Maria de Lourdes G. Ferreira

New compounds hybrids 1h-1,2,3-triazole-quinoline against Plasmodium falciparum.

Malaria is one of the most prevalent parasitic diseases in the world. The global importance of this disease, current vector control limitations, and the absence of an effective vaccine make the use of therapeutic antimalarial drugs the main strategy to control malaria. Chloroquine is a cost‐effective antimalarial drug with a relatively robust safety profile, or therapeutic index. However, chloroquine is no longer used alone to treat patients with Plasmodium falciparum due to the emergence and spread of chloroquine‐resistant strains, which have also been reported for Plasmodium vivax. However, the activity of 1,2,3‐triazole derivatives against chloroquine‐sensitive and chloroquine‐resistant strains of P. falciparum has been reported in the literature. To enhance the anti‐P. falciparum activity of quinoline derivatives, we synthesized 11 new quinoline‐1H‐1,2,3‐triazole hybrids with different substituents in the 4‐positions of the 1H‐1,2,3‐triazole ring, which were assayed against the W2‐chloroquine‐resistant P. falciparum clone. Six compounds exhibited activity against the P. falciparum W2 clone, chloroquine‐resistant, with IC50 values ranging from 1.4 to 46 μm. None of these compounds was toxic to a normal monkey kidney cell line, thus exhibiting good selectivity indexes, as high 351 for one compound (11).

Synthesis and anti-mycobacterial activity of novel amino alcohol derivatives

Thirteen new hydroxyethylamines have been synthesized from reactions of (2S,3S)Boc-phenylalanine epoxide, piperonylamine and arenesulfonyl chlorides in good yields. These compounds were evaluated as antibacterial agents against Mycobacterium tuberculosis H37Rv using the Alamar Blue susceptibility test and their activity expressed as the minimum inhibitory concentration (MIC) in μM. Two amino alcohols displayed significant activity when compared with first line drug ethambutol (EMB). Therefore this class of compounds could be a good starting point to develop new lead compounds in the treatment of tuberculosis.

Anti-Plasmodium falciparum activity of quinoline–sulfonamide hybrids

Fifteen quinoline-sulfonamide hybrids, with a 7-chloroquinoline moiety connected by a linker group to arylsulfonamide moieties with different substituents in the 4-position were synthesized and assayed against Plasmodium falciparum. The compounds displayed high schizonticidal blood activity in vitro, with IC50 values ranging from 0.05 to 1.63 μM, in the anti-HPR2 assay against clone W2-chloroquine-resistant; ten of them showed an IC50 (ranging from 0.05 to 0.40 μM) lower than that of chloroquine and sulfadoxine. Among them, two compounds inhibited Plasmodium berghei parasitemia by 47% and 49% on day 5 after mice inoculation. The most active, in vivo, hybrid 13 is considered to be a new prototype for the development of an antimalarial drug against chloroquine-resistant parasites.

Design, synthesis and anti-P. falciparum activity of pyrazolopyridine-sulfonamide derivatives.

Ten 1-phenyl-1H-pyrazolo[3,4-b]pyridine derivatives connected by a linker group to benzenesulfonamide moieties with different substituents in the 4-position were synthesized and assayed against Plasmodium falciparum. These ten compounds exhibited activity in vitro against the chloroquine-resistant clone W2 with IC50 values ranging from 3.46 to 9.30μM. The most active derivatives with substituent R2=Cl or CH3 at the benzenesulfonamide moiety exhibited the lowest IC50. Compounds with an R1=CO2Et substituent at the 5-position of the 1H-pyrazolo[3,4-b]pyridine ring presented lower activity than those with a CN substituent. The 1H-pyrazolo[3,4-b]pyridine system appears to be promising for further studies as an antimalarial for overcoming the burden of resistance in P. falciparum.

Structures of 1-(substituted-phenyl)-4-hydroxymethyl-and -4-fluoromethyl-1,2,3-triazoles

Abstract The crystal structures of 4-FCH2-1-(4-X-phenyl)-triazole (1: X = Cl, Br and CN) and 4-HOCH2-1-(4-X-phenyl)-triazole (2: X = Cl, Br and CN) are reported. Each of the pairs, (1: X = Cl) and (1: X = Br) and (2: X = Cl) and (2: X = Br), are isostructural. There are no strong intermolecular interactions in any of the compounds 1. Present in (1: X = CN), are C—H···N, C—H···F and C—H···π hydrogen bonds, and π···π stacking interactions, while in (2: X = Cl and Br) present are C—H···N, C—H···F and C—X···π, hydrogen bonds, with resulting different supramolecular arrays produced for the halo, on one hand, and cyano derivatives, on the other. The hydroxyl-triazole nitrogen interactions in 2 are the strongest intermolecular interactions present in 2. In the case of (2: X = Cl and Br), augmenting this strong O—H···N hydrogen bond with a weaker C—H···O hydrogen bond results in a [C(6)R22(10)] chain of molecules propagated head-to-tail along the b axis. In contrast, this strong O—H···N hydrogen bond in (2: X = CN), now augmented by C—H···N(cyano nitrogen), results in a chain of molecules, [C(19)R22(10)R22(10)]. Further weaker intermolecular interactions of the types, C—H···N and C—H···O hydrogen bonds and π···π stacking interactions for (2: X = CN), and of the types, C—H···O and C—X···π hydrogen bonds, and π···π stacking interactions for (2: X = Cl and Br) generate significantly different supramolecular arrays.

Characterization of herbicide-resistant Eucalyptus plants expressing phosphinothricin acetyltransferase gene

Herbicide resistant crops are commercially advantageous for efficient field productivity by enabling use of non-selective herbicides for weed management. Herbicide resistant trees could be used to improve productivity and reduce the costs of forest management through to the first and second years post tree establishment. We describe the introduction of the phosphinothricin acetyltransferase (bar) gene, which confers resistance to the herbicide glufosinate, into Eucalyptus pellita (clone EP11) and hybrid Eucalyptus (E. grandis x E. dunni - clone SP1383) under the control of a constitutive promoter. The transgenic lines produced showed a copy number ranging from 1 to 3 copies by Southern blot analysis. Herbicide resistance of the transgenic clones was assessed in the greenhouse by application of 200g/L phosphinotricin at the level of 6.0 L/ha and 4.0 L/ha (commercial rate). The effect of the two herbicide treatments was tested on 4-week and 6-month old plants derived from several transgenic events from the two different Eucalyptus clones. All 4-week old non-transgenic control plants, as well as whole shoots of 6-month old control plants were killed by the herbicide by fifteen days after application. The same herbicide treatment effectively killed all the weeds in field conditions. All the transgenic plants showed strong resistance to the herbicide in all treatments with no observed negative effects. The use of herbicide resistant trees may provide an additional means for improving the economic efficiency of plantation forest management.

Synthesis and anti-Plasmodium falciparum evaluation of novel pyrazolopyrimidine derivatives

Nine 1-phenyl-1H-pyrazolo[3,4-d]pyrimidine derivatives with different substituents in the 4-position of the phenyl group and benzenesulfonamide moiety were synthesized and evaluated against Plasmodium falciparum. Six compounds exhibited activity in vitro against the chloroquine-resistant clone W2 with IC50 values ranging from 5.13 to 12.22 µM. The most active derivative with substituents R1 = F / R2 = CH3 exhibited an IC50 value of 5.13 µM and an IS value of 62.90, which was higher than that of the control drug sulfadoxine. For this reason, it is possible to conclude that the 1H-pyrazolo[3,4-d]pyrimidine system is promising as a prototype for further studies of antimalarial candidates.

Different intra- and inter-molecular hydrogen-bonding patterns in (3S,4aS,8aS)-2-[(2R,3S)-3-(2,5-X2-benzamido)-2-(2,5-X2-benzo-yloxy)-4-phenyl-butyl]-N-tert-butyldeca-hydro-iso-quinoline-3-carboxamides (X = H or Cl) : compounds with moderate aspartyl protease inhibition activity

The closely related title compounds show different intra- and intermolecular hydrogen-bonding patterns.