Dillapiole as antileishmanial agent: discovery, cytotoxic activity and preliminary SAR studies of dillapiole analogues.

In this paper, the isolation of dillapiole (1) from Piper aduncum was reported as well as the semi-synthesis of two phenylpropanoid derivatives [di-hydrodillapiole (2), isodillapiole (3)], via reduction and isomerization reactions. Also, the compounds' molecular properties (structural, electronic, hydrophobic, and steric) were calculated and investigated to establish some preliminary structure-activity relationships (SAR). Compounds were evaluated for in vitro antileishmanial activity and cytotoxic effects on fibroblast cells. Compound 1 presented inhibitory activity against Leishmania amazonensis (IC(50) = 69.3 µM) and Leishmania brasiliensis (IC(50) = 59.4 µM) and induced cytotoxic effects on fibroblast cells mainly in high concentrations. Compounds 2 (IC(50) = 99.9 µM for L. amazonensis and IC(50) = 90.5 µM for L. braziliensis) and 3 (IC(50) = 122.9 µM for L. amazonensis and IC(50) = 109.8 µM for L. brasiliensis) were less active than dillapiole (1). Regarding the molecular properties, the conformational arrangement of the side chain, electronic features, and the hydrophilic/hydrophobic balance seem to be relevant for explaining the antileishmanial activity of dillapiole and its analogues.

The anti-inflammatory activity of dillapiole and some semisynthetic analogues.

CONTEXT: Piper aduncum L. (Piperaceae) produces an essential oil (dillapiole) with great exploitative potential and it has proven effects against traditional cultures of phytopathogens, such as fungi, bacteria and mollusks, as well as analgesic action with low levels of toxicity. OBJECTIVE: This study investigated the in vivo anti-inflammatory activity of dillapiole. Furthermore, in order to elucidate its structure-anti-inflammatory activity relationship (SAR), semisynthetic analogues were proposed by using the molecular simplification strategy. MATERIALS AND METHODS: Dillapiole and safrole were isolated and purified using column chromatography. The semisynthetic analogues were obtained by using simple organic reactions, such as catalytic reduction and isomerization. All the analogues were purified by column chromatography and characterized by (1)H and (13)C NMR. The anti-inflammatory activities of dillapiole and its analogues were studied in carrageenan-induced rat paw edema model. RESULTS: Dillapiole and di-hydrodillapiole significantly (p<0.05) inhibited rat paw edema. All the other substances tested, including safrole, were less powerful inhibitors with activities inferior to that of indomethacin. DISCUSSION AND CONCLUSION: These findings showed that dillapiole and di-hydrodillapiole have moderate anti-phlogistic properties, indicating that they can be used as prototypes for newer anti-inflammatory compounds. Structure-activity relationship studies revealed that the benzodioxole ring is important for biological activity as well as the alkyl groups in the side chain and the methoxy groups in the aromatic ring.

Optimization of the ultrasound-assisted synthesis of allyl 1-naphthyl ether using response surface methodology.

Allyl 1-naphthyl ethers are useful compounds for different purposes, but reported methods to synthesize them require long reaction times. In this work, we have obtained allyl 1-naphthyl ether in good yield using ultrasonic-assisted methodology in a 1-h reaction. A central composite design was used to obtain a statistical model and a response surface (p<0.05; R(2)=0.970; R(2)(adj)=0.949; R(2)(pred)=0.818) that can predict the optimal conditions to maximize the yield, validated experimentally.

Design, synthesis, and in vivo evaluation of oxamniquine methacrylate and acrylamide prodrugs.

Oxamniquine is an antiparasitic agent commonly used in therapeutics against Schistosoma mansoni. Although it is well tolerated, some adverse effects justify the search for new compounds with prolonged biological action, so that monomeric and polymeric oxamniquine prodrugs were designed. Synthetic results assisted by molecular modeling study showed the possibility to obtain the corresponding monomeric forms of the oxamniquine methacrylate (1) and oxamniquine acrylamide (2). Successful copolymerization procedure only occurred on the methacrylic compound, generating the oxamniquine methacrylate copolymer (3). Submitted to a preliminary in vivo biological evaluation, a similar oxamniquine profile was observed to the monomeric forms although an inadequate drug release may be responsible for the methacrylic copolymer failure.

Synthesis and antileishmanial activities of novel 3-substituted quinolines.

The antileishmanial efficacy of four novel quinoline derivatives was determined in vitro against Leishmania chagasi, using extracellular and intracellular parasite models. When tested against L. chagasi-infected macrophages, compound 3b demonstrated 8.3-fold greater activity than did the standard pentavalent antimony. No significant activity was found for compounds 3a, 4a, and 4b. The antilesihmanial effect of compound 3b was independent of host cell activation, as demonstrated by nitric oxide production. Ultrastructural studies of promastigotes treated with compound 3b showed mainly enlarged mitochondria, with matrix swelling and reduction in the number of cristae. Synthetic analogues based on the quinoline ring structure, already an established template for antiparasitic drugs, could provide further useful compounds.

Use of N-methylene phosphonic chitosan to obtain an isoniazid prodrug

Tuberculosis (TB) is one of the most neglected health problems and has out of control in many areas of the world. Since new antituberculous alternatives, including controlled classical drug delivery systems, are urgently needed to face this serious situation, the purpose of the present work was the sysnthesis and characterization of a prolonged action prodrug of isoniazid. The N-methylene phosphonic chitosan (NMPC), a hydrosoluble derivative of chitosan was the synthesis and characterization of a prolonged action prodrug of isoniazid. The N-methylene phosphonic chitosan (NMPC), a hydrosoluble derivative of chitosan was used as drug carrier. This analog, as well as its precursor, exhibits simulatory activity on macrophages, host cells of Mycobacterium tuberculosis...