The discovery of aryl-2-nitroethyl triamino pyrimidines as anti-Trypanosoma brucei agents.

Pteridine reductase 1 (PTR1) is a catalytic protein belonging to the folate metabolic pathway in Trypanosmatidic parasites. PTR1 is a known target for the medicinal chemistry development of antiparasitic agents against Trypanosomiasis and Leishmaniasis. In previous studies, new nitro derivatives were elaborated as PTR1 inhibitors. The compounds showing a diamino-pyrimidine core structure were previously developed but they showed limited efficacy. Therefore, a new class of phenyl-, heteroaryl- and benzyloxy-nitro derivatives based on the 2-nitroethyl-2,4,6-triaminopyrimidine scaffold were designed and tested. The compounds were assayed for their ability to inhibit T. brucei and L. major PTR1 enzymes and for their antiparasitic activity towards T. brucei and L. infantum parasites. To understand the structure-activity relationships of the compounds against TbPTR1, the X-ray crystallographic structure of the 2,4,6-triaminopyrimidine (TAP) was obtained and molecular modelling studies were performed. As a next step, only the most effective compounds against T. brucei were then tested against the amastigote cellular stage of T. cruzi, searching for a broad-spectrum antiprotozoal agent. An early ADME-Tox profile evaluation was performed. The early toxicity profile of this class of compounds was investigated by measuring their inhibition of hERG and five cytochrome P450 isoforms (CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4), cytotoxicity towards A549 cells and mitochondrial toxicity. Pharmacokinetic studies (SNAP-PK) were performed on selected compounds using hydroxypropyl-ß-cyclodextrins (50 % w/v) to preliminarily study their plasma concentration when administered per os at a dose of 20 mg/kg. Compound 1p, showed the best pharmacodynamic and pharmacokinetic properties, can be considered a good candidate for further bioavailability and efficacy studies.

Destabilizers of the thymidylate synthase homodimer accelerate its proteasomal degradation and inhibit cancer growth.

Drugs that target human thymidylate synthase (hTS), a dimeric enzyme, are widely used in anticancer therapy. However, treatment with classical substrate-site-directed TS inhibitors induces over-expression of this protein and development of drug resistance. We thus pursued an alternative strategy that led us to the discovery of TS-dimer destabilizers. These compounds bind at the monomer-monomer interface and shift the dimerization equilibrium of both the recombinant and the intracellular protein toward the inactive monomers. A structural, spectroscopic, and kinetic investigation has provided evidence and quantitative information on the effects of the interaction of these small molecules with hTS. Focusing on the best among them, E7, we have shown that it inhibits hTS in cancer cells and accelerates its proteasomal degradation, thus causing a decrease in the enzyme intracellular level. E7 also showed a superior anticancer profile to fluorouracil in a mouse model of human pancreatic and ovarian cancer. Thus, over sixty years after the discovery of the first TS prodrug inhibitor, fluorouracil, E7 breaks the link between TS inhibition and enhanced expression in response, providing a strategy to fight drug-resistant cancers.

In Vivo Biodistribution of Respirable Solid Lipid Nanoparticles Surface-Decorated with a Mannose-Based Surfactant: A Promising Tool for Pulmonary Tuberculosis Treatment?

The active targeting to alveolar macrophages (AM) is an attractive strategy to improve the therapeutic efficacy of 'old' drugs currently used in clinical practice for the treatment of pulmonary tuberculosis. Previous studies highlighted the ability of respirable solid lipid nanoparticle assemblies (SLNas), loaded with rifampicin (RIF) and functionalized with a novel synthesized mannose-based surfactant (MS), both alone and in a blend with sodium taurocholate, to efficiently target the AM via mannose receptor-mediated mechanism. Here, we present the in vivo biodistribution of these mannosylated SLNas, in comparison with the behavior of both non-functionalized SLNas and bare RIF. SLNas biodistribution was assessed, after intratracheal instillation in mice, by whole-body real-time fluorescence imaging in living animals and RIF quantification in excised organs and plasma. Additionally, SLNas cell uptake was determined by using fluorescence microscopy on AM from bronchoalveolar lavage fluid and alveolar epithelium from lung dissections. Finally, histopathological evaluation was performed on lungs 24 h after administration. SLNas functionalized with MS alone generated the highest retention in lungs associated with a poor spreading in extra-pulmonary regions. This effect could be probably due to a greater AM phagocytosis with respect to SLNas devoid of mannose on their surface. The results obtained pointed out the unique ability of the nanoparticle surface decoration to provide a potential more efficient treatment restricted to the lungs where the primary tuberculosis infection is located.

The Impact of Lipid Corona on Rifampicin Intramacrophagic Transport Using Inhaled Solid Lipid Nanoparticles Surface-Decorated with a Mannosylated Surfactant.

The mimicking of physiological conditions is crucial for the success of accurate in vitro studies. For inhaled nanoparticles, which are designed for being deposited on alveolar epithelium and taken up by macrophages, it is relevant to investigate the interactions with pulmonary surfactant lining alveoli. As a matter of fact, the formation of a lipid corona layer around the nanoparticles could modulate the cell internalization and the fate of the transported drugs. Based on this concept, the present research focused on the interactions between pulmonary surfactant and Solid Lipid Nanoparticle assemblies (SLNas), loaded with rifampicin, an anti-tuberculosis drug. SLNas were functionalized with a synthesized mannosylated surfactant, both alone and in a blend with sodium taurocholate, to achieve an active targeting to mannose receptors present on alveolar macrophages (AM). Physico-chemical properties of the mannosylated SLNas satisfied the requirements relative to suitable respirability, drug payload, and AM active targeting. Our studies have shown that a lipid corona is formed around SLNas in the presence of Curosurf, a commercial substitute of the natural pulmonary surfactant. The lipid corona promoted an additional resistance to the drug diffusion for SLNas functionalized with the mannosylated surfactant and this improved drug retention within SLNas before AM phagocytosis takes place. Moreover, lipid corona formation did not modify the role of nanoparticle mannosylation towards the specific receptors on MH-S cell membrane.

Discovery of a benzothiophene-flavonol halting miltefosine and antimonial drug resistance in Leishmania parasites through the application of medicinal chemistry, screening and genomics.

Leishmaniasis, a major health problem worldwide, has a limited arsenal of drugs for its control. The appearance of resistance to first- and second-line anti-leishmanial drugs confirms the need to develop new and less toxic drugs that overcome spontaneous resistance. In the present study, we report the design and synthesis of a novel library of 38 flavonol-like compounds and their evaluation in a panel of assays encompassing parasite killing, pharmacokinetics, genomics and ADME-Toxicity resulting in the progression of a compound in the drug discovery value chain. Compound 19, 2-(benzo[b]thiophen-3-yl)-3-hydroxy-6-methoxy-4H-chromen-4-one, exhibited a broad-spectrum activity against Leishmania spp. (EC50 1.9 µM for Leishmania infantum, 3.4 µM for L. donovani, 6.7 µM for L. major), Trypanosoma cruzi (EC50 7.5 µM) and T. brucei (EC50 0.8 µM). Focusing on anti-Leishmania activity, compound 19 challenge in vitro did not select for resistance markers in L. donovani, while a Cos-Seq screening for dominant resistance genes identified a gene locus on chromosome 36 that became ineffective at concentrations beyond EC50. Thus, compound 19 is a promising scaffold to tackle drug resistance in Leishmania infection. In vivo pharmacokinetic studies indicated that compound 19 has a long half-life (intravenous (IV): 63.2 h; per os (PO): 46.9 h) with an acceptable ADME-Toxicity profile. When tested in Leishmania infected hamsters, no toxicity and limited efficacy were observed. Low solubility and degradation were investigated spectroscopically as possible causes for the sub-optimal pharmacokinetic properties. Compound 19 resulted a specific compound based on the screening against a protein set, following the intrinsic fluorescence changes.

SAR Studies and Biological Characterization of a Chromen-4-one Derivative as an Anti-Trypanosoma brucei Agent.

Chemical modulation of the flavonol 2-(benzo[d][1,3]dioxol-5-yl)-chromen-4-one (1), a promising anti-Trypanosomatid agent previously identified, was evaluated through a phenotypic screening approach. Herein, we have performed structure-activity relationship studies around hit compound 1. The pivaloyl derivative (13) showed significant anti-T. brucei activity (EC50 = 1.1 µM) together with a selectivity index higher than 92. The early in vitro ADME-tox properties (cytotoxicity, mitochondrial toxicity, cytochrome P450 and hERG inhibition) were determined for compound 1 and its derivatives, and these led to the identification of some liabilities. The 1,3-benzodioxole moiety in the presented compounds confers better in vivo pharmacokinetic properties than those of classical flavonols. Further studies using different delivery systems could lead to an increase of compound blood levels.

An Overview on the Potential Antimycobacterial Agents Targeting Serine/Threonine Protein Kinases from Mycobacterium tuberculosis.

Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), still remains an urgent global health issue, mainly due to the emergence of multi-drug resistant strains. Therefore, there is a pressing need to develop novel and more efficient drugs to control the disease. In this context, targeting the pathogen virulence factors, and particularly signal mechanisms, seems to be a promising approach. An important transmembrane signaling system in Mtb is represented by receptor-type Serine/ Threonine protein kinases (STPKs). Mtb has 11 different STPKs, two of them, PknA and PknB, are essential. By contrast PknG and PknH are involved in Mtb virulence and adaptation, and are fundamental for the pathogen growth in infection models. Therefore, STPKs represent a very interesting group of pharmacological targets in M. tuberculosis. In this work, the principal inhibitors of the mycobacterial STPKs will be presented and discussed. In particular, medicinal chemistry efforts have been focused on discovering new antimycobacterial compounds, targeting three of these kinases, namely PknA, PknB and PknG. Generally, the inhibitory effect on these enzymes do not correlate with a significant antimycobacterial action in whole-cell assays. However, compounds with activity in the low micromolar range have been obtained, demonstrating that targeting Mtb STPKs could be a new promising strategy for the development of drugs to treat TB infections.

New insight into structure-activity of furan-based salicylate synthase (MbtI) inhibitors as potential antitubercular agents.

Starting from the analysis of the hypothetical binding mode of our previous furan-based hit (I), we successfully achieved our objective to replace the nitro moiety, leading to the disclosure of a new lead exhibiting a strong activity against MbtI. Our best candidate 1 h displayed a Ki of 8.8 µM and its antimycobacterial activity (MIC99 = 250 µM) is conceivably related to mycobactin biosynthesis inhibition. These results support the hypothesis that 5-phenylfuran-2-carboxylic derivatives are a promising class of MbtI inhibitors.

Enhancement of Benzothiazoles as Pteridine Reductase-1 Inhibitors for the Treatment of Trypanosomatidic Infections.

2-Amino-benzo[ d]thiazole was identified as a new scaffold for the development of improved pteridine reductase-1 (PTR1) inhibitors and anti-trypanosomatidic agents. Molecular docking and crystallography guided the design and synthesis of 42 new benzothiazoles. The compounds were assessed for Trypanosoma brucei and Leishmania major PTR1 inhibition and in vitro activity against T. brucei and amastigote Leishmania infantum. We identified several 2-amino-benzo[ d]thiazoles with improved enzymatic activity ( TbPTR1 IC50 = 0.35 µM; LmPTR1 IC50 = 1.9 µM) and low µM antiparasitic activity against T. brucei. The ten most active compounds against TbPTR1 were able to potentiate the antiparasitic activity of methotrexate when evaluated in combination against T. brucei, with a potentiating index between 1.2 and 2.7. The compound library was profiled for early ADME toxicity, and 2-amino- N-benzylbenzo[ d]thiazole-6-carboxamide (4c) was finally identified as a novel potent, safe, and selective anti-trypanocydal agent (EC50 = 7.0 µM). Formulation of 4c with hydroxypropyl-ß-cyclodextrin yielded good oral bioavailability, encouraging progression to in vivo studies.

Drugs/lamellae interface influences the inner structure of double-loaded liposomes for inhaled anti-TB therapy: An in-depth small-angle neutron scattering investigation.

With the aim of developing new drug carriers for inhalation therapy, we report here an in depth investigation of the structure of multilamellar liposomes loaded with two well-established anti-tubercular (anti-TB) drugs, isoniazid (INH) and rifampicin (RIF), by means of small-angle neutron-scattering (SANS) analysis. Unloaded, single drug-loaded and co-loaded liposomes were prepared using different amounts of drugs and characterized regarding size, encapsulation efficiency and drug release. Detailed information on relevant properties of the investigated host-guest structures, namely the steric bilayer thickness, particle dispersion, number of lamellae and drug localization was studied by SANS. Results showed that RIF-liposomes were less ordered than unloaded liposomes. INH induced a change in the inter-bilayer periodical spacing, while RIF-INH co-loading stabilized the multilamellar liposome architecture, as confirmed by the increment of the drug loading capacity. These findings could be useful for the understanding of in vitro and in vivo behavior of these systems and for the design of new drug carriers, intended for inhaled therapy.

Newly synthesized surfactants for surface mannosylation of respirable SLN assemblies to target macrophages in tuberculosis therapy.

The present study reports about new solid lipid nanoparticle assemblies (SLNas) loaded with rifampicin (RIF) surface-decorated with novel mannose derivatives, designed for anti-tuberculosis (TB) inhaled therapy by dry powder inhaler (DPI). Mannose is considered a relevant ligand to achieve active drug targeting being mannose receptors (MR) overexpressed on membranes of infected alveolar macrophages (AM), which are the preferred site of Mycobacterium tuberculosis. Surface decoration of SLNas was obtained by means of newly synthesized functionalizing compounds used as surfactants in the preparation of carriers. SLNas were fully characterized in vitro determining size, morphology, drug loading, drug release, surface mannosylation, cytotoxicity, macrophage internalization extent and ability to bind MR, and intracellular RIF concentration. Moreover, the influence of these new surface functionalizing agents on SLNas aerodynamic performance was assessed by measuring particle respirability features using next generation impactor. SLNas exhibited suitable drug payload, in vitro release, and more efficient ability to enter macrophages (about 80%) compared to bare RIF (about 20%) and to non-functionalized SLNas (about 40%). The involvement of MR-specific binding has been demonstrated by saturating MR of J774 cells causing a decrease of RIF intracellular concentration of about 40%. Furthermore, it is noteworthy that the surface decoration of particles produced a poor cohesive powder with an adequate respirability (fine particle fraction ranging from about 30 to 50%). Therefore, the proposed SLNas may represent an encouraging opportunity in a perspective of an efficacious anti-TB inhaled therapy.

Discovery and development of novel salicylate synthase (MbtI) furanic inhibitors as antitubercular agents.

We report on the virtual screening, synthesis, and biological evaluation of new furan derivatives targeting Mycobacterium tuberculosis salicylate synthase (MbtI). A receptor-based virtual screening procedure was applied to screen the Enamine database, identifying two compounds, I and III, endowed with a good enzyme inhibitory activity. Considering the most active compound I as starting point for the development of novel MbtI inhibitors, we obtained new derivatives based on the furan scaffold. Among the SAR performed on this class, compound 1a emerged as the most potent MbtI inhibitor reported to date (Ki = 5.3 µM). Moreover, compound 1a showed a promising antimycobacterial activity (MIC99 = 156 µM), which is conceivably related to mycobactin biosynthesis inhibition.

New Chromane-Based Derivatives as Inhibitors of Mycobacterium tuberculosis Salicylate Synthase (MbtI): Preliminary Biological Evaluation and Molecular Modeling Studies.

Tuberculosis is the leading cause of death from a single infectious agent worldwide; therefore, the need for new antitubercular drugs is desperate. The recently validated target salicylate synthase MbtI is the first enzyme involved in the biosynthesis of mycobactins, compounds able to chelate iron, an essential cofactor for the survival of Mycobacterium tuberculosis in the host. Here, we report on the synthesis and biological evaluation of chromane-based compounds as new potential inhibitors of MbtI. Our approach successfully allowed the identification of a novel lead compound (1), endowed with a promising activity against this enzyme (IC50 = 55 µM). Molecular modeling studies were performed in order to evaluate the binding mode of 1 and rationalize the preliminary structure-activity relationships, thus providing crucial information to carry out further optimization studies.

Aryl thiosemicarbazones for the treatment of trypanosomatidic infections.

Basing on a library of thiadiazole derivatives showing anti-trypanosomatidic activity, we have considered the thiadiazoles opened forms and reaction intermediates, thiosemicarbazones, as compounds of interest for phenotypic screening against Trypanosoma brucei (Tb), intracellular amastigote form of Leishmania infantum (Li) and Trypanosoma cruzi (Tc). Similar compounds have already shown interesting activity against the same organisms. The compounds were particularly effective against T. brucei and T. cruzi. Among the 28 synthesized compounds, the best one was (E)-2-(4-((3.4-dichlorobenzyl)oxy)benzylidene) hydrazinecarbothioamide (A14) yielding a comparable anti-parasitic activity against the three parasitic species (TbEC50 = 2.31 µM, LiEC50 = 6.14 µM, TcEC50 = 1.31 µM) and a Selectivity Index higher than 10 with respect to human macrophages, therefore showing a pan-anti-trypanosomatidic activity. (E)-2-((3'.4'-dimethoxy-[1.1'-biphenyl]-3-yl)methyle ne) hydrazinecarbothioamide (A12) and (E)-2-(4-((3.4-dichlorobenzyl)oxy)benzylidene)hydrazine carbothioamide (A14) were able to potentiate the anti-parasitic activity of methotrexate (MTX) when evaluated in combination against T. brucei, yielding a 6-fold and 4-fold respectively Dose Reduction Index for MTX. The toxicity profile against four human cell lines and a panel of in vitro early-toxicity assays (comprising hERG, Aurora B, five cytochrome P450 isoforms and mitochondrial toxicity) demonstrated the low toxicity for the thosemicarbazones class in comparison with known drugs. The results confirmed thiosemicarbazones as a suitable chemical scaffold with potential for the development of properly decorated new anti-parasitic drugs.

Aryl thiosemicarbazones for the treatment of trypanosomatidic infections

Basing on a library of thiadiazole derivatives showing anti-trypanosomatidic activity, we have considered the thiadiazoles opened forms and reaction intermediates, thiosemicarbazones, as compounds of interest for phenotypic screening against Trypanosoma brucei (Tb), intracellular amastigote form of Leishmania infantum (Li) and Trypanosoma cruzi (Tc). Similar compounds have already shown interesting activity against the same organisms. The compounds were particularly effective against T. brucei and T. cruzi. Among the 28 synthesized compounds, the best one was (E)-2-(4-((3.4-dichlorobenzyl)oxy)benzylidene) hydrazinecarbothioamide (A14) yielding a comparable anti-parasitic activity against the three parasitic species (TbEC50=231 mu M, LiEC50 = 6.14 mu M, TcEC50 = 1.31 mu M) and a Selectivity Index higher than 10 with respect to human macrophages, therefore showing a pan-anti-trypanosomatidic activity. (E)-2-((3'.4'-dimethoxy-[1.1'-biphenyl]-3-yl)methyle ne) hydrazinecarbothioamide (A12) and (E)-2-(4-((3.4-dichlorobenzyl)oxy)benzylidene)hydrazine carbothioamide (A14) were able to potentiate the anti parasitic activity of methotrexate (MTX) when evaluated in combination against T. brucei, yielding a 6 fold and 4-fold respectively Dose Reduction Index for MTX. The toxicity profile against four human cell lines and a panel of in vitro early-toxicity assays (comprising hERG, Aurora B, five cytochrome P450 isoforms and mitochondrial toxicity) demonstrated the low toxicity for the thosemicarbazones class in comparison with known drugs. The results confirmed thiosemicarbazones as a suitable chemical scaffold with potential for the development of properly decorated new anti-parasitic drugs.

Aryl thiosemicarbazones for the treatment of trypanosomatidic infections

Basing on a library of thiadiazole derivatives showing anti-trypanosomatidic activity, we have considered the thiadiazoles opened forms and reaction intermediates, thiosemicarbazones, as compounds of interest for phenotypic screening against Trypanosoma brucei (Tb), intracellular amastigote form of Leishmania infantum (Li) and Trypanosoma cruzi (Tc). Similar compounds have already shown interesting activity against the same organisms. The compounds were particularly effective against T. brucei and T. cruzi. Among the 28 synthesized compounds, the best one was (E)-2-(4-((3.4-dichlorobenzyl)oxy)benzylidene) hydrazinecarbothioamide (A14) yielding a comparable anti-parasitic activity against the three parasitic species (TbEC50=231 mu M, LiEC50 = 6.14 mu M, TcEC50 = 1.31 mu M) and a Selectivity Index higher than 10 with respect to human macrophages, therefore showing a pan-anti-trypanosomatidic activity. (E)-2-((3'.4'-dimethoxy-[1.1'-biphenyl]-3-yl)methyle ne) hydrazinecarbothioamide (A12) and (E)-2-(4-((3.4-dichlorobenzyl)oxy)benzylidene)hydrazine carbothioamide (A14) were able to potentiate the anti parasitic activity of methotrexate (MTX) when evaluated in combination against T. brucei, yielding a 6 fold and 4-fold respectively Dose Reduction Index for MTX. The toxicity profile against four human cell lines and a panel of in vitro early-toxicity assays (comprising hERG, Aurora B, five cytochrome P450 isoforms and mitochondrial toxicity) demonstrated the low toxicity for the thosemicarbazones class in comparison with known drugs. The results confirmed thiosemicarbazones as a suitable chemical scaffold with potential for the development of properly decorated new anti-parasitic drugs.

Exploiting the 2-Amino-1,3,4-thiadiazole Scaffold To Inhibit Trypanosoma brucei Pteridine Reductase in Support of Early-Stage Drug Discovery.

Pteridine reductase-1 (PTR1) is a promising drug target for the treatment of trypanosomiasis. We investigated the potential of a previously identified class of thiadiazole inhibitors of Leishmania major PTR1 for activity against Trypanosoma brucei (Tb). We solved crystal structures of several TbPTR1-inhibitor complexes to guide the structure-based design of new thiadiazole derivatives. Subsequent synthesis and enzyme- and cell-based assays confirm new, mid-micromolar inhibitors of TbPTR1 with low toxicity. In particular, compound 4m, a biphenyl-thiadiazole-2,5-diamine with IC50 = 16 µM, was able to potentiate the antitrypanosomal activity of the dihydrofolate reductase inhibitor methotrexate (MTX) with a 4.1-fold decrease of the EC50 value. In addition, the antiparasitic activity of the combination of 4m and MTX was reversed by addition of folic acid. By adopting an efficient hit discovery platform, we demonstrate, using the 2-amino-1,3,4-thiadiazole scaffold, how a promising tool for the development of anti-T. brucei agents can be obtained.

Surface engineering of Solid Lipid Nanoparticle assemblies by methyl α-d-mannopyranoside for the active targeting to macrophages in anti-tuberculosis inhalation therapy.

This study describes the development of new mannosylated Solid Lipid Nanoparticle assemblies (SLNas) delivering rifampicin for an inhaled treatment of tuberculosis. SLNas were surface engineered with mannose residues to recognize mannose receptors located on infected alveolar macrophages and facilitate cell internalization. Two sets of SLNas were produced by the melt emulsifying technique using biocompatible lipid components, i.e. cholesteryl myristate combined with palmitic acid (PA set) or tripalmitin (TP set), in the presence of the targeting moiety, methyl α-d-mannopyranoside. Mannosylated SLNas were examined for their physical properties, drug payloads and release, as well as respirability in terms of emitted dose and respirable fraction determined by Next Generation Impactor. The most appropriate formulations were assessed for mannosylation using FTIR, XPS, SEM coupled with EDX analysis, and wettability assay, in comparison with the respective non-functionalized SLNas. Besides, cytotoxicity and cell internalization ability were established on J774 murine macrophage cell line. Mannosylated SLNas exhibited physical properties suitable for alveolar macrophage passive targeting, adequate rifampicin payloads (10-15%), and feasible drug maintenance within SLNas along the respiratory tract before macrophage internalization. Despite respirability impaired by powder cohesiveness, surface mannosylation provided quicker macrophage phagocytosis, giving evidence of an active targeting promotion.

Laparoscopic Transarterial Embolization of Type II Endoleak after Branched/Fenestrated Thoracoabdominal Aortic Aneurysm Endovascular Repair.

Type II endoleak is the most frequent procedure-related complication during endovascular aneurysm exclusion. Actually, there is little controversy in the management of type I and III endoleak, while type II endoleak still generates conflicting reports about their timing and type of treatment. Currently, the intervention is needed only in case of sac enlargement but not in case of persistent endoleak alone. We report the case of a 77-year-old man treated with a custom-made branched/fenestrated endograft for a type III thoracoabdominal aortic aneurysm. A low-flow type II endoleak was detected at the end of the intervention, and a conservative approach was adopted. The sixth month follow-up computed tomography scan demonstrated a 6-mm aneurysm sac growth that required the type II endoleak management. The endoleak nidus, situated between the inferior mesenteric artery (IMA) and left renal artery stent graft, was embolized through the IMA punctured laparoscopically. IMA origin laparoscopic clipping completed the intervention. To our knowledge, this is a unique case in the literature. Type II endoleak management should be reserved to selected patients. The combination of different techniques may offer safe and feasible treatment options in complex aneurysms treated with advanced endovascular materials.

Methoxylated 2'-hydroxychalcones as antiparasitic hit compounds.

Chalcones display a broad spectrum of pharmacological activities. Herein, a series of 2'-hydroxy methoxylated chalcones was synthesized and evaluated towards Trypanosoma brucei, Trypanosoma cruzi and Leishmania infantum. Among the synthesized library, compounds 1, 3, 4, 7 and 8 were the most potent and selective anti-T. brucei compounds (EC50 = 1.3-4.2 µM, selectivity index >10-fold). Compound 4 showed the best early-tox and antiparasitic profile. The pharmacokinetic studies of compound 4 in BALB/c mice using hydroxypropil-ß-cyclodextrins formulation showed a 7.5 times increase in oral bioavailability.