. To illustrate this potential, conditions were developed for the successful coupling of the tris-pegylating reagent to a model pentapeptide.     

Synthesis and photodynamic activity of novel asymmetrically substituted fluorinated phthalocyanines

A series of asymmetrically substituted dodecafluorinated phthalocyanines has been synthesized via the Kobayashi ring expansion reaction of the corresponding dodecafluorinated boron subphthalocyanine with differently substituted 1,3-diiminoisoindolines. The mild reaction conditions employed during this ring expansion reaction gave rise exclusively to 3:1 asymmetrically substituted dodecafluorinated phthalocyanines. Metal insertion into the metal-free phthalocyanines was accomplished by heating at 40 degrees C in N,N-dimethylformamide in the presence of zinc bromide. The resulting zinc dodecafluorophthalocyanines were formulated as Cremophor EL oil-water emulsions and evaluated as photosensitizers in vitro against EMT-6 mouse mammary tumor cells. As compared to the previously studied zinc hexadecafluorophthalocyanine, these new asymmetrical zinc dodecafluorophthalocyanines exhibited improved photodynamic activity.     

Synthesis and antimalarial activity of 6-cycloalkylvinyl substituted 1,2,4-trioxanes

6-Cycloalkylvinyl substituted 1,2,4-trioxanes 6-15 have been prepared and tested against multi-drug resistant Plasmodium yoelii in mice. The most active trioxane 11 provides 80% protection to the treated mice. Further derivatization of 11 leads to decrease in antimalarial activity.     

Synthesis and evaluation of NO-release from symmetrically substituted furoxans

A series of symmetrically substituted dibenzoyl furoxans were synthesized and investigated for their potential to release nitric oxide, which plays a key role in the nervous and cardiovascular systems. Cysteine was employed to promote nitric oxide release from furoxan via the formation of an S-nitrosothiol intermediate. Transition metal ion-mediated S-nitrosocysteine decomposition liberates nitric oxide that, in aqueous aerobic solutions, is converted to reactive nitrogen oxide species. The percent nitric oxide released was quantified colorimetrically by the Griess reagent system.     

Synthesis and antimalarial activity of chain substituted pivaloyloxymethyl ester analogues of Fosmidomycin and FR900098

Fosmidomycin is a promising antimalarial drug candidate with a unique chemical structure and a novel mode of action. Chain substituted pivaloyloxymethyl ester derivatives of Fosmidomycin and its acetyl analogue FR900098 have been synthesized and their in vitro antimalarial activity versus the Chloroquine sensitive strain 3D7 of Plasmodium falciparum has been determined.     

Synthesis,antimalarial and antitubercular activity of acetylenic chalcones

A series of acetylenic chalcones were evaluated for antimalarial and antitubercular activity. The antimalarial data for this series suggests that growth inhibition of the W2 strain of Plasmodium falciparum can be imparted by the introduction of a methoxy group ortho to the acetylenic group. Most compounds were more active against non-replicating than replicating cultures of Mycobacterium tuberculosis H₃₇Rv, an unusual pattern with respect to existing anti-TB agents.     

Synthesis,antimalarial activity,and cellular toxicity of new arylpyrrolylaminoquinolines

A set of nine new arylpyrrolyl derivatives of 7-chloro-4-aminoquinoline, characterized by different substituents on the phenyl ring or different distance between the pyrrolic nitrogen and the 4-aminoquinoline, has been synthesized and tested for their activity against D-10 (CQ-S) and W-2 (CQ-R) strains of Plasmodium falciparum. All compounds exhibited activity against the CQ-S strain in the low nM range, comparable to that of chloroquine. Some of them were also highly active against the CQ-R strain and not toxic against normal cells. The antimalarial activity of this new class of compounds seems to be related to the inhibition of heme detoxification process of parasites, as in the case of chloroquine.     

Synthesis and antimalarial activity of new haemanthamine-type derivatives

Thirty one derivatives were prepared from the natural alkaloids haemanthamine (1), haemanthidine (2) and 11-hydroxyvittatine (3). They were evaluated for their in vitro antimalarial activity against chloroquine-sensitive strains of Plasmodium falciparum and some structure-activity relationships were outlined. For haemanthamine derivatives having a methoxy group at C-3, the presence of a free hydroxyl group at C-11 is important for the activity. The double bond at C-1-C-2 plays also an important role to achieve good inhibitory activity. Compound 35 with two nicotinate groups at C-3 and at C-11 was the most active compound with a IC(50)=0.8±0.06μM.     

Synthesis,antimicrobial and antiviral activity of substituted benzimidazoles

In the present study we have synthesized (4-nitrophenyl)-[2-(substituted phenyl)-benzoimidazol-1-yl]-methanones, (2-bromophenyl)-[2-(substituted phenyl)-benzoimidazol-1-yl]-methanone analogues (1–14) and evaluated them for their antimicrobial and antiviral potential. The results of antimicrobial screening indicated that none of the synthesized compounds were effective against the tested bacterial strains. Compounds 3, 11, 13 and compounds 5, 11, 12 were found to be active against Aspergillus niger and Candida albicans respectively, and may be further developed as antifungal agents. Furthermore, evaluation against a panel of different viruses pointed out the selective activity of compounds 5 and 6 against vaccinia virus and Coxsackie virus B4.     

Synthesis, antimalarial activity and inhibition of haem detoxification of novel bisquinolines

The synthesis of novel bisquinoline compounds comprising 4-(4-diethylamino-1-methylbutyl)aminoquinoline units joined through the 2-position by a (CH(2))(n) linker is described. Their ability to inhibit the growth of both chloroquine-sensitive (D10) and chloroquine-resistant (K1) strains of Plasmodium falciparum, the hydrogen peroxide-mediated pathway for decomposition of haem, and the conversion of haem to beta-haematin have been measured. The activity was affected by the length of the linker and the most active (6c, n=12) showed effects similar to chloroquine in three of the assays. However, it was even more active against the resistant strain [IC(50), 17 nM (K1); 43 nM (D10)], much superior to chloroquine (IC(50), 540 nM) and slightly better than mefloquine (IC(50), 30 nM) in this regard.     

Synthesis, antimalarial activity and cytotoxicity of 10-aminoethylether derivatives of artemisinin

In this study, a series of 11 10-aminoethylether derivatives of artemisinin were synthesised and their antimalarial activity against both the chloroquine sensitive (D10) and resistant (Dd2) strains of Plasmodium falciparum was determined. The compounds were prepared by introducing aliphatic, alicyclic and aromatic amine groups with linkers of various chain lengths through an ethyl ether bridge at C-10 of artemisinin using conventional and microwave assisted syntheses, and their structures were confirmed by NMR and HRMS. All derivatives proved to be active against both strains of the parasite. The highest overall activity was displayed by the short chain aromatic derivative 8 (IC(50)=1.44nM), containing only one nitrogen atom, while long chain polyamine derivatives were found to have the lowest activity against both strains. An interesting correlation between the IC(50), pK(a) values and resistance index (RI) was found.     

Synthesis of substituted indole derivatives as a new class of antimalarial agents

A series of substituted indole derivatives were synthesized and evaluated for their in vitro antimalarial activity against P. falciparum. Out of the 24 compounds synthesized six compounds have shown MIC of 1 microg/mL. These compounds are in vitro several folds more active than pyrimethamine.     

Synthesis and antiviral activity of substituted quercetins

Influenza viruses are important pathogens that cause respiratory infections in humans and animals. In addition to vaccination, antiviral drugs against influenza virus play a significant role in controlling viral infections by reducing disease progression and virus transmission. Plant derived polyphenols are associated with antioxidant activity, anti-carcinogenic, and cardio- and neuro-protective actions. Some polyphenols, such as resveratrol and epigallocatechin gallate (EGCG), showed significant anti-influenza activity in vitro and/or in vivo. Recently we showed that quercetin and isoquercetin (quercetin-3-β-d-glucoside), a glucoside form of quercetin, significantly reduced the replication of influenza viruses in vitro and in vivo (isoquercetin). The antiviral effects of isoquercetin were greater than that of quercetin with lower IC(50) values and higher in vitro therapeutic index. Thus, we investigated the synthesis and antiviral activities of various quercetin derivatives with substitution of C3, C3', and C5 hydroxyl functions with various phenolic ester, alkoxy, and aminoalkoxy moieties. Among newly synthesized compounds, quercetin-3-gallate which is structurally related to EGCG showed comparable antiviral activity against influenza virus (porcine H1N1 strain) to that of EGCG with improved in vitro therapeutic index.     

Kinetics of the subtransition of asymmetrically substituted phosphatidylcholines

The thermodynamics and kinetics of the subtransition L epsilon----P beta of sonicated unilamellar vesicles of 1-myristoyl-2-stearoylphosphatidylcholine (1M-2S-PC) and of 1-stearoyl-2-myristoylphosphatidylcholine (1S-2M-PC) were studied by equilibrium cooling curves and temperature-jump relaxation spectrometry with an anthracenophane cryptand as a mobile fluorescent probe. The unilamellar vesicles exhibit the midpoint temperature TsII of the subtransition about 10 degrees C below the respective main transition. The kinetics of the subtransition in the time range between 10(-4) and 10(3) s is characterized by a cooperative relaxation process in the range of milliseconds and a further noncooperative process in the range of seconds. The slow process is assigned to the rearrangement of lattice defects. The fast process is evaluated in terms of a cyclic reaction scheme that consists of two pathways for the biomolecular association of probe and vesicle coupled with the conformational change of the lipid matrix during the subtransition. The analysis reveals that the fast process comprises the nucleation and growth of cluster. The cooperative lattice transformation of the subtransition follows a first-order rate law. The rate constants at TsII are 70 s-1 for 1S-2M-PC and 170 s-1 for 1M-2S-PC. Since the plots of the relaxation time vs. the degree of transition are in accordance with the predictions of the linear Ising model, it is concluded that clusters are propagated anisotropically in a linear fashion; e.g., fluidlike P beta conformations grow along the ripple.     

Synthesis,antimalarial activity and cytotoxic potential of new monocarbonyl analogues of curcumin

A series of novel monocarbonyl analogues of curcumin have been designed, synthesized and tested for their activity against Molt4, HeLa, PC3, DU145 and KB cancer cell lines. Six of the analogues showed potent cytotoxicity towards these cell lines with IC₅₀ values below 1 μM, which is better than doxorubicin, a US FDA approved drug. Several analogues were also found to be active against both CQ-resistant (W2 clone) and CQ-sensitive (D6) strains of Plasmodium falciparum in an in-vitro antimalarial screening. This level of activity warrants further investigation of the compounds for development as anticancer and antimalarial agents.     

Synthesis,in vitro antimalarial activity and cytotoxicity of novel 4-aminoquinolinyl-chalcone amides

A series of 4-aminoquinolinyl-chalcone amides 11–19 were synthesized through condensation of carboxylic acid-functionalized chalcone with aminoquinolines, using 1,1′-carbonyldiimidazole as coupling agent. These compounds were screened against the chloroquine sensitive (3D7) and chloroquine resistant (W2) strains of Plasmodium falciparum. Their cytotoxicity towards the WI-38 cell line of normal human fetal lung fibroblast was determined. All compounds were found active, with IC₅₀ values ranging between 0.04–0.5 μM and 0.07–1.8 μM against 3D7 and W2, respectively. They demonstrated moderate to high selective activity towards the parasitic cells in the presence of mammalian cells. However, amide 15, featuring the 1,6-diaminohexane linker, despite possessing predicted unfavourable aqueous solubility and absorption properties, was the most active of all the amides tested. It was found to be as potent as CQ against 3D7, while it displayed a two-fold higher activity than CQ against the W2 strain, with good selective antimalarial activity (SI = 435) towards the parasitic cells. During this study, amide 15 was thus identified as the best drug-candidate to for further investigation as a potential drug in search for new, safe and effective antimalarial drugs.     

Synthesis, characterization and antimalarial activity of new chromium arene-quinoline half sandwich complexes

Organometallic analogs of chloroquine (CQ) are of interest as drug candidates that may be able to overcome the widespread chloroquine resistance developed by malaria parasites. Two new chromium arene CQ-analogs: [η⁶-N-(7-chloroquinolin-4-yl)-N′-(2-dimethylamino-methylbenzyl)-ethane-1,2-diamine]tricarbonylchromium 4 and [η⁶-N-(7-chloroquinolin-4-yl)-N′-(2-dimethylaminobenzyl)-ethane-1,2-diamine]tricarbonylchromium 9 have been synthesized and characterized. In addition, X-ray crystal structures of the intermediates (η⁶-benzyldimethylamine)tricarbonylchromium 2, [η⁶-2-((dimethylamino)methyl) benzaldehyde]tricarbonylchromium 3 and p-(η⁶-dimethylaminobenzaldehyde)tricarbonyl chromium 8 are reported. Compound 4 was more active than chloroquine against both CQ-sensitive and CQ-resistant strains of Plasmodium falciparum when antimalarial activity was tested in vitro. The activity of 4 against the CQ-resistant parasite strain was twice as high as for the organic ligand alone (IC₅₀ values of 33.9 nM versus 63.1 nM).     

Synthesis and antimalarial activity of calothrixins A and B, and their N-alkyl derivatives

We synthesized calothrixin B using our developed biomimetic method and derived N-alkyl-calothrixins A and B. The in vitro antimalarial activity of the calothrixin derivatives, including calothrixins A and B, against the Plasmodium falciparum FCR-3 strain was evaluated. All test compounds exhibited antimalarial activity over a concentration range of 6.4×10(-6)-1.2×10(-7) M.     

Synthesis and antimalarial activity of a new series of trioxaquines

Trioxanes 8a-b, easily accessible in two steps from allylic alcohol 6a-b, on reductive amination with 4-aminoquinolines 4a-c furnish a new series of trioxaquines 9a-b, 10a-b, 11a-b in 32-77% yields. Dicitrate salts of these trioxaquines have been evaluated for antimalarial activity against multidrug resistant Plasmodium yoelii in mice model.