Potent, selective and reversible hMAO-B inhibition by benzalphthalides: Synthesis, enzymatic and cellular evaluations and virtual docking and predictive studies.

Monoaminooxidases (MAOs) are important targets for drugs used in the treatment of neurological and psychiatric disorders and particularly on Parkinson's Disease (PD). Compounds containing a trans-stilbenoid skeleton have demonstrated good selective and reversible MAO-B inhibition. Here, twenty-two (Z)-3-benzylidenephthalides (benzalphthalides, BPHs) displaying a trans-stilbenoid skeleton have been synthesised and evaluated as inhibitors of the MAO-A and MAO-B isoforms. Some BPHs have selectively inhibited MAO-B, with IC50 values ranging from sub-nM to µM. The most potent compound with IC50 = 0.6 nM was the 3',4'-dichloro-BPH 16, which showed highly selective and reversible MAO-B inhibitory activity. Furthermore, the most selective BPHs displayed a significant protection against the apoptosis, and mitochondrial toxic effects induced by 6-hydroxydopamine (6OHDA) on SH-SY5Y cells, used as a cellular model of PD. The results of virtual binding studies on the most potent compounds docked in MAO-B and MAO-A were in agreement with the potencies and selectivity indexes found experimentally. Additionally, related to toxicity risks, drug-likeness and ADME properties, the predictions found for the most relevant BPHs in this research were within those ranges established for drug candidates.

A new host-targeted antiviral cyclolignan (SAU-22.107) for Dengue Virus infection in cell cultures. Potential action mechanisms based on cell imaging.

Dengue virus (DENV) infection is the most arbovirosis in the world. However, medications have not been approved for its treatment. Drug discovery based on the host-targeted antiviral (HTA) constitutes a new promising strategy, considering their high genetic barrier to resistance and the low probability of selecting drug resistance strains. In this study, we have tested fifty-seven podophyllotoxin-related cyclolignans on DENV-2 infected cells and found the most promising compound was S.71. Using cellular and molecular biology experiments, we have discovered that the new lignan altered the distribution of microtubules, induced changes in cell morphology, and caused retraction of the rough endoplasmic reticulum. In addition, the compound alters the viral envelope protein and the double-stranded RNA, while there is a decrease in negative-strand RNA synthesis; especially when the compound was added between 6- and 12-hours post-infection. Altogether, S.71 decreases the viral yield through an HTA-related mechanism of action, possibly altering the DENV genome replication and/or polyprotein translation, through the alteration of microtubule distribution and endoplasmic reticulum deterioration. Finally, pharmacokinetic predictors show that S.71 falls within the standard ranges established for drugs.

Trypanocidal effect of alcoholic extract of Castanedia santamartensis (Asteraceae) leaves is based on altered mitochondrial function.

The deficit of effective treatments for Chagas disease has led to searching for new substances with therapeutic potential. Natural products possess a wide variety of chemical structural motifs and are thus a valuable source of diverse lead compounds for the development of new drugs. Castanedia santamartensis is endemic to Colombia, and local indigenous communities often use it to treat skin sores from leishmaniasis; however, its mechanism of action against the infective form of Trypanosoma cruzi has not been determined. Thus, we performed chemical and biological studies of two alcoholic leaf extracts of C. santamartensis to identify their active fractions and relate them to a trypanocidal effect and evaluate their mechanism of action. Alcoholic extracts were obtained through cold maceration at room temperature and fractionated using classical column chromatography. Both ethanolic and methanolic extracts displayed activity against T. cruzi. Chemical studies revealed that kaurenoic acid was the major component of one fraction of the methanolic extract and two fractions of the ethanolic extract of C. santamartensis leaves. Moreover, caryophyllene oxide, kaurenol, taraxasterol acetate, pentadecanone, and methyl and ethyl esters of palmitate, as well as a group of phenolic compounds, including ferulic acid, caffeic acid, chlorogenic acid, myricetin, quercitrin, and cryptochlorogenic acid were identified in the most active fractions. Kaurenoic acid and the most active fractions CS400 and CS402 collapsed the mitochondrial membrane potential in trypomastigotes, demonstrating for the first time the likely mechanism against T. cruzi, probably due to interactions with other components of the fractions.

Antiproliferative potential of solidagenone isolated of Solidago chilensis

ABSTRACT Plants are considered among the main sources of biologically active chemicals. The species Solidago chilensis Meyen, Asteraceae, is native to the southern parts of South America, where the aerial parts of the plant are commonly used for the treatment of inflammatory conditions. However, the effects of S. chilensis on human cancer cells remain to be elucidated. In this study, we evaluated the antiproliferative effects of the hydroalcoholic and dichloromethane extracts of S. chilensis, as well as their chemical constituents quercitrin and solidagenone against the five human tumor cell lines in vitro. The dichloromethane extract showed a promisor antiproliferative effects in vitro, especially against glioma cell line. Besides, the hydroalcoholic extract and quercitrin were inactive. The diterpene solidagenone showed highly potent antiproliferative effects against breast (MCF-7), kidney (786-0), and prostate cancer (PC-3) cells (total growth inhibition: TGI < 6.25 µg/ml). Solidagenone meets the theoretical physico-chemical criteria for bioavailability of drugs, according to the "Rule of Five" and, by theorical studies, the observed biological effects were probably related to the interaction of the molecule with nuclear receptors and as an enzymatic inhibitor. This study contributes to chemical study and to the identification of antiproliferative molecules in S. chilensis.

Neoflavonoids as Inhibitors of HIV-1 Replication by Targeting the Tat and NF-κB Pathways.

Twenty-eight neoflavonoids have been prepared and evaluated in vitro against HIV-1. Antiviral activity was assessed on MT-2 cells infected with viral clones carrying the luciferase reporter gene. Inhibition of HIV transcription and Tat function were tested on cells stably transfected with the HIV-LTR and Tat protein. Seven 4-phenylchromen-2-one derivatives showed HIV transcriptional inhibitory activity but only the phenylchrome-2-one 10 inhibited NF-κB and displayed anti-Tat activity simultaneously. Compounds 10, 14, and 25, inhibited HIV replication in both targets at concentrations <25 µM. The assays of these synthetic 4-phenylchromen-2-ones may aid in the investigation of some aspects of the anti-HIV activity of such compounds and could serve as a scaffold for designing better anti-HIV compounds, which may lead to a potential anti-HIV therapeutic drug.

Chemical Composition and Antinociceptive Potential of Campomanesia reitziana Fruits.

The methanolic extract from Campomanesia reitziana fruits and the main active principle, identified as 4',6'-dihydroxy-3',5'-dimethyl-2'-methoxy chalcone or dimethyl cardamonin (1), exhibited pronounced antinociceptive effects against two models of pain in mice. Compound 1 caused dose-dependent inhibition of abdominal constrictions, with a calculated ID50 value of 8.1 (6.5-10.1) µmol/kg (i.p.), being about 16-fold more potent than two reference analgesic drugs. Methanolic extract and 1 were also effective against the formalin model, inhibiting both phases of pain, causing reductions of 39.9% and 26.8% (extract, 10 mg/kg) and 52.9% and 57.6% (compound 1, 5 mg/kg) for the first and second phases, respectively.

Synthesis of Leubethanol derivatives and evaluation against Mycobacterium tuberculosis.

Twenty-five derivatives of the natural diterpene leubethanol, including several potential pro-drugs, with changes in the functionality of the aliphatic chain or modifications of the phenolic group, were synthesized and tested in vitro by the MABA technique for their activity against the H37Rv strain of Mycobacterium tuberculosis. Several compounds showed antimycobacterial potencies similar to that of the lead compound and two of them displayed higher selectivity indexes.

Diamine and aminoalcohol derivatives active against Trypanosoma brucei.

Twenty compounds selected as representative members of three series of long-chain 1,2-diamines, 2-amino-1-alkanols and 1-amino-2-alkanols structurally related to dihydrosphingosin, were synthesized and tested in vitro for their ability to inhibit the sleeping sickness parasites Trypanosoma bruceirhodesiense and Trypanosoma brucei gambiense. Eight compounds showed EC(50) values in the submicromolar range, with selectivity indexes up to 39 related to the respective cytotoxicity values for Vero cells. The parasite phenotype detected after treatment with the most potent compounds showed irreversible cell morphology alterations of the flagellar pocket that lead to inhibition of cell growth and parasite death.

Chemical constituents of the bark of Dipteryx alata vogel, an active species against Bothrops jararacussu venom.

The effect of four sub-extracts prepared from the lyophilized hydroalcoholic bark of Dipteryx alata (Leguminosae-Papilionoideae) dissolved in a methanol-water (80:20) mixture through a liquid-liquid partition procedure has been investigated against the neuromuscular blockade of the venom of the snake Bothrops jararacussu. The active CH2Cl2 sub-extract has been extensively analyzed for its chemical constituents, resulting in the isolation of four lupane-type triterpenoids: lupeol, lupenone, 28-hydroxylup-20(29)-en-3-one, betulin, nine isoflavonoids: 8-O-methylretusin, 7-hydroxy-5,6,4'-trimethoxyisoflavone, afrormosin, 7-hydroxy-8,3',4'-trimethoxyisoflavone, 7,3'-dihydroxy-8,4'-dimethoxyisoflavone, odoratin, 7,8,3'-trihydroxy-4'-methoxyisoflavone, 7,8,3'-trihydroxy-6,4'-dimethoxyisoflavone, dipteryxin, one chalcone: isoliquiritigenin, one aurone: sulfuretin and three phenolic compounds: vanillic acid, vanillin, and protocatechuic acid. Their chemical structures were elucidated on the basis of spectroscopic analysis, including HRMS, 1D- and 2D-NMR techniques.

Simple dihydrosphyngosine analogues with potent activity against MDR-Mycobacterium tuberculosis.

Fifteen dihydrosphingosine analogues have been synthesized and tested in vitro against Mycobacterium tuberculosis (MTB). Two ether (3 and 4b) and one diamine (8b) derivatives have displayed high mycobactericidal potency, with similar MIC values of 1.25 microg/mL, against the virulent strain H37Rv, as well as against a clinical isolate resistant to the five first-line anti-TB drugs. The three compounds, tested on other eleven cultured MTB strains with different multi-drug-resistance (MDR) patterns, retained their MIC values for most strains, or even lowered it, as in the case of compound 4b, which, assayed on strain No. 332, also resistant to all first-line anti-TB drugs, attained the MIC value of 0.78 microg/mL.

Synthesis and evaluation of some lipidic aminoalcohols and diamines as immunomodulators.

Lymphoproliferation inhibition and cytotoxicity of a number of lipidic aminoacids, aminoalcohols and diamines were evaluated as a preliminary screening to select potential immunomodulators. The four most potent/less toxic compounds were submitted to delayed hypersensibility (DTH) assays to define the best to be evaluated further Graft-vs-Host, NO production and other immunoevaluation (CD4(+), CD45, CD8, CD11b, I-Ek, and NK cells) assays, to establish their immunomodulation potential for being further considered as auxiliary agents for vaccination against some parasitic infections. Compounds 5d, 6d, 6f, 7a, and 9a, fairly inhibited the lymphoproliferation (71.6-79.5%, at 3.2-2.4 nM), while the aminoalcohol derivative 6f and the diamine 7a gave the most promising results in the DTH assays. Diamine derivative 8b induced nitrite production on normal macrophages, whereas compounds 6f and 7a induced nitrite production on LPS pre-stimulated macrophages. These two last compounds have been selected to follow in vivo vaccination assays.

Synthesis and cytotoxicity of new heterocyclic terpenylnaphthoquinones.

Several 2-arylamino-, 2-aryloxy- and 2-arylsulfanyl-6(7)-alkyl-1,4-naphthoquinones (NQ) have been prepared and further transformed into the corresponding heterocyclic-fused naphthoquinones by palladium (II)-catalyzed oxidative cyclization. The compounds synthesized have been evaluated against neoplastic cell lines. The extension of the polycyclic system clearly decreased the cytotoxic potency of the 2-substituted terpenylnaphthoquinones.

Mesuol, a natural occurring 4-phenylcoumarin, inhibits HIV-1 replication by targeting the NF-kappaB pathway.

Coumarins and structurally related compounds have been recently shown to inhibit replication of human immunodeficiency virus (HIV) and thus, exhibit a therapeutic potential. In this study we report that mesuol and isomesuol, two 4-phenyl coumarins, isolated from the tree Marila pluricostata, suppress HIV-1 replication in Jurkat T cells. These coumarins do not affect the reverse transcription and integration steps of the viral cycle and their antiviral effect is additive with that of azidothymidine (AZT). In addition, mesuol inhibits TNFalpha-induced HIV-1-LTR transcriptional activity by targeting the nuclear factor-kappaB (NF-kappaB) pathway. While mesuol does not prevent either the binding of NF-kappaB to DNA or the phosphorylation and degradation of NF-kappaB inhibitory protein, IkappaBalpha, it inhibits the phosphorylation and the transcriptional activity of the NF-kappaB p65 subunit in TNFalpha-stimulated cells. These results highlight the potential of the NF-kappaB transcription factor as a target for anti-HIV-1 compounds such as 4-phenyl coumarins, which could serve as lead compounds for the development of additional therapeutic approaches against AIDS.