Beatrice Trucchi

The evolution of drug resistance is a recurrent problem that has plagued efforts to treat and control malaria. Recent emergence of artemisinin resistance in Southeast Asia underscores the need to develop novel antimalarials and identify new targetable pathways in Plasmodium parasites. Transmission-​blocking approaches, which typically target gametocytes or other parasite stages in the mosquito gut, are recognized collectively as a viable strategy that when used in combination with… Visualizza altro

The evolution of drug resistance is a recurrent problem that has plagued efforts to treat and control malaria. Recent emergence of artemisinin resistance in Southeast Asia underscores the need to develop novel antimalarials and identify new targetable pathways in Plasmodium parasites. Transmission-​blocking approaches, which typically target gametocytes or other parasite stages in the mosquito gut, are recognized collectively as a viable strategy that when used in combination with antimalarials targeting erythrocytic stages will not only cure malaria but will also break the parasite life cycle and prevent subsequent transmission. The authors tested four derivs. of (+)​-​usnic acid, a metabolite isolated from lichens, for transmission-​blocking activity against Plasmodium falciparum using the std. membrane feeding assay. For two of the derivs., BT37 and BT122, the authors obsd. a consistent dose-​response relationship between concn. in the blood meal and oocyst intensity in the midgut. To explore their mechanism of action the authors used the murine model Plasmodium berghei and found that both derivs. interfere with ookinete maturation. Using fluorescence microscopy the authors demonstrated that in the presence of each compd. P. berghei macro- and microgametes successfully form zygotes but fail to elongate and mature into ookinetes. The obsd. phenotype matches those in recent descriptions of inner membrane complex 1 (IMC1) protein mutants. IMC1 proteins are part of the subpellicular lattice of intermediate filaments that contributes to ookinete polarization and shape. The authors discuss the implications of the findings and the high-​throughput screening approach to identify next generation, transmission-​blocking antimalarials based on the scaffolds of these (+)​-​usnic acid derivs. Meno dettagli

Wound healing is a significant concern in many pathologies (post-​surgeries, burns, scars) and the search for new chem. entities is advisable. The lichen compd. (+)​-​usnic acid (1) has found application in dermatol. and cosmetic prepns., due to its bacteriostatic and antioxidant activities. The compd. has also been shown to stimulate the wound closure of keratinocyte monolayers at subtoxic doses. Here we describe the design and synthesis of usnic acid enamines (compds. 2-​11)​, obtained… Visualizza altro

Wound healing is a significant concern in many pathologies (post-​surgeries, burns, scars) and the search for new chem. entities is advisable. The lichen compd. (+)​-​usnic acid (1) has found application in dermatol. and cosmetic prepns., due to its bacteriostatic and antioxidant activities. The compd. has also been shown to stimulate the wound closure of keratinocyte monolayers at subtoxic doses. Here we describe the design and synthesis of usnic acid enamines (compds. 2-​11)​, obtained through nucleophilic attack of amino acids or decarboxyamino acids at the acyl carbonyl of the enolized 1,​3 diketone. The wound repair properties of these derivs. were evaluated using in vitro and in vivo assays. Compds. 8 and 9 combine low cytotoxicity with high wound healing performance, suggesting their possible use in wound healing-​promoting or antiage skin preparations. Meno dettagli

Valosine contg. protein (VCP)​, also known as p97, is a member of AAA ATPase family that is involved in several biol. processes and plays a central role in the ubiquitin-​mediated degrdn. of misfolded proteins. VCP is an ubiquitously expressed, highly abundant protein and has been found overexpressed in many tumor types, sometimes assocd. with poor prognosis. In this respect, VCP has recently received a great deal of attention as a potential new target for cancer therapy. In this paper, the… Visualizza altro

Valosine contg. protein (VCP)​, also known as p97, is a member of AAA ATPase family that is involved in several biol. processes and plays a central role in the ubiquitin-​mediated degrdn. of misfolded proteins. VCP is an ubiquitously expressed, highly abundant protein and has been found overexpressed in many tumor types, sometimes assocd. with poor prognosis. In this respect, VCP has recently received a great deal of attention as a potential new target for cancer therapy. In this paper, the discovery and structure-​activity relationships of alkylsulfanyl-​1,​2,​4-​triazoles, a new class of potent, allosteric VCP inhibitors, are described. Medicinal chem. manipulation of 3-​(isopropylthio)​-​5-​(phenoxymethyl)​-​4-​phenyl-​1,​2,​4-​triazole, identified via HTS, led to the discovery of potent and selective inhibitors with submicromolar activity in cells and clear mechanism of action at consistent doses. This represents a first step toward a new class of potential anticancer agents. Meno dettagli

We report a new approach to design new antimalarial agents through natural products conjugation.

The Strecker-​type reaction of isatin derived chiral ketimines with TMSCN was investigated in the presence of Lewis acids. The desired α-​amino nitriles have been obtained in good yields with moderate diastereoselectivity. Further elaboration of the cyanide group allowed the prepn. of a new oxindole-​based peptidomimetic and a pharmaceutically relevant spirohydantoin.

Gliosis is a biol. process that occurs during injury repair in the central nervous system and is characterized by the overexpression of the intermediate filaments (IFs) glial fibrillary acidic protein (GFAP) and vimentin. A common thread in many retinal diseases is reactive Mueller cell gliosis, an untreatable condition that leads to tissue scarring and even blindness. Here, we demonstrate that the vimentin-​targeting small mol. withaferin A (WFA) is a novel chem. probe of GFAP. Using mol… Visualizza altro

Gliosis is a biol. process that occurs during injury repair in the central nervous system and is characterized by the overexpression of the intermediate filaments (IFs) glial fibrillary acidic protein (GFAP) and vimentin. A common thread in many retinal diseases is reactive Mueller cell gliosis, an untreatable condition that leads to tissue scarring and even blindness. Here, we demonstrate that the vimentin-​targeting small mol. withaferin A (WFA) is a novel chem. probe of GFAP. Using mol. modeling studies that build on the x-​ray crystal structure of tetrameric vimentin rod 2B domain we reveal that the WFA binding site is conserved in the corresponding domain of tetrameric GFAP. Consequently, we demonstrate that WFA covalently binds sol. recombinant tetrameric human GFAP at cysteine 294. In cultured primary astrocytes, WFA binds to and down-​regulates sol. vimentin and GFAP expression to cause cell cycle G0/G1 arrest. Exploiting a chem. injury model that overexpresses vimentin and GFAP in retinal Mueller glia, we demonstrate that systemic delivery of WFA down-​regulates sol. vimentin and GFAP expression in mouse retinas. This pharmacol. knockdown of sol. IFs results in the impairment of GFAP filament assembly and inhibition of cell proliferative response in Mueller glia. We further show that a more severe GFAP filament assembly deficit manifests in vimentin-​deficient mice, which is partly rescued by WFA. These findings illustrate WFA as a chem. probe of type III IFs and illuminate this class of withanolide as a potential treatment for diverse gliosis-​dependent central nervous system traumatic injury conditions and diseases, and for orphan IF-​dependent pathologies. Meno dettagli

Salvia somalensis Vatke, a wild sage native of Somalia, has been studied with the aim of assessing the potential cosmetic application of its essential oil, recovered from fresh aerial parts by solvent-​free microwave extn. - SFME. To evaluate the efficiency and reliability of this ecofriendly procedure, the recovery of the essential oil was also processed by conventional hydrodistn. (HD) and the results compared. The essential oils obtained by both SFME and HD were analyzed by gas… Visualizza altro

Salvia somalensis Vatke, a wild sage native of Somalia, has been studied with the aim of assessing the potential cosmetic application of its essential oil, recovered from fresh aerial parts by solvent-​free microwave extn. - SFME. To evaluate the efficiency and reliability of this ecofriendly procedure, the recovery of the essential oil was also processed by conventional hydrodistn. (HD) and the results compared. The essential oils obtained by both SFME and HD were analyzed by gas chromatog.-​mass spectrometry using apolar and polar capillary columns. The essential oil recovered by SFME was submitted to an odor evaluation that revealed peculiar olfactive characteristics interesting in alc. male perfumery and body detergents. In vitro cytotoxicity assays were carried out using NCTC 2544 human keratinocytes as target cells. The oil displayed slight cytotoxic effects, which were three orders of magnitude lower than those found for sodium dodecyl sulfate pos. control. The promising results in terms of chem. compn., scent and safety seem to indicate this essential oil as an interesting potential functional ingredient useful in a cosmetic context. Meno dettagli

Several alcohols - interesting as cosmetic fragrances whose main preparative route on an industrial scale or in the research lab. is the redn. of the corresponding carbonyl compd. - were obtained by a solvent-​free methodol. in a green chem. context. The process involves the simple mixing of the carbonyl compd. with sodium borohydride dispersed in wet alumina in the solid state; the conversions of the carbonyl compds. were obtained in good yields within short reaction times, without energy… Visualizza altro

Several alcohols - interesting as cosmetic fragrances whose main preparative route on an industrial scale or in the research lab. is the redn. of the corresponding carbonyl compd. - were obtained by a solvent-​free methodol. in a green chem. context. The process involves the simple mixing of the carbonyl compd. with sodium borohydride dispersed in wet alumina in the solid state; the conversions of the carbonyl compds. were obtained in good yields within short reaction times, without energy consumption. The following carbinols were studied: octan-​3-​ol, 2-​cineolylols (endo-​exo mixt.)​, α-​ionol, 4-​methylbenzyl alc., 1-​phenylethanol, trans-​cinnamyl alc., p-​anisyl alc., 4-​phenyl-​3-​buten-​2-​ol. Meno dettagli