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In the present work five acetylene derivatives (1-5), including three unknowns (1, 3 and 4), were isolated from seeds of Porcelia macrocarpa (Annonaceae). The structures of isolated compounds were determined as docos-13-yn-21-enoic acid (1), 3-hydroxy-4-methylene-2-(eicos-11’-yn-19’-enyl)but-2-enolide (2), 3-hydroxy-4-methylene-2-(octadec-9’-yn-17’-enyl)but-2-enolide (3), 3-hydroxy-4-methylene-2-(hexadec-7’-yn-15’-enyl)but-2-enolide (4), and (2S,3R,4R)-3-hydroxy-4-methyl-2-(eicos-11’-yn-19’-enyl)butanolide (5) by analysis of nuclear magnetic resonance (NMR) and electrospray ionization high-resolution mass spectrometry (ESI-HRMS) data. Moreover, all isolated compounds demonstrated selectivity towards intracellular amastigotes of Leishmania (L.) infantum, especially 2-4 with 50% inhibitory concentration (IC50) values of 9.2, 10.4 and 11.0 µM, respectively, indicating superior activity of that determined to positive control miltefosine (IC50 of 17.8 µM). Furthermore, these compounds showed higher selectivity index (SI) in comparison with miltefosine. Since related acetylene fatty acid 1 displayed reduced antiparasitic potential (IC50 of 48.5 µM), the obtained results suggested that the γ-lactone plays an important role in the antileishmanial activity. However, 2-4 exhibited cytotoxicity to mammalian NCTC cells (CC50 ca. 80 µM), which could be a result of the presence of a conjugated carbonyl system in the lactone ring, since 5, the only acetogenin that presents the saturated ring, lacked mammalian cytotoxicity (CC50 > 200 µM).

Infrared photodissociation analyses are supported by theoretical calculations that allow a trustworthy interpretation of experimental spectra of gaseous ions. B3LYP calculations are the most prominent method used to model IR spectra, as detailed in our bibliographic survey. However, this and other commonly used methods are known to provide inaccurate energy values and geometries, especially when it comes to long-range interactions, such as intramolecular H-bonds, which show increased anharmonicity. Therefore, we evaluated some of the most commonly used density functional theory methods (B3LYP, CAM-B3LYP, and M06-2X) and basis sets (6-31+G(d,p), 6-311++G(d,p), 6-311++G(3df,2pd), aug-cc-pVDZ, and aug-cc-pVTZ), including anharmonicity and dispersion corrections. The results were compared to MP2 calculations and to experimental high-frequency (2000-4000 cm-1) IR multiphotonic dissociation (IRMPD) spectra of two protonated model molecules containing intramolecular hydrogen bonds: biotin and tryptophan. M06-2X/6-31+G(d,p) was shown to be the most cost-effective level of theory, whereas CAM-B3LYP was the most efficient method to describe the van der Waals interactions. The use of the dispersion correction D3, proposed by Grimme, improved the description of O-H vibrations involved in H-bonding but worsened the description of N-H stretches. Anharmonic calculations were shown to be extremely expensive when compared to other approaches. The efficiencies of well-established scaling factors (SFs) in opposition to sample-dependent SFs were also discussed and the use of fitted SFs were shown to be the most cost-effective approach to predict IRMPD spectra. M06-2X/6-31+G(d,p) and CAM-B3LYP/aug-cc-pVDZ were also tested against the fingerprint region. Our results suggest that these methods can also be used for analysis in this lower frequency range and should be regarded as the methods of choice for cost-effective IRMPD simulations rather than the ubiquitous B3LYP method, especially when further molecular properties are needed.

Made available in DSpace on 2015-10-21T20:24:02Z (GMT). No. of bitstreams: 0 Previous issue date: 2015-05-01. Added 1 bitstream(s) on 2015-10-22T09:48:13Z : No. of bitstreams: 1 WOS000357157600044.pdf: 621633 bytes, checksum: 7832aa36076025e2fc5c9982aa2fd287 (MD5) Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) Chagas'disease is caused by a parasitic protozoan and affects the poorest population in the world, causing high mortality and morbidity. As a result of the toxicity and long duration of current treatments, the discovery of novel and more efficacious drugs is crucial. In this work, the hexane extract from seeds of Porcelia macrocarpa R.E. Fries (Annonaceae) displayed in vitro antitrypanosomal activity against trypomastigote forms of T. cruzi by the colorimetric MTT assay (IC50 of 65.44 g/mL). Using chromatographic fractionation over SiO2, this extract afforded a fraction composed by one active compound (IC50 of 10.70 mu g/mL), which was chemically characterized as 12,14-octadecadiynoic acid (macrocarpic acid). Additionally, two new inactive acetylene compounds (,'-dimacro-carpoyl--oleylglycerol and -macrocarpoyl-'-oleylglycerol) were also isolated from the hexane extract. The complete characterization of the isolated compounds was performed by analysis of NMR and MS data as well as preparation of derivatives. Univ Estadual Paulista, Inst Quim, Nucleo Bioensaios Biossintese &Ecofisiol Prod Na, BR-14800060 Araraquara, SP, Brazil Adolfo Lutz Inst, Ctr Parasitol &Micol, BR-01246902 Sao Paulo, SP, Brazil Univ Fed Sao Paulo, Inst Ciencias Ambientais Quim &Farmaceut, BR-09972270 Diadema, SP, Brazil Univ Fed Rio de Janeiro, Inst Pesquisa Prod Nat, BR-21941902 Rio De Janeiro, RJ, Brazil Univ Estadual Paulista, Departamento de Química Orgânica, Inst Quim, Nucleo Bioensaios Biossintese &Ecofisiol Prod Na, BR-14800060 Araraquara, SP, Brazil CNPq: 300546/2012-2 CNPq: 471458/2012-0 FAPESP: 1998/01735-2 FAPESP: 2011/51739-0 FAPESP: 2012/18756-1