Synthesis and SAR of novel, non-MPEP chemotype mGluR5 NAMs identified by functional HTS

This Letter describes the discovery and SAR of three novel series of mGluR5 non-competitive antagonists/negative allosteric modulators (NAMs) not based on manipulation of an MPEP/MTEP chemotype identified by a functional HTS approach. This work demonstrates fundamentally new mGluR5 NAM chemotypes with submicromolar potencies, and further examples of a mode of pharmacology 'switch' to provide PAMs with a non-MPEP scaffold. (C) 2009 Elsevier Ltd. All rights reserved.

Effect of substrata on the development of stem cuttings of Lippia alba (Mill.) NEBR. - Limonene-carvone chemotype

Studies were conducted to show the effect of different substrata on the development of stem cuttings of Lippia alba made of limonene-carvone chemotype. The experiment was done in the College of Agronomical Sciences, UNESP, Botucatu, SP, Brazil in 2000. The cuttings were planted in polystyrene trays consisting of 72 cells. The cuttings had about 0.20 m of length and were put in the following substrata:Fine sand (T1), commercial substratum (T2), carbonised rice peel and local soil (T3), local soil, cow manure and carbonised rice peel (T4), vermiculite (T5), and carbonised rice peel (T6). After 40 days the development of stem cuttings were evaluated. High rate of rooting of stem cuttings was verified, with average of 95 10 and no significant difference between the treatments. In relation to dry mass of aerial parts and dry mass of roots, significant differences were found. For dry mass production of aerial parts the commercial substratum (T2) and the local soil, cow manure, carbonised rice peel (T4) were optimal. For mass of roots the local soil, cow manure, carbonised rice peel (T4) proved to be the best.

Effect of substrata on the development of stem cuttings of Lippia alba (Mill.) N. E. BR. - Limonene-carvone chemotype

Studies were conducted to show the effect of different substrata on the development of stem cuttings of Lippia alba made of limonene-carvone chemotype. The experiment was done in the College of Agronomical Sciences, UNESP, Botucatu, SP, Brazil in 2000. The cuttings were planted in polystyrene trays consisting of 72 cells. The cuttings had about 0.20 m of length and were put in the following substrata: Fine sand (T1), commercial substratum (T2), carbonised rice peel and local soil (T3), local soil, cow manure and carbonised rice peel (T4), vermiculite (T5), and carbonised rice peel (T6). After 40 days the development of stem cuttings were evaluated. High rate of rooting of stem cuttings was verified, with average of 95% and no significant difference between the treatments. In relation to dry mass of aerial parts and dry mass of roots, significant differences were found. For dry mass production of aerial parts the commercial substratum (T2) and the local soil, cow manure, carbonised rice peel (T4) were optimal. For mass of roots the local soil, cow manure, carbonised rice peel (T4) proved to be the best.

Bioactivity of tea tree oil from Melaleuca alternifolia against sheep lice (Bovicola ovis Schrank) in vitro

Tea tree oil (TTO) from the Australian native plant Melaleuca alternifolia has wide ranging bio-active properties, including insecticidal and repellent activity against arthropods. Furthermore, composition of commercially available Australian TTO is specified under an International Organization for Standardization standard (ISO 4730), reducing the potential for variable effects often noted with botanical pesticides. The effect of TTO, meeting the ISO standard for terpinen-4-ol chemotype, was tested against sheep lice (Bovicola ovis Schrank) in a series of laboratory studies. Immersion of wool for 60s in formulations containing concentrations of 1% TTO and above caused 100% mortality of adult lice and eggs. Exposure to vapours from TTO, delivered as droplets in fumigation chambers and when applied to wool also caused high mortality in both lice and eggs. The main active component of TTO in the fumigant tests was terpinen-4-ol. Treated surface assays and tests with wool where the formulation was allowed to dry before exposure of lice indicated low persistence. These studies demonstrate that TTO is highly toxic to sheep lice and active at concentrations that suggest potential for the development of TTO-based ovine lousicides. (C) 2012 Elsevier B.V. All rights reserved.

Discovery and SAR of a novel series of non-MPEP site mGlu(5) PAMs based on an aryl glycine sulfonammide scaffold

Herein we report the discovery and SAR of a novel series of non-MPEP site metabotropic glutamate receptor 5 (mGlu(5)) positive allosteric modulators (PAMs) based on an aryl glycine sulfonamide scaffold. This series represents a rare non-MPEP site mGlu(5) PAM chemotype.

Flat SAR of P3-methylsulphonamide based small molecule legumain inhibitors

This letter describes the design, development and SAR exploration of a novel series of small legumain inhibitors. The SAR of a new small molecule legumain inhibitor chemotype was explored and found to have improved physiochemical properties compared to previously developed inhibitors within our group. However, further development of this series was found to be limited as the SAR was observed to be relatively flat.

Medicinal chemistry approaches to malaria drug discovery

Tese de doutoramento, Farmácia (Química Farmacêutica e Terapêutica), Universidade de Lisboa, Faculdade de Farmácia, 2016

Influência do horário de colheita sobre o rendimento e composição do óleo essencial de erva-cidreira brasileira [Lippia alba (Mill.) N. E. Br.]

Este trabalho teve como objetivo verificar se o horário de colheita da erva-cidreira brasileira [Lippia alba (Mill.) N. E. Br.], fenotipo carvona-limoneno, tem influência sobre a produção de massa foliar, rendimento e composição do óleo essencial. Foram avaliados cinco horários de colheita quando a cultura estava com 145 dias desde o transplante: 8:00, 10:00, 12:00, 14:00 e 16:00 h com cinco repetições, distribuídos em blocos casualizados. O experimento foi conduzido na Fazenda Experimental Lageado da FCA-UNESP/Botucatu no Setor de Horticultura do Departamento de Produção Vegetal. A colheita foi realizada a 15 cm da superfície do solo e o óleo essencial obtido através de hidrodestilação, em aparelho tipo Clevenger. Levou-se em consideração os fatores agronômicos e o rendimento obtido por hidrodestilação. O óleo essencial foi analisado em cromatógrafo gasoso acoplado a espectrômetro de massas (CG/EM). Os resultados foram submetidos à análise de variância (Teste F) e as médias comparadas pelo teste de Tukey. Não houve diferença estatística para produção de massa foliar, teor de óleo essencial e produtividade de óleo essencial em massa fresca e seca. No entanto, entre os compostos majoritários do óleo essencial das folhas, carvona e limoneno, a melhor produtividade de carvona foi obtida às 10:00 h, em matéria fresca (2,050 L ha-1) e em matéria seca (2,068 L ha-1), e para o limoneno às 16:00 h, em matéria fresca (1,068 L ha-1) e em matéria seca (1,060 L ha-1).

Intraspecific variability of flavonoid glycosides and styrylpyrones from leaves of Cryptocarya mandioccana Meisner (Lauraceae)

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Chemical composition of flavonoids and styrylpyrones and the genetic variability of isozymes in natural populations of Cryptocarya mandioccana Meisner (Lauraceae)

The chemical composition of leaves of 57 trees of Cryptocarya mandioccana from three populations of southeastern Brazil was investigated through HPLC, assaying six flavonoids, seven styrylpyrones, and seven unidentified compounds. From 51 of the former trees, genotypes were obtained from 40 polymorphic loci of 19 isozymes. Cluster analyses of the phytochemical and genetical variation revealed that trees exhibited four chemotypes and five clusters from isozymes, respectively. Discriminant analyses from selected variables of the isozymic and chemical data sets were performed, respectively, in relation to the four chemotypes and the five isozyme clusters. The classification of individuals presented respective error estimates of 9.16% and 13.57%, indicating that the genetic data could explain the clusters from chernotypes and vice versa at acceptable error levels. Linear regressions with Dummy variable showed significant association of locus Skdh-2 with quercetin-3-O-beta-D-glucopyranoside and cryptofolione, indicating that its alleles would be responsible for the chemotype variation between individuals. (c) 2006 Elsevier Ltd. All rights reserved.

Épocas de plantio, idades e horários de colheita na produção e qualidade do óleo essencial de Lippia alba (Mill.) N.E. Br., quimiotipo limoneno-carvona

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Variabilidade intraespecifica de estirilpironas em quimiotipos de Cryptocarya mandioccana: avaliacao da producao em diferentes orgaos e em extratos enzimaticos

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

Fusarium species responsible for mycotoxin production in wheat crop: involvement in food safety

Fusarium Head Blight (FHB) is a worldwide cereal disease responsible of significant yield reduction, inferior grain quality, and mycotoxin accumulation. Fusarium graminearum and F. culmorum are the prevalent causal agents. FHB has been endemic in Italy since 1995, while there are no records about its presence in Syria. Forty-eight and forty-six wheat kernel samples were collected from different localities and analyzed for fungal presence and mycotoxin contamination. Fusarium strains were identified morphologically but the molecular confirmation was performed only for some species. Further differentiation of the chemotypes for trichothecene synthesis by F. graminearum and F. culmorum strains was conducted by PCR assays. Fusarium spp. were present in 62.5% of Syrian samples. 3Acetyl-Deoxynivalenol and nivalenol chemotypes were found in F. culmorum whilst all F. graminearum strains belonged to NIV chemotype. Italian samples were infected with Fusarium spp for 67.4%. 15Ac-DON was the prevalent chemotype in F. graminearum, while 3Ac-DON chemotype was detected in F. culmorum. The 60 Syrian Fusarium strains tested for mycotoxin production by HPLC-MS/MS have shown the prevalence of zearalenone while the emerging mycotoxins were almost absent. The analysis of the different Syrian and Italian samples of wheat kernels for their mycotoxin content showed that Syrian kernels were mainly contaminated with storage mycotoxins, aflatoxins and ochratoxin whilst Italian grains with mainly Fusarium mycotoxins. The aggressiveness of several Syrian F. culmorum isolates was estimated using three different assays: floret inoculation in growth chamber, ear inoculation in the field and a validated new Petri-dish test. The study of the behaviour of different Syrian wheat cultivars, grown under different conditions, has revealed that Jory is a FHB Syrian tolerant cultivar. This is the first study in Syria on Fusarium spp. associated to FHB, Fusarium mycotoxin producers and grain quality.