Search

Targeted protein degradation (TPD) is emerging as one of the most innovative strategies to tackle infectious diseases. Particularly, proteolysis-targeting chimera (PROTAC)-mediated protein degradation may offer several benefits over classical anti-infective small-molecule drugs. Because of their peculiar and catalytic mechanism of action, anti-infective PROTACs might be advantageous in terms of efficacy, toxicity, and selectivity. Importantly, PROTACs may also overcome the emergence of antimicrobial resistance. Furthermore, anti-infective PROTACs might have the potential to (i) modulate "undruggable"targets, (ii) "recycle"inhibitors from classical drug discovery approaches, and (iii) open new scenarios for combination therapies. Here, we try to address these points by discussing selected case studies of antiviral PROTACs and the first-in-class antibacterial PROTACs. Finally, we discuss how the field of PROTAC-mediated TPD might be exploited in parasitic diseases. Since no antiparasitic PROTAC has been reported yet, we also describe the parasite proteasome system. While in its infancy and with many challenges ahead, we hope that PROTAC-mediated protein degradation for infectious diseases may lead to the development of next-generation anti-infective drugs.

Alzheimer's disease (AD), the most common type of dementia, currently represents an extremely challenging and unmet medical need worldwide. Amyloid-β (Aβ) and Tau proteins are prototypical AD hallmarks, as well as validated drug targets. Accumulating evidence now suggests that they synergistically contribute to disease pathogenesis. This could not only help explain negative results from anti-Aβ clinical trials but also indicate that therapies solely directed at one of them may have to be reconsidered. Based on this, herein, we describe the development of a focused library of 2,4-thiazolidinedione (TZD)-based bivalent derivatives as dual Aβ and Tau aggregation inhibitors. The aggregating activity of the 24 synthesized derivatives was tested in intact Escherichia coli cells overexpressing Aβ42 and Tau proteins. We then evaluated their neuronal toxicity and ability to cross the blood-brain barrier (BBB), together with the in vitro interaction with the two isolated proteins. Finally, the most promising (most active, nontoxic, and BBB-permeable) compounds 22 and 23 were tested in vivo, in a Drosophila melanogaster model of AD. The carbazole derivative 22 (20 μM) showed extremely encouraging results, being able to improve both the lifespan and the climbing abilities of Aβ42 expressing flies and generating a better outcome than doxycycline (50 μM). Moreover, 22 proved to be able to decrease Aβ42 aggregates in the brains of the flies. We conclude that bivalent small molecules based on 22 deserve further attention as hits for dual Aβ/Tau aggregation inhibition in AD., This work was conducted by A.E.G during a scholarship at the University of Bologna, Italy, supported by the International Cooperation Program CAPES/ PDSE Process #88881.187586/ 2018-01. O.S. acknowledges the Ministry of Education, Youth and Sports of the Czech Republic (project ERDF no. CZ.02.1.01/0.0/0.0/18_069/0010054). DMT: grant PID2020-118127RB-I00 funded by MCIN/AEI/10.13039/501100011033. M.L.B. and M.B. would also like to acknowledge the University of Bologna (RFO 2019) and the Italian Ministry of Education, Universities and Research (MIUR), for financial support.

Background: Molecules with a phenothiazine scaffold have been considered versatile organic structures with a wide variety of biological activities, such as antipsychotic, anticancer, antibacterial, antifungal, antiviral, anti-inflammatory, antimalarial, and trypanocidal, etc. It was first discovered in the 19th century as a histochemical dye, phenothiazine methylene blue. Since then, its derivatives have been studied, showing new activities; moreover, they have also been repurposed. Objective: This review aims to describe the main synthetic routes of phenothiazines and, particularly, the anticancer and antiprotozoal activities reported during the second decade of the 2000s (2010 - 2020). Results: Several studies on phenothiazines against cancer and protozoa have revealed that these compounds show IC50 values in the micromolar and near nanomolar range. The structural analyses have revealed that compounds bearing halogens or electron-withdrawing groups at 2-position have favorable anticancer activity. Phenothiazine dyes have shown a photosensitizing activity against trypanosomatids at a micromolar range. Tetra and pentacyclic azaphenothiazines are structures with a high broad-spectrum anticancer activity. Conclusion: The phenothiazine scaffold is favorable for developing anticancer agents, especially those bearing halogens and electron-withdrawing groups bound at 2-position with enhanced biological activities through a variety of aromatic, aliphatic and heterocyclic substituents in the thiazine nitrogen. Further studies are warranted along these investigation lines to attain more active anticancer and antiprotozoal compounds with minimal to negligible cytotoxicity.

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.

Prion diseases are a group of neurodegenerative disorders characterized by the accumulation of misfolded prion protein (called PrPSc). Although conversion of the cellular prion protein (PrPC) to PrPSc is still not completely understood, most of the therapies developed until now are based on blocking this process. Here, we propose a new drug strategy aimed at clearing prions without any direct interaction with neither PrPC nor PrPSc. Starting from the recent discovery of SERPINA3/SerpinA3n upregulation during prion diseases, we have identified a small molecule, named compound 5 (ARN1468), inhibiting the function of these serpins and effectively reducing prion load in chronically infected cells. Although the low bioavailability of this compound does not allow in vivo studies in prion-infected mice, our strategy emerges as a novel and effective approach to the treatment of prion disease.

The multifactorial nature of Alzheimer's disease (AD) is a reason for the lack of effective drugs as well as a basis for the development of "multi-target-directed ligands" (MTDLs). As cases increase in developing countries, there is a need of new drugs that are not only effective but also accessible. With this motivation, we report the first sustainable MTDLs, derived from cashew nutshell liquid (CNSL), an inexpensive food waste with anti-inflammatory properties. We applied a framework combination of functionalized CNSL components and well-established acetylcholinesterase (AChE)/butyrylcholinesterase (BChE) tacrine templates. MTDLs were selected based on hepatic, neuronal, and microglial cell toxicity. Enzymatic studies disclosed potent and selective AChE/BChE inhibitors (5, 6, and 12), with subnanomolar activities. The X-ray crystal structure of 5 complexed with BChE allowed rationalizing the observed activity (0.0352 nM). Investigation in BV-2 microglial cells revealed antineuroinflammatory and neuroprotective activities for 5 and 6 (already at 0.01 mu M), confirming the design rationale.

Chromenopyrrole derivatives with multiple stereocenters and variable ring fusion pattern are found in many natural products and biologically appealing molecules. By employing a build/couple/pair strategy, we have recently reported on the discovery of a serendipitous cascade to access a diverse collection of chromenopyrroles. This protocol features a one-pot cascade that includes the generation of azomethine ylide and intramolecular [3 + 2]-cycloaddition. Phenotypic screening of the developed pilot library enabled the identification of chemical probes that efficiently suppress mitochondrial membrane potential, elevate reactive oxygen species content, and deplete ATP content in a hepatoma cell line (Hepa1-6), without affecting the proliferation of T- or B-cells. This selective targeting represents a new approach for the treatment of cancer. [Figure not available: see fulltext.]

Thanks to the widespread use and safety profile of donepezil (1) in the treatment of Alzheimer's disease (AD), one of the most widely adopted multi-target-directed ligand (MTDL) design strategies is to modify its molecular structure by linking a second fragment carrying an additional AD-relevant biological property. Herein, supported by a proposed combination therapy of 1 and the quinone drug idebenone, we rationally designed novel 1-based MTDLs targeting Aβ and oxidative pathways. By exploiting a bioisosteric replacement of the indanone core of 1 with a 1,4-naphthoquinone, we ended up with a series of highly merged derivatives, in principle devoid of the “physicochemical challenge” typical of large hybrid-based MTDLs. A preliminary investigation of their multi-target profile identified 9, which showed a potent and selective butyrylcholinesterase inhibitory activity, together with antioxidant and antiaggregating properties. In addition, it displayed a promising drug-like profile.

Despite the applicability of histone deacetylase inhibitors (HDACis) for cancer treatment, several works in the literature have shown that these inhibitors can be used in several other diseases, such as neurodegenerative diseases (NDs). This review begins by discussing the signaling pathways of HDACs, focused on the context of NDs, presenting a discussion about the pharmacophoric features of HDACis and crystal structure analysis and discussing interesting case studies from the literature about the development of HDACis. Additionally, a discussion about the consequences of isoform-selective inhibition vs pan-HDACis on neurotoxic effects and clinical trial investigations of HDACis for NDs is also presented. Finally, we describe our perspective related to the future use of these inhibitors in the pharmacotherapy of NDs.

The last two decades or so have witnessed an upsurge in defining the art of designing complex natural products and nature-inspired molecules. Throughout these decades, fundamental insights into stereocontrolled, step-economic and atom-economical synthesis principles were achieved by the numerous synthetic accomplishments particularly in diversity-oriented synthesis (DOS). This has empowered the visualization of the third dimension in synthetic design and thus has resulted in a dramatic increase with today's diversity-oriented synthesis (DOS) at the forefront enabling access to diverse scaffolds with a high degree of stereochemical and skeletal complexity. To this end, a starting material-based approach is one of the powerful tools utilized in DOS that allows rapid access to molecular architectures with a high sp3 content. Skeletal and stereochemical diversity is often paramount for the selective modulation of the biological function of a complementary protein in the biological space. In this context, stereocontrolled transformation of cyclohexadienone scaffolds has positioned itself as a powerful platform for the rapid generation of stereochemically enriched and natural product-inspired compound collections. In this review, we cover multidirectional synthetic strategies that utilized cyclohexadienone derivatives as pluripotent building blocks en route for the construction of novel chemical space. This journal is

Polypharmacology is a new trend in amyotrophic lateral sclerosis (ALS) therapy and an effective way of addressing a multifactorial etiology involving excitotoxicity, mitochondrial dysfunction, oxidative stress, and microglial activation. Inspired by a reported clinical trial, we converted a riluzole (1)-rasagiline (2) combination into single-molecule multi-target-directed ligands. By a ligand-based approach, the highly structurally integrated hybrids 3-8 were designed and synthesized. Through a target- and phenotypic-based screening pipeline, we identified hit compound 6. It showed monoamine oxidase A (MAO-A) inhibitory activity (IC50 = 6.9 mu M) rationalized by in silico studies as well as in vitro brain permeability. By using neuronal and non-neuronal cell models, including ALS-patient-derived cells, we disclosed for 6 a neuroprotective/neuroinflammatory profile similar to that of the parent compounds and their combination. Furthermore, the unexpected MAO inhibitory activity of 1 (IC50 = 8.7 mu M) might add a piece to the puzzle of its anti-ALS molecular profile.

Proteolysis targeting chimera (PROTAC)-mediated protein degradation has prompted a radical rethink and is at a crucial stage in driving a drug discovery transition. To fully harness the potential of this technology, a growing paradigm toward enriching PROTACs with other therapeutic modalities has been proposed. Could researchers successfully combine two modalities to yield multifunctional PROTACs with an expanded profile? In this Perspective, we try to answer this question. We discuss how this possibility encompasses different approaches, leading to multitarget PROTACs, light-controllable PROTACs, PROTAC conjugates, and macrocycle-and oligonucleotide-based PROTACs. This possibility promises to further enhance PROTAC efficacy and selectivity, minimize side effects, and hit undruggable targets. While PROTACs have reached the clinical investigation stage, additional steps must be taken toward the translational development of multifunctional PROTACs. A deeper and detailed understanding of the most critical challenges is required to fully exploit these opportunities and decisively enrich the PROTAC toolbox.

Prion diseases are fatal neurodegenerative disorders, for which there are no effective therapeutic and diagnostic agents. The main pathological hallmark has been identified as conformational changes of the cellular isoform prion protein (PrP

The transcriptional regulators YAP (Yes-associated protein) and TAZ (transcriptional co-activator with PDZ-binding motif) are the major downstream effectors in the Hippo pathway and are involved in cancer progression through modulation of the activity of TEAD (transcriptional enhanced associate domain) transcription factors. To exploit the advantages of drug repurposing in the search of new drugs, we developed a similar approach for the identification of new hits interfering with TEAD target gene expression. In our study, a 27-member in-house library was assembled, characterized, and screened for its cancer cell growth inhibition effect. In a secondary luciferase-based assay, only seven compounds confirmed their specific involvement in TEAD activity. IA5 bearing a p-quinoid structure reduced the cytoplasmic level of phosphorylated YAP and the YAP–TEAD complex transcriptional activity and reduced cancer cell growth. IA5 is a promising hit compound for TEAD activity modulator development.

The aim of this tutorial review is to provide a general overview of processes, technologies and challenges in the production of pharmaceutical and bioactive compounds from food waste and lignocellulosic residues. Particular attention is given to benign-by-design processes instinctively devoted to environmental sustainability for the recovery of bioactive compounds from food waste as well as for the production of alcohols, acids, polyols, furans and aromatic compounds from lignocellulosic residues. At the same time, novel green synthetic routes for the production of active pharmaceutical ingredients and the development of novel bioactive compounds are discussed. Recent success industrial stories on the use of food waste and lignocellulosic residues for pharmaceutical and nutraceutical applications are also discussed. This journal is

Alzheimer’s disease (AD) is a complex neurodegenerative disorder with a multifaceted pathogenesis. This fact has long halted the development of effective anti-AD drugs. Recently, a therapeutic strategy based on the exploitation of Brazilian biodiversity was set with the aim of discovering new disease-modifying and safe drugs for AD. In this review, we will illustrate our efforts in developing new molecules derived from Brazilian cashew nut shell liquid (CNSL), a natural oil and a byproduct of cashew nut food processing, with a high content of phenolic lipids. The rational modification of their structures has emerged as a successful medicinal chemistry approach to the development of novel anti-AD lead candidates. The biological profile of the newly developed CNSL derivatives towards validated AD targets will be discussed together with the role of these molecular targets in the context of AD pathogenesis.

Despite Alzheimer’s disease (AD) incidence being projected to increase worldwide, the drugs currently on the market can only mitigate symptoms. Considering the failures of the classical paradigm “one target-one drug-one disease” in delivering effective medications for AD, polypharmacology appears to be a most viable therapeutic strategy. Polypharmacology can involve combinations of multiple drugs and/or single chemical entities modulating multiple targets. Taking inspiration from an ongoing clinical trial, this work aims to convert a promising cromolyn–ibuprofen drug combination into single-molecule “codrugs.” Such codrugs should be able to similarly modulate neuroinflammatory and amyloid pathways, while showing peculiar pros and cons. By exploiting a linking strategy, we designed and synthesized a small set of cromolyn–ibuprofen conjugates (4–6). Preliminary plasma stability and neurotoxicity assays allowed us to select diamide 5 and ethanolamide 6 as promising compounds for further studies. We investigated their immunomodulatory profile in immortalized microglia cells, in vitro anti-aggregating activity towards Aβ42-amyloid self-aggregation, and their cellular neuroprotective effect against Aβ42-induced neurotoxicity. The fact that 6 effectively reduced Aβ-induced neuronal death, prompted its investigation into an in vivo model. Notably, 6 was demonstrated to significantly increase the longevity of Aβ42-expressing Drosophila and to improve fly locomotor performance.

In this chapter we discuss the possibility of using biomass as reagents for the synthesis of biologically active compounds. The selected examples only scratch the surface on the volume of research being carried out on the topics, but are significant of its strengths and challenges. As is delineated below, the data collected so far offers significant support for the continuation of an interdisciplinary research for the development of new pharmaceutically relevant products from biomass.

As part of our efforts to develop sustainable drugs for Alzheimer's disease (AD), we have been focusing on the inexpensive and largely available cashew nut shell liquid (CNSL) as a starting material for the identification of new acetylcholinesterase (AChE) inhibitors. Herein, we decided to investigate whether cardanol, a phenolic CNSL component, could serve as a scaffold for improved compounds with concomitant anti-amyloid and antioxidant activities. Ten new derivatives, carrying the intact phenolic function and an aminomethyl functionality, were synthesized and first tested for their inhibitory potencies towards AChE and butyrylcholinesterase (BChE). 5 and 11 were found to inhibit human BChE at a single-digit micromolar concentration. Transmission electron microscopy revealed the potential of five derivatives to modulate A beta aggregation, including 5 and 11. In HORAC assays, 5 and 11 performed similarly to standard antioxidant ferulic acid as hydroxyl scavenging agents. Furthermore, in in vitro studies in neuronal cell cultures, 5 and 11 were found to effectively inhibit reactive oxygen species production at a 10 mu M concentration. They also showed a favorable initial ADME/Tox profile. Overall, these results suggest that CNSL is a promising raw material for the development of potential disease-modifying treatments for AD.

Since 2002, no clinical candidate against Alzheimer's disease has reached the market; hence, an effective therapy is urgently needed. We followed the so-called "multitarget directed ligand" approach and designed 36 novel tacrine-phenothiazine heterodimers which were in vitro evaluated for their anticholinesterase properties. The assessment of the structure-activity relationships of such derivatives highlighted compound 1dC as a potent and selective acetylcholinesterase inhibitor with IC50 = 8 nM and 1aA as a potent butyrylcholinesterase inhibitor with IC50 = 15 nM. Selected hybrids, namely, 1aC, 1bC, 1cC, 1dC, and 2dC, showed a significant inhibitory activity toward τ(306-336) peptide aggregation with percent inhibition ranging from 50.5 to 62.1%. Likewise, 1dC and 2dC exerted a remarkable ability to inhibit self-induced Aβ1-42 aggregation. Notwithstanding, in vitro studies displayed cytotoxicity toward HepG2 cells and cerebellar granule neurons; no pathophysiological abnormality was observed when 1dC was administered to mice at 14 mg/kg (i.p.). 1dC was also able to permeate to the CNS as shown by in vitro and in vivo models. The maximum brain concentration was close to the IC50 value for acetylcholinesterase inhibition with a relatively slow elimination half-time. 1dC showed an acceptable safety and good pharmacokinetic properties and a multifunctional biological profile.

Starting from six potential hits identified in a virtual screening campaign directed to a cryptic pocket of BACE-1, at the edge of the catalytic cleft, we have synthesized and evaluated six hybrid compounds, designed to simultaneously reach BACE-1 secondary and catalytic sites and to exert additional activities of interest for Alzheimer's disease (AD). We have identified a lead compound with potent in vitro activity towards human BACE-1 and cholinesterases, moderate Aβ42 and tau antiaggregating activity, and brain permeability, which is nontoxic in neuronal cells and zebrafish embryos at concentrations above those required for the in vitro activities. This compound completely restored short- and long-term memory in a mouse model of AD (SAMP8) relative to healthy control strain SAMR1, shifted APP processing towards the non-amyloidogenic pathway, reduced tau phosphorylation, and increased the levels of synaptic proteins PSD95 and synaptophysin, thereby emerging as a promising disease-modifying, cognition-enhancing anti-AD lead.

According to the World Health Organization, more than 1 billion people are at risk of or are affected by neglected tropical diseases. Examples of such diseases include trypanosomiasis, which causes sleeping sickness; leishmaniasis; and Chagas disease, all of which are prevalent in Africa, South America, and India. Our aim within the New Medicines for Trypanosomatidic Infections project was to use (1) synthetic and natural product libraries, (2) screening, and (3) a preclinical absorption, distribution, metabolism, and excretion-toxicity (ADME-Tox) profiling platform to identify compounds that can enter the trypanosomatidic drug discovery value chain. The synthetic compound libraries originated from multiple scaffolds with known antiparasitic activity and natural products from the Hypha Discovery MycoDiverse natural products library. Our focus was first to employ target-based screening to identify inhibitors of the protozoan Trypanosoma brucei pteridine reductase 1 ( TbPTR1) and second to use a Trypanosoma brucei phenotypic assay that made use of the T. brucei brucei parasite to identify compounds that inhibited cell growth and caused death. Some of the compounds underwent structure-activity relationship expansion and, when appropriate, were evaluated in a preclinical ADME-Tox assay panel. This preclinical platform has led to the identification of lead-like compounds as well as validated hits in the trypanosomatidic drug discovery value chain.

Neurodegenerative diseases, including Alzheimer’s disease (AD), are associated with neuroinflammation which initiates the degeneration of neurons by over-activating microglia in the brain. It is now widely accepted that clustered populations of reactive microglia are hallmarks of AD, and these brain cells are likely to contribute to the mechanisms of neuronal damage and cognitive loss. Therefore, the prevention and/or modulation of key pro-inflammatory molecules from microglia is a promising strategy for the prevention and possible treatment of AD. In the present study, the anti-inflammatory activity of eight novel synthetized compounds obtained derivatizing tacrine with lipids extracted from cashew nut shell liquid was assessed in BV-2 microglial cells. Cells were treated with different concentrations of the compounds for 24 h, then exposed to LPS and cell viability evaluated by MTT assay. Only 5 of the tested compounds were able to significantly counteract the reduction of cell viability induced by LPS. To verify if this protection could be ascribed to an anti-inflammatory mechanism, real time PCR analysis were carried out to assess the expression of interleukin 1 and TNF-. All of the 5 compounds were able to significantly reduce interleukin 1 expression, while only 4 compounds reduced TNF- expression. These results suggest a therapeutic potential of these compounds as novel anti-inflammatory drugs in neurodegenerative diseases, mediating favorable modulation of pro-inflammatory functions of microglia. This work was supported by MIUR-PRIN 2015 (No. 20152HKF3Z).

The continued drug discovery failures in complex neurodegenerative diseases, including Alzheimer's disease (AD), has raised questions about the classical paradigm "one-drug, one-target, one-disease." In parallel, the ever-increasing awareness of the multiplicity of the underlying pathways has led to the affirmation of polypharmacological approaches. Polypharmacology, which broadly embodies the use of pharmaceutical agents acting on multiple targets, seems to be the best way to restore the complex diseased network and to provide disease-modifying effects in AD. In this review, our aim is to provide a roadmap into a world that is still only partly explored and that should be seen as a continuum of pharmacological opportunities, from drug combinations to multitarget-directed ligands (both codrugs and hybrids). Each modality has unique features that can be effectively exploited by medicinal chemists. We argue that understanding their advantages and drawbacks is very helpful in choosing a proper approach and developing successful AD multitarget drug-discovery endeavors. We also briefly dwell on (co)target validation, an aspect that is quite often neglected, but critical for an efficient clinical translation. We substantiate our discussion with instructive examples taken from the recent literature. Our wish is that, in spite of the specter of the high attrition rates, best researchers preferring to enter, stay, and progress in the field would help grow the sector and develop AD polypharmacology to full potential.

Journal of Medicinal Chemistry is proud to share the release of its first special issue dedicated to “Women in Medicinal Chemistry”, jointly published with ACS Medicinal Chemistry Letters.

Our goal was the evaluation of a series of N-1,2,3-triazole-isatin derivatives for multi-target activity which included cholinesterase (ChE) inhibition and β-amyloid (Aβ) peptide anti-aggregation. The compounds have shown considerable promise as butyrylcholinesterase (BuChE) inhibitors. Although the inhibition of eel acetylcholinesterase (eeAChE) was weak, the inhibitions against equine BuChE (eqBuChE) and human BuChE (hBuChE) were more significant with a best inhibition against eqBuChE of 0.46 μM. In some cases, these molecules gave better inhibitions for hBuChE than eqBuChE. For greater insights into their mode of action, molecular docking studies were carried out, followed by STD-NMR validation. In addition, some of these compounds showed weak Aβ anti-aggregation activity. Hepatotoxicity studies showed that they were non-hepatoxic and neurotoxicity studies using neurite outgrowth experiments led to the conclusion that these compounds are only weakly neurotoxic.

Multiple sclerosis (MS) is a complex inflammatory, degenerative, and demyelinating disease of the central nervous system. Although treatments exist, MS cannot be cured by available drugs, which primarily target neuroinflammation. Thus, it is feasible that a well concerted polypharmacological approach able to act at multiple points within the intricate network of inflammation, neurodegeneration, and demyelination/remyelination pathways would succeed where other drugs have failed. Starting from reported beneficial effects of α-linolenic acid (ALA) and valproic acid (VPA) in MS, and by applying a rational strategy, we developed a small set of codrugs obtained by conjugating VPA and ALA through proper linkers. A cellular profiling identified 1 as a polypharmacological tool able not only to modulate microglia polarization, but also to counteract neurodegeneration and demyelination and induce oligodendrocyte precursor cell differentiation, by acting on multiple biochemical and epigenetic pathways.

[Image: see text] To attract and retain women in medicinal chemistry, a toolbox of resources and opportunities is suggested. Scientific meetings, books, affinity groups, training courses, and networks all can provide support and strategies to help increase the percentage of women in the field.

The LIBRA compound library is a collection of 522 non-commercial molecules contributed by various Italian academic laboratories. These compounds have been designed and synthesized during different medicinal chemistry programs and are hosted by the Italian Institute of Technology. We report the screening of the LIBRA compound library against Trypanosoma brucei and Leishmania major pteridine reductase 1, TbPTR1 and LmPTR1. Nine compounds were active against parasitic PTR1 and were selected for cell-based parasite screening, as single agents and in combination with methotrexate (MTX). The most interesting TbPTR1 inhibitor identified was 4-(benzyloxy)pyrimidine-2,6-diamine (LIB_66). Subsequently, six new LIB_66 derivatives were synthesized to explore its Structure-Activity-Relationship (SAR) and absorption, distribution, metabolism, excretion and toxicity (ADMET) properties. The results indicate that PTR1 has a preference to bind inhibitors, which resemble its biopterin/folic acid substrates, such as the 2,4-diaminopyrimidine derivatives.

Diseases of infection, of neurodegeneration (such as Alzheimer’s and Parkinson’s diseases), and of malignancy (cancers) have complex and varied causative factors. Modern drug discovery has the power to identify potential modulators for multiple targets from millions of compounds. Computational approaches allow the determination of the association of each compound with its target before chemical synthesis and biological testing is done. These approaches depend on the prior identification of clinically and biologically validated targets. This Perspective will focus on the molecular and computational approaches that underpin drug design by medicinal chemists to promote understanding and collaboration with clinical scientists.

[Image: see text] Polypharmacology has expanded enormously over the last ten years, with several multitarget drugs (MTDs) already in the market. This Viewpoint provides a basis for a discussion about the critical need to develop MTDs in a more rationale and conscious way. A checklist to maximize success in polypharmacology is proposed.

L’invenzione brevettata fa riferimento ad un dispositivo medico impiantabile per il rilascio locale controllato nel tempo di una combinazione di farmaci mai prima associati. L’invenzione ha inoltre aspetti d’uso innovativi: è progettata infatti per il trattamento della fase acuta delle lesioni del sistema nervoso centrale con componente infiammatoria, per la quale non esistono terapie. Si tratta di una nuova soluzione di farmacoterapia costituita dall’inserimento di due farmaci (un antiinfiammatorio ed un promielinizzante) in un materiale polimerico, realizzato mediante elettrofilatura, che consente il rilascio locale controllato nel tempo dei due farmaci, e che va impiegato nella prevenzione della degenerazione secondaria all’evento traumatico.