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14 p.-11 fig., Prion diseases are characterized by the self-assembly of pathogenic misfolded scrapie isoforms (PrPSc) of the cellular prion protein (PrPC). In an effort to achieve a theranostic profile, symmetrical bifunctional carbazole derivatives were designed as fluorescent rigid analogues of GN8, a pharmacological chaperone that stabilizes the native PrPC conformation and prevents its pathogenic conversion. A focused library was synthesized via a four-step route, and a representative member was confirmed to have native fluorescence, including a band in the near-infrared region. After a cytotoxicity study, compounds were tested on the RML-infected ScGT1 neuronal cell line, by monitoring the levels of protease-resistant PrPSc. Small dialkylamino groups at the ends of the molecule were found to be optimal in terms of therapeutic index, and the bis-(dimethylaminoacetamido)carbazole derivative 2b was selected for further characterization. It showed activity in two cell lines infected with the mouse-adapted RML strain (ScGT1 and ScN2a). Unlike GN8, 2b did not affect PrPC levels, which represents a potential advantage in terms of toxicity. Amyloid Seeding Assay (ASA) experiments showed the capacity of 2b to delay the aggregation of recombinant mouse PrP. Its ability to interfere with the amplification of the scrapie RML strain by Protein Misfolding Cyclic Amplification (PMCA) was shown to be higher than that of GN8, although 2b did not inhibit the amplification of human vCJD prion. Fluorescent staining of PrPSc aggregates by 2b was confirmed in living cells. 2b emerges as an initial hit compound for further medicinal chemistry optimization towards strain-independent anti-prion compounds., This work was partially supported by Associazione Italiana Encefalopatie da Prioni (AIEnP) and the Italian Ministry of Health (RRC) to FM. Financial support from Ministerio de Ciencia e Innovación, Spain, through grants RTI2018-097662-B-I00 and PID2021-124983OB-I00 (to JCM) and PID2019-105600RB-I00 (to AM), is also gratefully acknowledged.

58 p.-6 fig.-1 tab.-5 schem.-1 graph.abst, A new class of quinoline derivatives, bearing amino chains at C-4 and a styryl group at C-2, were tested on Leishmania donovani promastigotes and axenic and intracellular Leishmania pifanoi amastigotes. The introduction of the C-4 substituent improves the activity, which is due to interference with the mitochondrial activity of the parasite and its concomitant bioenergetic collapse by ATP exhaustion. Some compounds show a promising antileishmanial profile, with low micromolar or submicromolar activity on promastigote and amastigote forms and a good selectivity index., This research was supported by the following grants; (a) MLB: MIUR, PRIN 201274BNKN_003; (b) JCM: Universidad Complutense (GR3/14) and MINECO (CTQ2015-68380-R); (c) LR: RD16/0027/0010, CSIC PIE-201020E054 and MINECO SAF2015-65740-R. A predoctoral contracts to MS from Universidad Complutense and a FPI contract to MP from MINECO (BES-2016–076410P) are also gratefully acknowledged.

Although the progress made, poverty-related trypanosomatid diseases remain an area of concern for the drug discovery community. The inadequacy of available treatments, especially in terms of low access, high toxicity and complicated administration regimens, calls for endeavors focused on sustainable principles. These should guide all involved stakeholders, including medicinal chemists. Accordingly, a strategy exploiting privileged-structures-based phenotypic libraries might be useful to identify hits in a cost- and time-effective manner. On these bases, we generated a library by fast assembling phenothiazine, biphenyl and phenylpiperazine privileged fragments via a Huisgen cycloaddition. Thanks to available screening facilities, the library was screened for activity against Trypanosoma brucei and cruzi, Leishmania infantum and donovani, for selectivity against mammalian cells, and for ADME-Tox properties. Despite the small number of synthesized compounds, this strategy led to the successful identification of interesting hits with promising profiles. Another extraordinary possibility is the development of new drugs based on food industry wastes as sustainable starting materials. Toward this aim, we developed a series of novel T. brucei hits obtained by combining a 2-phenoxy-1,4-naphthoquinone scaffold with phenolic constituents from the cashew nut shell liquid (CNSL), a by-product and a pollutant from cashew nut processing factories. We envisage that such compounds, easily obtained from a waste material produced in high quantity in the endemic countries, might be ethically, environmentally and economically sustainable starting point for the development of new anti-trypanosomatid drugs.

Therapy of prion diseases represents an extremely challenging effort for scientists working in the field. These challenges are epitomized by 20 years of failures in clinical trials and preclinical investigations. However, the discovery that misfolded proteins involved in other neurodegenerative diseases show a prion-like mechanism of spreading, is positively impacting the prion drug discovery field. Herein, we describe those efforts that have contributed to strengthen the drug discovery process in prion diseases. Accordingly, we analyze the historical course of clinical trials that have assessed the efficacy of several chemically unrelated repositioned drugs. Unfortunately, none of them resulted successful. Thus, alternative approaches aiming at identifying innovative drugs with a completely new mechanism of action, have been recently pursued. In this respect, the multifactorial nature of prion diseases provides a strong foundation to the development of small molecules directed to two or multiple pathological targets, critically involved in the intricate disease pathogenesis (i.e., multitarget compounds). Second, the fact that misfolded proteins can be considered not only as therapeutic target, but also as neuropathological hallmark, lends support to the development of theranostics, i.e., single molecules with concomitant therapeutic and diagnostic properties. Although nobody knows whether these innovative tools will be brought to clinical trials, and the process is certainly time-consuming and demanding, the rewards are well worth the effort.

In this work, we report a rational structure-based approach aimed at the discovery of new 2-aminoimidazoles as β-secretase inhibitors. Taking advantage of a microwave-assisted synthetic protocol, a small library of derivatives was obtained and biologically evaluated. Two compounds showed promising activities in both enzymatic and cellular assays. Moreover, one of them exhibited the capability to cross the blood-brain barrier as assessed by the parallel artificial membrane permeability assay. © 2011 Elsevier Ltd. All rights reserved.

The concept that polyamines may represent a passe-partout (Master key) for G—protein—coupled receptors recognition is illustrated. Using a linear tetraamine as the focus, appropriate structural modifications have allowed to obtain novel tetraamines displaying selectivity for different receptor systems. It is shown that tetraamines have receptor subtype selectivity since they are site-directed, owing to different chain lengths separating the protonable nitrogens and to the presence of those peculiar structural elements which make them able of discriminating at the binding stage.