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Tuberculosis (TB) of the central nervous system (CNS) is considered one of the most severe forms of presentation of the disease. Although only 1% of TB cases involve the CNS, these cases represent around between 5 and 15% of extrapulmonary forms.1 2 Tuberculous meningitis (TBM) is the most frequent form of CNS TB. The granulomas formed in the cerebral tuberculoma may cause hydrocephalus and other symptoms indicative of a CNS mass lesion. In the absence of active TB or TBM, the symptoms may be interpreted as indicative of tumors.3 4 The prognosis is directly related to the early diagnosis and proper treatment installation.5 We report the case of a patient with intracranial hypertension syndrome, expansive mass in the parieto-occipital region, accompanied by a lesion in the rib, initially thought to be a metastatic lesion, although posteriorly diagnosed as a cerebral tuberculoma.

Background and Purpose: Many of the addictive and rewarding effects of nicotine are due to its actions on the neuronal nicotinic ACh receptor (nAChR) subtypes expressed in dopaminergic mesocorticolimbic cells. The partial agonists, cytisine and varenicline, are helpful smoking cessation aids. These drugs have a number of side effects that limit their usefulness. The aim of this study was to investigate the preclinical pharmacology of the cytisine dimer1,2-bisN-cytisinylethane (CC4).Experimental Approach: The effects of CC4 on nAChRs were investigated using in vitro assays and animal behaviours.Key Results: When electrophysiologically tested using heterologously expressed human subtypes, CC4 was less efficacious than cytisine on neuronal α4β2, α3β4, α7 and muscle-type receptors, and had no effect on 5-hydroxytryptamine3 receptors. Acting through α4β2 and α6β2 nAChRs, CC4 is a partial agonist of nAChR-mediated striatal dopamine release and, when co-incubated with nicotine, prevented nicotine's maximal effect on this response. In addition, it had low affinity for, and was less efficacious than nicotine and cytisine on the α3β4 and α7-nAChR subtypes. Like cytisine and nicotine, CC4-induced conditioned place preference (CPP), and its self-administration shows an inverted-U dose-response curve. Pretreatment with non-reinforcing doses of CC4 significantly reduced nicotine-induced self-administration and CPP without affecting motor functions.Conclusion and Implications: Our in vitro and in vivo findings reveal that CC4 selectively reduces behaviours associated with nicotine addiction consistent with the partial agonist selectivity of CC4 for β2-nAChRs. The results support the possible development of CC4 or its derivatives as a promising drug for tobacco smoking cessation. [ABSTRACT FROM AUTHOR]

Vestibular schwannomas (VSs) account for ∼ 70% of all tumors of the cerebellopontine angle (CPA). Their clinical presentation is often insidious, with progressive hearing loss and involvement of other cranial nerves. Spontaneous hemorrhage in those tumors is very unusual, and generally presents with acute clinical features such as nausea, vomiting, headache and altered consciousness, usually with marked dysfunction of the cranial nerve involved, and with new deficits of neighboring cranial nerves. Asymptomatic patients are extremely rare. We present a case report of an incidental VS with asymptomatic bleeding, which evolved to death after surgery.

The search and development of effective sirtuin small molecule inhibitors (SIRTIs) continues to draw great attention due to their wide range of pharmacological applications. Based on SIRTs' involvement in different biological pathways, their ligands were investigated for many diseases, such as cancer, neurodegenerative disorders, diabetes, cardiovascular diseases and autoimmune diseases. The elucidation of a substantial number of SIRT2-ligand complexes is steering the identification of novel and more selective modulators. Among them, SIRT2 in the presence of the SirReal2 analog series was the most studied. On this basis, we recently reported structure-based analyses leading to the discovery of thiazole-based compounds acting as SIRT2 inhibitors ( T1 , SIRT2 IC 50 = 17.3 µM). Herein, ligand-based approaches followed by molecular docking simulations allowed us to evaluate in silico a novel small series of thiazoles ( 3a - 3d and 5a , 5d ) as putative SIRT2 inhibitors. Results from the computational studies revealed comparable molecular interaction fields (MIFs) and docking positionings of most of these compounds with respect to reference SIRT2Is. Biochemical and biological assays validated this study and pointed to compound 5a (SIRT2 IC 50 = 9.0 µM) as the most interesting SIRT2I that was worthy of further development as an anticancer agent.

To further extend the structure-activity relationships (SARs) of 5-aminopyrazoles (5APs) and identify novel compounds able to interfere with inflammation, oxidative stress, and tumorigenesis, 5APs 1-4 have been designed and prepared. Some chemical modifications have been inserted on cathecol function or in aminopyrazole central core; in detail: (i) smaller, bigger, and more lipophilic substituents were introduced in meta and para positions of catechol portion (5APs 1 ); (ii) a methyl group was inserted on C3 of the pyrazole scaffold (5APs 2 ); (iii) a more flexible alkyl chain was inserted on N1 position (5APs 3 ); (iv) the acylhydrazonic linker was moved from position 4 to position 3 of the pyrazole scaffold (5APs 4 ). All new derivatives 1-4 have been tested for radical scavenging (DPPH assay), anti-aggregating/antioxidant (in human platelets) and cell growth inhibitory activity (MTT assay) properties. In addition, in silico pharmacokinetics, drug-likeness properties, and toxicity have been calculated. 5APs 1 emerged to be promising anti-proliferative agents, able to suppress the growth of specific cancer cell lines. Furthermore, derivatives 3 remarkably inhibited ROS production in platelets and 5APs 4 showed interesting in vitro radical scavenging properties. Overall, the collected results further confirm the pharmaceutical potentials of this class of compounds and support future studies for the development of novel anti-proliferative and antioxidant agents.

To meet the urgent need for new antibacterial molecules, a small library of pyrazolyl thioureas (PTUs) was designed, synthesized and tested against difficult-to-treat human pathogens. The prepared derivatives are characterized by a carboxyethyl functionality on C4 and different hydroxyalkyl chains on N1. Compounds 1a - o were first evaluated against a large panel of Gram-positive and Gram-negative pathogens. In particular, the majority of PTUs proved to be active against different species of the Staphylococcus genus, with MIC values ranging from 32 to 128 µg/mL on methicillin-resistant Staphylococcus strains, often responsible for severe pulmonary disease in cystic fibrosis patients. Time-killing experiments were also performed for the most active compounds, evidencing a bacteriostatic mechanism of action. For most active derivatives, cytotoxicity was evaluated in Vero cells, and at the tested concentrations and at the experimental exposure time of 24 h, none of the compounds analysed showed significant toxicity. In addition, favourable drug-like, pharmacokinetic and toxicity properties were predicted for all new synthesized derivatives. Overall, the collected data confirmed the PTU scaffold as a promising chemotype for the development of novel antibacterial agents active against Gram-positive multi-resistant strains frequently isolated from cystic fibrosis patients.

Neuroblastoma (NB) is a paediatric cancer with noteworthy heterogeneity ranging from spontaneous regression to high-risk forms that are characterised by cancer relapse and the acquisition of drug resistance. The most-used anticancer drugs exert their cytotoxic effect by inducing oxidative stress, and long-term therapy has been demonstrated to cause chemoresistance by enhancing the antioxidant response of NB cells. Taking advantage of an in vitro model of multidrug-resistant (MDR) NB cells, characterised by high levels of glutathione (GSH), the overexpression of the oncoprotein BMI-1, and the presence of a mutant P53 protein, we investigated a new potential strategy to fight chemoresistance. Our results show that PTC596, an inhibitor of BMI-1, exerted a high cytotoxic effect on MDR NB cells, while PRIMA-1 MET , a compound able to reactivate mutant P53, had no effect on the viability of MDR cells. Furthermore, both PTC596 and PRIMA-1 MET markedly reduced the expression of epithelial-mesenchymal transition proteins and limited the clonogenic potential and the cancer stemness of MDR cells. Of particular interest is the observation that PTC596, alone or in combination with PRIMA-1 MET and etoposide, significantly reduced GSH levels, increased peroxide production, stimulated lipid peroxidation, and induced ferroptosis. Therefore, these findings suggest that PTC596, by inhibiting BMI-1 and triggering ferroptosis, could be a promising approach to fight chemoresistance.

Fourteen quinolizidine derivatives, structurally related to the alkaloids lupinine and cytisine and previously studied for other pharmacological purposes, were presently tested for antiarrhythmic, and other cardiovascular effects on isolated guinea pig heart tissues in comparison to well-established reference drugs. According to their structures, the tested compounds are assembled into three subsets: (a) N-(quinolizidinyl-alkyl)-benzamides; (b) 2-(benzotriazol-2-yl)methyl-1-(quinolizidinyl)alkyl-benzimidazoles; (c) N-substituted cytisines. All compounds but two displayed antiarrhythmic activity that was potent for compounds 4 , 1 , 6 , and 5 (in ascending order). The last compound (N-(3,4,5-trimethoxybenzoyl)aminohomolupinane) was outstanding, exhibiting a nanomolar potency (EC 50 = 0.017 µM) for the increase in the threshold of ac-arrhythmia. The tested compounds shared strong negative inotropic activity; however, this does not compromise the value of their antiarrhythmic action. On the other hand, only moderate or modest negative chronotropic and vasorelaxant activities were commonly observed. Compound 5 , which has high antiarrhythmic potency, a favorable cardiovascular profile, and is devoid of antihypertensive activity in spontaneously hypertensive rats, represents a lead worthy of further investigation.

The indole heterocycle represents one of the most important scaffolds in medicinal chemistry and is shared among a number of drugs clinically used in different therapeutic areas. Due to its varied biological activities, high unique chemical properties and significant pharmacological behaviors, indole derivatives have drawn considerable interest in the last decade as antitumor agents active against different types of cancers. The research of novel antiproliferative drugs endowed with enhanced efficacy and reduced toxicity led to the approval by U.S. Food and Drug Administration of the indole-based anticancer agents Sunitinib, Nintedanib, Osimertinib, Panobinostat, Alectinib and Anlotinib. Additionally, new drug delivery systems have been developed to protect the active principle from degradation and to direct the drug to the specific site for clinical use, thus reducing its toxicity. In the present work is an updated review of the recently approved indole-based anti-cancer agents and the nanotechnology systems developed for their delivery.

Inhibitor of Apoptosis Proteins (IAPs) are validated targets for cancer therapy, and the deregulation of their activities within the NF-κB pathway correlates with chemoresistance events, even after treatment with IAPs-antagonists in the clinic (Smac-mimetics). The molecule FC2 was identified as a NF-κB pathway modulator in MDA-MB-231 adenocarcinoma cancer cells after virtual screening of the Chembridge library against the Baculoviral IAP Repeat 1 (BIR1) domain of cIAP2 and XIAP. An improved cytotoxic effect is observed when FC2 is combined with Smac-mimetics or with the cytokine Tumor Necrosis Factor (TNF). Here, we propose a library of 22 derivatives of FC2, whose scaffold was rationally modified starting from the position identified as R 1 . The cytotoxic effect of FC2 derivatives was evaluated in MDA-MB-231 and binding to the cIAP2- and XIAP-BIR1 domains was assessed in fluorescence-based techniques and virtual docking. Among 22 derivatives, 4m and 4p display improved efficacy/potency in MDA-MB-231 cells and low micromolar binding affinity vs the target proteins. Two additional candidates ( 4b and 4u ) display promising cytotoxic effects in combination with TNF, suggesting the connection between this class of molecules and the NF-κB pathway. These results provide the rationale for further FC2 modifications and the design of novel IAP-targeting candidates supporting known therapies.

Retinoblastoma is a rare, sometimes hereditary, pediatric cancer. In high-income countries this disease has a survival rate approaching 100%, while in low- and middle-income countries the prognosis is fatal for about 80% of cases. Depending on the stage of the disease, different therapeutic protocols are applied. In more advanced forms of the disease, surgical removal of the entire globe and its intraocular contents (enucleation) is, unfortunately, necessary, whereas in other cases, conventional chemotherapy is normally used. To overcome the side-effects and reduced efficacy of traditional chemotherapic drugs, nanodelivery systems that ensure a sustained drug release and manage to reach the target site have more recently been developed. This review takes into account the current use and advances of nanomedicine in the treatment of retinoblastoma and discusses nanoparticulate formulations that contain conventional drugs and natural products. In addition, future developments in retinoblastoma treatment are discussed.

The pyrazole ring represents a widely applied chemical scaffold in medicinal chemistry research and we have observed that the physicochemical and biological features of highly substituted pyrazoles can be successfully improved by their encapsulation in dendrimer nanoparticles (NPs). For the future development of new optimized antibacterial delivery systems, we report the synthesis and biological evaluation of 5-amino functionalized pyrazole library (compounds 2 - 7 ). In detail, new derivatives 2 - 7 were differently decorated in C3, C4 and C5 positions. An in silico study predicted pyrazoles 2 - 7 to exert good drug-like and pharmacokinetic properties. Compounds 3c and 4b were endowed with moderate, but nanotechnologically improvable activity against multidrug-resistant (MDR) clinical isolates of Gram-positive species, especially of the Staphylococcus genus (MICs = 32-64 µg/mL). In addition, derivatives 3c and 4a showed moderate activities against Mycobacterium tuberculosis and 4a evidenced activity also against MDR strains. Overall, the collected evidence supported that, upon nano-formulation with proper polymer matrices, the new synthesized compounds could provide new pyrazole-based drug delivery systems with an enhanced and enlarged-spectrum of antibacterial activity.

Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase over-expressed in different solid cancers. In recent years, FAK has been recognized as a new target for the development of antitumor agents, useful to contrast tumor development and metastasis formation. To date, studies on the role of FAK and FAK inhibitors are of great interest for both pharmaceutical companies and academia. This review is focused on compounds able to block FAK with different potencies and with different mechanisms of action, that have appeared in the literature since 2017. Furthermore, new emerging PROTAC molecules have appeared in the literature. This summary could improve knowledge of new FAK inhibitors and provide information for future investigations, in particular, from a medicinal chemistry point of view.

Cystic fibrosis (CF) is a genetic disease affecting the lungs and pancreas and causing progressive damage. CF is caused by mutations abolishing the function of CFTR, a protein whose role is chloride's mobilization in the epithelial cells of various organs. Recently a therapy focused on small molecules has been chosen as a main approach to contrast CF, designing and synthesizing compounds acting as misfolding (correctors) or defective channel gating (potentiators). Multi-drug therapies have been tested with different combinations of the two series of compounds. Previously, we designed and characterized two series of correctors, namely, hybrids, which were conceived including the aminoarylthiazole (AAT) core, merged with the benzodioxole carboxamide moiety featured by VX-809. In this paper, we herein proceeded with molecular modeling studies guiding the design of a new third series of hybrids, featuring structural variations at the thiazole moiety and modifications on position 4. These derivatives were tested in different assays including a YFP functional assay on models F508del-CFTR CFBE41o-cells, alone and in combination with VX-445, and by using electrophysiological techniques on human primary bronchial epithelia to demonstrate their F508del-CFTR corrector ability. This study is aimed (i) at identifying three molecules ( 9b, 9g, and 9j ), useful as novel CFTR correctors with a good efficacy in rescuing the defect of F508del-CFTR; and (ii) at providing useful information to complete the structure-activity study within all the three series of hybrids as possible CFTR correctors, supporting the development of pharmacophore modelling studies, taking into account all the three series of hybrids. Finally, in silico evaluation of the hybrids pharmacokinetic (PK) properties contributed to highlight hybrid developability as drug-like correctors.

Bruton's tyrosine kinase (BTK) represented, in the past ten years, an important target for the development of new therapeutic agents that could be useful for cancer and autoimmune disorders. To date, five compounds, able to block BTK in an irreversible manner, have been launched in the market, whereas many reversible BTK inhibitors (BTKIs), with reduced side effects that are more useful for long-term administration in autoimmune disorders, are under clinical investigation. Despite the presence in the literature of many articles and reviews, studies on BTK function and BTKIs are of great interest for pharmaceutical companies as well as academia. This review is focused on compounds that have appeared in the literature from 2017 that are able to block BTK in an irreversible or reversible manner; also, new promising tunable irreversible inhibitors, as well as PROTAC molecules, have been reported. This summary could improve the knowledge of the chemical diversity of BTKIs and provide information for future studies, particularly from the medicinal chemistry point of view. Data reported here are collected from different databases (Scifinder, Web of Science, Scopus, Google Scholar, and Pubmed) using "BTK" and "BTK inhibitors" as keywords.

In the past few years, Bruton's tyrosine Kinase (Btk) has emerged as new target in medicinal chemistry. Since approval of ibrutinib in 2013 for treatment of different hematological cancers (as leukemias and lymphomas), two other irreversible Btk inhibitors have been launched on the market. In the attempt to overcome irreversible Btk inhibitor limitations, reversible compounds have been developed and are currently under evaluation. In recent years, many Btk inhibitors have been patented and reported in the literature. In this review, we summarized the (ir)reversible Btk inhibitors recently developed and studied clinical trials and preclinical investigations for malignancies, chronic inflammation conditions and SARS-CoV-2 infection, covering advances in the field of medicinal chemistry. Furthermore, the nanoformulations studied to increase ibrutinib bioavailability are reported.

Nanotechnology is an important application in modern cancer therapy. In comparison with conventional drug formulations, nanoparticles ensure better penetration into the tumor mass by exploiting the enhanced permeability and retention effect, longer blood circulation times by a reduced renal excretion and a decrease in side effects and drug accumulation in healthy tissues. The most significant classes of nanoparticles (i.e., liposomes, inorganic and organic nanoparticles) are here discussed with a particular focus on their use as delivery systems for small molecule tyrosine kinase inhibitors (TKIs). A number of these new compounds (e.g., Imatinib, Dasatinib, Ponatinib) have been approved as first-line therapy in different cancer types but their clinical use is limited by poor solubility and oral bioavailability. Consequently, new nanoparticle systems are necessary to ameliorate formulations and reduce toxicity. In this review, some of the most important TKIs are reported, focusing on ongoing clinical studies, and the recent drug delivery systems for these molecules are investigated.

Two series of naphthoquinone and anthraquinone derivatives decorated with an aromatic/heteroaromatic chain have been synthesized and evaluated as potential promiscuous agents capable of targeting different factors playing a key role in Alzheimer's disease (AD) pathogenesis. On the basis of the in vitro biological profiling, most of them exhibited a significant ability to inhibit amyloid aggregation, PHF6 tau sequence aggregation, acetylcholinesterase (AChE), and monoamine oxidase (MAO) B. In particular, naphthoquinone 2 resulted as one of the best performing multitarget-directed ligand (MTDL) experiencing a high potency profile in inhibiting β-amyloid (Aβ 40 ) aggregation (IC 50 = 3.2 μM), PHF6 tau fragment (91% at 10 μM), AChE enzyme (IC 50 = 9.2 μM) jointly with a remarkable inhibitory activity against MAO B (IC 50 = 7.7 nM). Molecular modeling studies explained the structure-activity relationship (SAR) around the binding modes of representative compound 2 in complex with hMAO B and hAChE enzymes, revealing inhibitor/protein key contacts and the likely molecular rationale for enzyme selectivity. Compound 2 was also demonstrated to be a strong inhibitor of Aβ 42 aggregation, with potency comparable to quercetin. Accordingly, atomic force microscopy (AFM) revealed that the most promising naphthoquinones 2 and 5 and anthraquinones 11 and 12 were able to impair Aβ 42 fibrillation, deconstructing the morphologies of its fibrillar aggregates. Moreover, the same compounds exerted a moderate neuroprotective effect against Aβ 42 toxicity in primary cultures of cerebellar granule cells. Therefore, our findings demonstrate that these molecules may represent valuable chemotypes toward the development of promising candidates for AD therapy.

Alzheimer's disease (AD) is a progressive neurodegenerative disease that is characterized by memory loss, cognitive impairment, and functional decline leading to dementia and death. AD imposes neuronal death by the intricate interplay of different neurochemical factors, which continue to inspire the medicinal chemist as molecular targets for the development of new agents for the treatment of AD with diverse mechanisms of action, but also depict a more complex AD scenario. Within the wide variety of reported molecules, this review summarizes and offers a global overview of recent advancements on naphthoquinone (NQ) and anthraquinone (AQ) derivatives whose more relevant chemical features and structure-activity relationship studies will be discussed with a view to providing the perspective for the design of viable drugs for the treatment of AD. In particular, cholinesterases (ChEs), β-amyloid (Aβ) and tau proteins have been identified as key targets of these classes of compounds, where the NQ or AQ scaffold may contribute to the biological effect against AD as main unit or significant substructure. The multitarget directed ligand (MTDL) strategy will be described, as a chance for these molecules to exhibit significant potential on the road to therapeutics for AD.

Background: Cystic fibrosis (CF) is the autosomal recessive disorder most common in Caucasian populations. It is caused by mutations in the cystic fibrosis transmembrane regulator protein (CFTR). CFTR is predominantly expressed at the apical plasma membranes of the epithelial cells lining several organs, and functions as a cAMP-regulated chloride/bicarbonate channel. To address the underlying causes of cystic fibrosis, two biomolecular activities are required, namely correctors to increase CFTR levels at the cell surface, and potentiators to allow the effective opening of the CFTR channel., Objective: In our previous data, we demonstrated that some aminoarylthiazoles (AATs) have peculiar activity acting as correctors and as potentiator-like molecules. Curiously, a compound called 1 has been shown to be markedly active as a potentiator. Now, we have further modified its scaffold at different portions, for the identification of molecules with improved potency and effectiveness on mutant CFTR., Methods: Starting from this active compound, we synthesized a small library trying to improve the activity as potentiators. To extrapolate the contribution of a particular structural portion to bioactivity, we selectively modified one portion at a time., Results: Our study has provided a structure-activity relationship (SAR) on AATs and led to the identification of some compounds, with a particular ability to act as CFTR potentiators., Conclusion: Two compounds 2 and 13 appear to be promising molecules and could be used for the future development of potentiators of the chloride transport defect in cystic fibrosis., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: Focal adhesion kinase (Fak) is a cytoplasmic protein tyrosine kinase overexpressed and activated in different solid cancers; it has shown an important role in metastasis formation, cell migration, invasion and angiogenesis and consequently it has been proposed as a potential target in cancer therapy, particularly in a metastatic phase. In recent years, different investigations have highlighted the importance of new Fak inhibitors as potential anti-cancer drugs, but other studies evidenced its role in different pathologies related to the cardiac function or viral infection., Methods: An extensive bibliographic research (104 references) has been done concerning the structure of Fak, its importance in tumor development, but also in other pathologies currently under study. The compounds currently subjected to clinical studies were therefore treated using the appropriate databases. Finally, the main chemical scaffolds currently under preclinical investigation were analyzed, focusing on their molecular structures and on the activity structure relationships (SAR)., Results: At the moment, only a few reversible ATP-competitive inhibitors are under investigation in pre-clinical studies and clinical trials. Other compounds, with different chemical scaffolds, are investigated to obtain more active and selective Fak inhibitors. This mini-review is a summary of different Fak functions in cancer and other pathologies; the compounds today in clinical trials and the recent chemical scaffolds (also included in patents) giving the most interesting results are investigated. In addition, PROTAC molecules are reported., Conclusion: All reported results evidenced that additional studies are necessary to design and synthesize new selective and more active compounds, although promising information has been obtained from associations between Fak inhibitors and other different anti- cancer drugs. In addition, the other important roles evidenced, both at the nuclear level and in non-cancerous cells, make this protein an increasingly important target in pharmaceutical chemistry., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Cystic fibrosis (CF) is the autosomal recessive disorder most recurrent in Caucasian populations. It is caused by different mutations in the cystic fibrosis transmembrane regulator protein (CFTR) gene, with F508del being the most common. During the last years, small-molecule therapy chosen to contrast CF relied on compounds that correct CFTR misfolding and ER retention (correctors such as VX-809), or defective channel gating (potentiators such as VX-770). Combination therapy with the two series of drugs has been applied, leading to the approval of several multi-drugs such as Orkambi. Despite this, this treatment proved to be only partially effective making the search for novel modulators an urgent need to contrast CF. Recently, we reported compound 2a as reference compound of a series of aminoarylthiazole-VX-809 hybrid derivatives exhibiting promising F508del-CFTR corrector ability. Herein, we report exploring the docking mode of the prototype VX-809 and of 2a in order to derive useful guidelines for the rational design of novel optimized analogues. To demonstrate experimentally their effective F508del-CFTR-binding and rescuing potential, the most promising derivatives had been synthesized and evaluated in biological assays including YFP functional assay on F508del-CFTR CFBE41o-cells, trans epithelial electrical resistance (TEER) and surface plasmon resonance (SPR). This multidisciplinary strategy led to the discovery of a second series of hybrids including 7j and 7m endowed with higher potency than the prototype., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

Cystic fibrosis (CF) is the autosomal recessive disorder most recurrent in Caucasian populations. Different mutations involving the cystic fibrosis transmembrane regulator protein (CFTR) gene, which encodes the CFTR channel, are involved in CF. A number of life-prolonging therapies have been conceived and deeply investigated to combat this disease. Among them, the administration of the so-called CFTR modulators, such as correctors and potentiators, have led to quite beneficial effects. Recently, based on QSAR (quantitative structure activity relationship) studies, we reported the rational design and synthesis of compound 2 , an aminoarylthiazole-VX-809 hybrid derivative exhibiting promising F508del-CFTR corrector ability. Herein, we explored the docking mode of the prototype VX-809 as well as of the aforementioned correctors in order to derive useful guidelines for the rational design of further analogues. In addition, we refined our previous QSAR analysis taking into account our first series of in-house hybrids. This allowed us to optimize the QSAR model based on the chemical structure and the potency profile of hybrids as F508del-CFTR correctors, identifying novel molecular descriptors explaining the SAR of the dataset. This study is expected to speed up the discovery process of novel potent CFTR modulators.

Leishmaniases are neglected diseases that are endemic in many tropical and sub-tropical Countries. Therapy is based on different classes of drugs which are burdened by severe side effects, occurrence of resistance and high costs, thereby creating the need for more efficacious, safer and inexpensive drugs. Herein, sixteen 9-thioxanthenone derivatives (lucanthone analogues) and four compounds embodying the diarylethene substructure of amitriptyline (amitriptyline analogues) were tested in vitro for activity against Leishmania tropica and L. infantum promastigotes. All compounds were characterized by the presence of a bulky quinolizidinylalkyl moiety. All compounds displayed activity against both species of Leishmania with IC 50 values in the low micromolar range, resulting in several fold more potency than miltefosine, comparable to that of lucanthone, and endowed with substantially lower cytotoxicity to Vero-76 cells, for the best of them. Thus, 4-amino-1-(quinolizidinylethyl)aminothioxanthen-9-one ( 14 ) and 9-(quinolizidinylmethylidene)fluorene ( 17 ), with selectivity index (SI) in the range 16-24, represent promising leads for the development of improved antileishmanial agents. These two compounds also exhibited comparable activity against intramacrophagic amastigotes of L. infantum . Docking studies have suggested that the inhibition of trypanothione reductase (TryR) may be at the basis (eventually besides other mechanisms) of the observed antileishmanial activity. Therefore, these investigated derivatives may deserve further structural improvements and more in-depth biological studies of their mechanisms of action in order to develop more efficient antiparasitic agents.

Sirtuin 6 (SIRT6) is an NAD + -dependent deacetylase regulating important functions: modulators of its enzymatic activity have been considered as possible therapeutic agents. Besides the deacetylase activity, SIRT6 also has NAD + -dependent deacylase activity, whereby it regulates the secretion of cytokines and proteins. We identified novel SIRT6 modulators with a lysine-based structure: compound 1 enhances SIRT6 deacylase while inhibiting the deacetylase activity. As expected based on the biological effects of SIRT6 deacetylase activity, compound 1 increased histone 3 lysine 9 acetylation and the activity of glycolytic enzymes. Moreover, the fact that compound 1 enhanced SIRT6 deacylase activity was accompanied by an increased TNF-α release. In conclusion, new SIRT6 modulators with a lysine-like structure were identified, with differential effects on specific SIRT6 activities. The novel SIRT6 modulator concomitantly inhibits deacetylase and enhances deacylase activity.

Two sets of benzimidazole derivatives were synthesised and tested in vitro for activity against promastigotes of Leishmania tropica and L. infantum. Most of the tested compounds resulted active against both Leishmania species, with IC 50 values in the low micromolar/sub-micromolar range. Among the set of 2-(long chain)alkyl benzimidazoles, whose heterocyclic head was quaternised, compound 8 resulted about 100-/200-fold more potent than miltefosine, even if the selectivity index (SI) versus HMEC-1 cells was only moderately improved. In the set of 2-benzyl and 2-phenyl benzimidazoles, bearing a basic side chain in position 1, compound 28 (2-(4-chlorobenzyl)-1-lupinyl-5-trifluoromethylbenzimidazole) was 12-/7-fold more potent than miltefosine, but exhibited a further improved SI. Therefore, compounds 8 and 28 represent interesting hit compounds, susceptible of structural modification to improve their safety profiles.

Herein we continued our previous work on the development of CB2 ligands, reporting the design and synthesis of a series of benzimidazole-containing derivatives that were explored as selective CB2 ligands with binding affinity towards both CB1 and CB2 receptors. Seven out of eighteen compounds exhibited preferential binding ability to CB2 over CB1 receptors with potencies in the sub-micromolar or low micromolar range. In particular, we identified two promising hit compounds, the agonist 1-[2-( N , N -diethylamino)ethyl]-2-(4-ethoxybenzyl)-5-trifluoromethylbenzimidazole ( 3 ) (CB2: K i = 0.42 μM) and the inverse agonist/antagonist 1-butyl-2-(3,4-dichlorobenzyl)-5-trifluoromethylbenzimidazole ( 11 ) (CB2: K i = 0.37 μM). Docking studies also performed on other benzimidazoles reported in the literature supported the structure-activity relationship observed in this series of compounds and allowed the key contacts involved in the agonist and/or inverse agonist behaviour displayed by these derivatives to be determined. The in silico evaluation of ADMET properties suggested a favorable pharmacokinetic and safety profile, promoting the drug-likeness of these compounds towards a further optimization process.

The most common CF mutation, F508del, impairs the processing and gating of CFTR protein. This deletion results in the improper folding of the protein and its degradation before it reaches the plasma membrane of epithelial cells. Present correctors, like VX809 only induce a partial rescue of the mutant protein. Our previous studies reported a class of compounds, called aminoarylthiazoles (AATs), featuring an interesting activity as correctors. Some of them show additive effect with VX809 indicating a different mechanism of action. In an attempt to construct more interesting molecules, it was thought to generate chemically hybrid compounds, blending a portion of VX809 merged to the thiazole scaffold. This approach was guided by the development of QSAR analyses, which were performed based on the F508del correctors so far disclosed in the literature. This strategy was aimed at exploring the key requirements turning in the corrector ability of the collected derivatives and allowed us to derive a predictive model guiding for the synthesis of novel hybrids as promising correctors. The new molecules were tested in functional and biochemical assays on bronchial CFBE41o-cells expressing F508del-CFTR showing a promising corrector activity., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

Positive inotropic agents are fundamental in the treatment of heart failure; however, their arrhythmogenic liability and the increased myocardial oxygen demand strongly limit their therapeutic utility. Pursuing our study on cardiovascular activities of lupin alkaloid derivatives, several 2-(4-substituted-phenyl)-2-dehydrosparteines and 2-(4-substituted-phenyl)sparteines were prepared and tested for inotropic and chronotropic activities on isolated guinea pig atria. Four compounds (6b, 6e, 7b, and 7f) exhibited significant inotropism that, at the higher concentrations, was followed by negative inotropism or toxicity. Compound 7e (2-(4-tolyl)sparteine) exhibited a steep dose-depending inotropic activity up to the highest concentration tested (300 µM) with an E max of 116.5 ± 3.4% of basal force, proving less potent but much more active in comparison to the highest concentrations tested of digoxin and milrinone having E max of 87.5 ± 3.1% and 52.2 ± 1.1%, respectively. Finally, docking studies suggested that the relevant sparteine derivatives could target the sigma-1 receptor, whose involvement in cardiac activity is well documented.

Respiratory syncytial virus (RSV) has been identified as a main cause of hospitalisation in infants and children. To date, the current therapeutic arsenal is limited to ribavirin and palivizumab with variable efficacy. In this work, starting from a number of in-house series of previously described anti-RSV agents based on the benzimidazole scaffold, with the aim at gaining a better understanding of the related chemical features involved in potency and safety profiles, we applied a computational study including two focussed comparative molecular fields analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA). The results allowed us to derive useful suggestions for the design of derivatives and also to set up statistical models predicting the potency and selectivity index (SI = CC 50 /EC 50 ) of any new analogue prior to synthesis. Accordingly, here, we discuss preliminary results obtained through the applied exhaustive QSAR analyses, leading to design and synthesise more effective anti-RSV agents.

We have identified a series of 1-aryl-4,6-diamino-1,2-dihydrotriazines, structurally related to the antimalarial drug cycloguanil, as new inhibitors of influenza A and B virus and respiratory syncytial virus (RSV) via targeting of the host dihydrofolate reductase (DHFR) enzyme. Most analogues proved active against influenza B virus in the low micromolar range, and the best compounds (11, 13, 14 and 16) even reached the sub-micromolar potency of zanamivir (EC 50  = 0.060 μM), and markedly exceeded (up to 327 times) the antiviral efficacy of ribavirin. Activity was also observed for two influenza A strains, including a virus with the S31N mutant form of M2 proton channel, which is the most prevalent resistance mutation for amantadine. Importantly, the compounds displayed nanomolar activity against RSV and a superior selectivity index, since the ratio of cytotoxic to antiviral concentration was >10,000 for the three most active compounds 11, 14 and 16 (EC 50 ∼0.008 μM), far surpassing the potency and safety profile of the licensed drug ribavirin (EC 50  = 5.8 μM, SI > 43)., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

We tested the efficacy of novel cyclooxygenase 2 (COX-2) inhibitors in counteracting glia-driven neuroinflammation induced by the amyloidogenic prion protein fragment PrP90-231 or lipopolysaccharide (LPS). In search for molecules with higher efficacy than celecoxib, we focused our study on its 2,3-diaryl-1,3-thiazolidin-4-one analogues. As experimental models, we used the immortalized microglial cell line N9, rat purified microglial primary cultures, and mixed cultures of astrocytes and microglia. Microglia activation in response to PrP90-231 or LPS was characterized by growth arrest, morphology changes and the production of reactive oxygen species (ROS). Moreover, PrP90-231 treatment caused the overexpression of the inducible nitric oxide synthase (iNOS) and COX-2, with the consequent nitric oxide (NO), and prostaglandin E 2 (PGE 2 ) accumulation. These effects were challenged by different celecoxib analogues, among which Q22 (3-[4-(sulfamoyl)phenyl]-2-(4-tolyl)thiazolidin-4-one) inhibited microglia activation more efficiently than celecoxib, lowering both iNOS and COX-2 activity and reducing ROS release. During neurodegenerative diseases, neuroinflammation induced by amyloidogenic peptides causes the activation of both astrocytes and microglia with these cell populations mutually regulating each other. Thus the effects of PrP90-231 and LPS were also studied on mixed glial cultures containing astrocytes and microglia. PrP90-231 treatment elicited different responses in the co-cultures induced astrocyte proliferation and microglia growth arrest, resulting in a differential ability to release proinflammatory molecules with the production of NO and ROS mainly attributable on microglia, while COX-2 expression was induced also in astrocytes. Q22 effects on both NO and PGE 2 secretion were more significant in the mixed glial cultures than in purified microglia, demonstrating Q22 ability to revert the functional interaction between astrocytes and microglia. These results demonstrate that Q22 is a powerful drug able to revert glial neuroinflammatory responses and might represent a lead to explore the chemical space around celecoxib frameworks to design even more effective agents, paving the way to novel approaches to contrast the neuroinflammation-dependent toxicity., (Copyright © 2016 Elsevier Ltd. All rights reserved.)