Morita-Baylis-Hillman adducts derived from thymol: synthesis, in silico studies and biological activity against Giardia lamblia.

Giardiasis is a neglected disease, and there is a need for new molecules with less side effects and better activity against resistant strains. This work describes the evaluation of the giardicidal activity of thymol derivatives produced from the Morita-Baylis-Hillman reaction. Thymol acrylate was reacted with different aromatic aldehydes, using 1,4-diazabicyclo[2.

The Role Ionic Liquid [BMIM][PF] in One-Pot Synthesis of Tetrahydropyran Rings through Tandem Barbier-Prins Reaction.

Tetrahydropyran (THP) rings are common in several natural products, therefore, various strategies are being developed to synthesize these rings. The present work described the study of a one-pot synthesis of 2,4,6-trisubstituted tetrahydropyran compounds promoted by the ionic liquid 1-butyl-3-methylimidazolium hexafluorophosphate [BMIM][PF] through a Barbier-Prins reaction between allyl bromide and aldehydes. The use of [BMIM][PF] gave Prins products from several aldehydes in good yields and reaction times.

Synthesis, anti-proliferative activity, theoretical and H NMR experimental studies of Morita-Baylis-Hillman adducts from isatin derivatives.

Quaternary or spirocyclic 3-substituted-3-hydroxy-2-oxindole is considered a privileged scaffold. In other words, it is a molecular core present on several compounds with a wide spectrum of biological activities. Among its precursors, activated ketones (isatin nucleus) can be used as interesting starting points to Morita-Baylis-Hillman adducts derivatives, a class of compounds with good cytotoxic potential.

One-Electron Reduction Potentials: Calibration of Theoretical Protocols for Morita⁻Baylis⁻Hillman Nitroaromatic Compounds in Aprotic Media.

Nitroaromatic compounds-adducts of Morita⁻Baylis⁻Hillman (MBHA) reaction-have been applied in the treatment of malaria, leishmaniasis, and Chagas disease. The biological activity of these compounds is directly related to chemical reactivity in the environment, chemical structure of the compound, and reduction of the nitro group. Because of the last aspect, electrochemical methods are used to simulate the pharmacological activity of nitroaromatic compounds.

Morita-Baylis-Hillman Adducts Display Anti-Inflammatory Effects by Modulating Inflammatory Mediator Expression in RAW264.7 Cells.

Inflammatory response plays an important role not only in the normal physiology but also in pathologies such as cancers. The Morita-Baylis-Hillman adducts (MBHA) are a novel group of synthetic molecules that have demonstrated many biological activities against some parasitic cells such as , , and , and antimitotic activity against sea urchin embryonic cells was also related. However, little is known about the mechanisms induced by MBHA in inflammatory process and its relation with anticancer activity.

Synthesis and activity of novel homodimers of Morita-Baylis-Hillman adducts against Leishmania donovani: A twin drug approach.

It is reported here the synthesis of novel Homodimers 12-19 of Morita-Baylis-Hillman adducts (MBHA) from one-pot Morita-Baylis-Hillman Reaction (MBHR) between aromatic aldehydes as eletrophiles and ethylene glycol diacrylate as Michael acceptor (35-94% yields) using cheap and green conditions. The bioactivities were evaluated against promastigote form of Leishmania donovani. All homodimers showed to be more potent than corresponding monomers.

Synthesis, Cytotoxic Activity on Leukemia Cell Lines and Quantitative Structure-Activity Relationships (QSAR) Studies of Morita-Baylis-Hillman Adducts.

Background: The Morita-Baylis-Hillman reaction is an organocatalyzed chemical transformation that allows access to small poly-functionalized molecules and has considerable synthetic potential and promising biological profiles. The Morita-Baylis-Hillman adducts (MBHA) are a new class of bioactive compounds and highlight its potentialities to the discovery of new cheaper and efficient drugs, e.g.

Antihyperalgesic effect of [(±)-(2,4,6-cis)-4-chloro-6-(naphthalen-1-yl)-tetrahydro-2H-pyran-2-yl]methanol: participation of the NO/cGMP/KATP pathway and κ-opioid receptor.

The present study used behavioral analyses to investigate the involvement of the NO/cGMP/KATP pathway, serotoninergic, and opioid systems in the antinociceptive action of [(±)-(2,4,6-cis)-4-chloro-6-(naphthalen-1-yl)-tetrahydro-2H-pyran-2-yl]methanol (CTHP) in mice. Oral administration of CTHP (1, 5, 10, and 30 mg/kg) exerted effects at higher doses in chemical models of nociception (the acetic acid writhing and formalin tests) as well as a thermal model (the tail-flick test). It was also found that pretreatment with L-N-nitroarginine methyl ester (nonselective nitric oxide synthase inhibitor), 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (selective inhibitor of nitric oxide-sensitive guanosyl cyclase), glibenclamide (selective ATP-sensitive K channel blocker), naloxone (nonselective opioid receptor blocker), and nor-binaltorphimine (selective κ-opioid receptor blocker), but not methylnaltrexone (peripheral μ-opioid receptor blocker) or naltrindole (selective δ-opioid receptor blocker), reversed the antinociceptive effect of CTHP.

Trypanosoma cruzi cell death induced by the Morita-Baylis-Hillman adduct 3-Hydroxy-2-methylene-3-(4-nitrophenylpropanenitrile).

Chagas disease, caused by the protozoan Trypanosoma cruzi, remains a serious health concern due to the lack of effective vaccines or satisfactory treatment. In the search for new compounds against this neglected disease, we have previously demonstrated that the compound 3-Hydroxy-2-methylene-3-(4-nitrophenylpropanenitrile) (MBHA3), derived from the Morita-Baylis-Hillman reaction, effectively caused a loss of viability in both the epimastigote and trypomastigote forms. However, the mechanisms of parasite death elicited by MBHA3 remain unknown.

High analgesic and anti-inflammatory in vivo activities of six new hybrids NSAIAs tetrahydropyran derivatives.

We present in this article syntheses of six new hybrids compounds (4-9) that were efficiently prepared in one or two steps (70-84.6%) from our previous prototype (±)-cis-4-chloro-6-(naphthalen-1-yl)-tetrahydro-2H-pyran-2-yl)methanol (3) and the NSAIAs: acetyl salicylic acid, indomethacin, ibuprofen, ketoprofen, naproxen and diclofenac. The acetic acid-induced writhing method is able to determine that all investigated new hybrids showed stronger antinociceptive properties (2- to 10-fold less ED50 values) than their precursors.

The antinociceptive properties of the novel compound (±)-trans-4-hydroxy-6-propyl-1-oxocyclohexan-2-one in acute pain in mice.

The compound (±)-trans-4-hydroxy-6-propyl-1-oxocyclohexan-2-one [(±)-δ-lactone] was isolated from the plant Vitex cymosa Bertero, and determined to be the active principle. The present study aimed to evaluate the antinociceptive effect of (±)-δ-lactone and to elucidate its mechanism of action. Mice were subjected to in-vivo models of acute pain (acetic acid-induced abdominal writhing, formalin and hot-plate tests) and the open-field test.

Design, Prins-cyclization reaction promoting diastereoselective synthesis of 10 new tetrahydropyran derivatives and in vivo antinociceptive evaluations.

We described in this article the very efficient 2,6-cis ou 2,4,6-cis diastereoselective synthesis (2 or 3 steps, 62-65% global yields) from Prins-cyclization reaction as synthetic key-step to tetrahydropyran rings construction of 10 new congeners compounds (3-12) designed from Naproxen structure. These tetrahydropyran derivatives were in vivo bioevaluated on antinociceptive effect in the acetic acid-induced abdominal writhing test, the tail-flick test, the rota-rod performance and open field tests. All new compounds showed greater antinociceptive activity compared to compound 1a, an analgesic tetrahydropyran derivative previously described by us.

Antimitotic activity on sea urchin embryonic cells of seven antiparasitic Morita-Baylis-Hillman adducts: a potential new class of anticancer drugs.

In the present work we described improvements in the 1-7 antiparasitic Morita-Baylis-Hillman Adducts synthesis and their antimitotic activity on sea urchin embryonic cells. The 2-[Hydroxy(2-nitrophenyl)methyl]acrylonitrile (1) and 2-[Hydroxy(4-bromophenyl) methyl]acrylonitrile (4) were the most effective compounds to block the progression to embryonic morula stage (EC(50) = 75.8 μM and 72.

Morita-Baylis-Hillman adducts: biological activities and potentialities to the discovery of new cheaper drugs.

This review aims to present by the first time the Morita-Baylis-Hillman adducts (MBHA) as a new class of bioactive compounds and highlight its potentialities to the discovery of new cheaper and efficient drugs. Now, most these compounds can be prepared fast and on a single synthetic step (one-pot reaction) in high yields and using ecofriendly synthetic protocols. We highlight here the aromatic MBHA, which have shown diverse biological activities as anti-Leishmania chagasi and Leishmania amazonensis (parasites that cause cutaneous and visceral leishmaniasis), anti-Trypanosoma cruzi (parasite that cause Chagas disease), anti-Plasmodium falciparum and Plasmodium berghei (parasites that cause malaria), lethal against Biomphalaria glabrata (the snail transmitter of schistosomiasis), antibacterial, antifungal, herbicide and actives against some human tumor cell lines.

Synthesis, evaluation against Leishmania amazonensis and cytotoxicity assays in macrophages of sixteen new congeners Morita-Baylis-Hillman adducts.

We report the design, synthesis, in vitro evaluation against Leishmania amazonensis (IC(50)), cytotoxicity assays in macrophages (CC(50)), and selectivity index (SICC(50)/IC(50)) of sixteen new congeners aromatic Morita-Baylis-Hillman adducts 1-16. The 1-16 were prepared in good to excellent yields (58%-97%) from the "one pot" Morita-Baylis-Hillman Reaction between the aldehydes 29-36 and the acrylates 27 or 28 under DABCO as promoter. The MBHA 2-[Hydroxy(2-nitrophenyl)propyl] propanoate (1, IC(50) = 7.

Design, synthesis and antileishmanial in vitro activity of new series of chalcones-like compounds: a molecular hybridization approach.

The chalcone-like series 1a-1g was efficiently synthesized from Morita-Baylis-Hillman reaction (52-74% yields). Compounds 1a-1g were designed by molecular hybridization based on the anti-inflammatory drug methyl salicylate (3) and the antileishmanial moiety of the Morita-Baylis-Hillman adducts 2a-2g. The 1a-1g compounds were much more actives than precursor series 2a-2g, for example, IC(50)=7.

Antinociceptive activity of (-)-(2S,6S)-(6-ethyl-tetrahydropyran-2-yl)-formic acid on acute pain in mice.

Pain is a major cause of distress, both physical and psychological. There is a continuous search for new pharmacologically active analgesic agents with minor adverse effects. Recently, the synthesis of (-)-(2S,6S)-(6-ethyl-tetrahydropyran-2-yl)-formic acid [tetrahydropyran derivative (TD)] was described.

Efficient synthesis of 16 aromatic Morita-Baylis-Hillman adducts: Biological evaluation on Leishmania amazonensis and Leishmania chagasi.

Sixteen aromatic Morita-Baylis-Hillman adducts (MBHA) 1-16 were efficiently synthesized in a one step Morita-Baylis-Hillman reaction (MBHR) involving commercial aldehydes with methyl acrylate or acrylonitrile (81-100% yields) without the formation of side products on DABCO catalysis and at low temperature (0°C). The toxicities of these compounds were assessed against promastigote form of Leishmania amazonensis and Leishmania chagasi. The low synthetic cost of these MBHA, green synthetic protocols, easy one-step synthesis from commercially available and cheap reagents as well as the very good antileishmanial activity obtained for 14 and 16 (IC₅₀ values of 6.

3-Hydroxy-2-methylene-3-(4-nitrophenylpropanenitrile): A new highly active compound against epimastigote and trypomastigote form of Trypanosoma cruzi.

We have synthesized the Morita-Baylis-Hillman adduct (MBHA) 3-hydroxy-2-methylene-3-(4-nitrophenyl)-propanenitrile (3) in quantitative yield and evaluated on Trypanosoma cruzi epimastigote and bloodstream trypomastigote forms. Compound 3 strongly inhibited epimastigote growth, with IC(50)/72hof 28.5 microM and also caused intense trypomastigotes lysis, with an IC(50)/24h of 25.

Structural determination Vitex cymosa Bertero active principle: Diastereoselective synthesis of (+/-)-trans-4-hydroxy-6-propyl-1-oxocyclohexan-2-one and its antinociceptive activity.

The diastereoselective synthesis of (+/-)-trans-4-hydroxy-6-propyl-1-oxocyclohexan-2-one, as a mixture trans:cis (3:1), was accomplished using a protocol that combine the Prins cyclization and RuO(4) oxidation. The synthesis this lactone allowed the elucidation of the correct structure of the substance isolated from the barks of Vitex cymosa. The delta-lactones mixture showed significant antinociceptive properties in preliminary tests using the tail flick model assay.

Improved synthesis of seven aromatic Baylis-Hillman adducts (BHA): evaluation against Artemia salina Leach. and Leishmania chagasi.

We described a very efficient procedure to prepare seven aromatic compounds (1-7), a new class of antileishmanial substances, through Baylis-Hillman reaction (BHR). With one, all the Baylis-Hillman adducts were prepared in quantitative yields by reaction of the corresponding aromatic aldehydes in acrylonitrile at 0 degrees C in only 10-40min reaction time. We present our results about the toxicities of these compounds evaluated on the microcrustaceous Artemia salina Leach.

Antinociceptive action of (+/-)-cis-(6-ethyl-tetrahydropyran-2-yl)-formic acid in mice.

The objective of this study was to investigate spinal and supraspinal antinociceptive effects of a new synthetic compound, (+/-)-cis-(6-ethyl-tetrahydropyran-2-yl)-formic acid (tetrahydropyran derivative). Its activity was compared with those from morphine. In peripheral models of inflammation and hyperalgesia, tetrahydropyran derivative significantly reduced nociceptive effect induced by acetic acid or formalin in mice.