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Alzheimer's disease (AD) is a multifactorial neurodegenerative disease towards which pleiotropic approach using Multi-Target Directed Ligands is nowadays recognized as probably convenient. Among the numerous targets which are today validated against AD, acetylcholinesterase (ACh) and Monoamine Oxidase-B (MAO-B) appear as particularly convincing, especially if displayed by a sole agent such as ladostigil, currently in clinical trial in AD. Considering these results, we wanted to take benefit of the structural analogy lying in donepezil (DPZ) and rasagiline, two indane derivatives marketed as AChE and MAO-B inhibitors, respectively, and to propose the synthesis and the preliminary in vitro biological characterization of a structural compromise between these two compounds, we called propargylaminodonepezil (PADPZ). The synthesis of racemic trans PADPZ was achieved and its biological evaluation established its inhibitory activities towards both (h)AChE (IC50 = 0.4 µM) and (h)MAO-B (IC50 = 6.4 µM). [ABSTRACT FROM AUTHOR]

Research for new drugs to combat drug resistance in tuberculosis bacilli is one of the solutions to overcome this disease. In this sense, we have designed, synthesized, and fully characterized the chemical structures of about 20 derivatives of 1,10- phenanthrolinone. The evaluation of the antitubercular activities of Mycobacterium tuberculosis revealed that some of these compounds are highly active. Furthermore, the research of the structure-activity connection showed that the derivatives with the nitro group at C6, a carboxylic acid, ester, amide, or hydrazine-like function at C3, and a methyl or ethyl alkylated pyrrolic nitrogen atom at C3 had the best antitubercular activities. The QSAR studies undertaken showed that it is possible to establish a mathematical relationship between antitubercular activities and chemical structures. The obtained QSAR model highlighted that antitubercular activity was significantly affected by chemical softness (s), chemical hardness (η) and chemical potential (μ). In other words, substituents that increase the overall molecular reactivity of 1,10-phenanthrolinone will lead to good antitubercular activities. Furthermore, the prediction of ADMET properties showed that 1,10-phenanthrolinones possess good pharmacokinetic properties. Further, molecular docking confirmed the importance of the carboxylic acid chemical function in position 3 and the nitro group in position 6 for a good affinity of 6-nitro 1,10-phenanthrolinones with deazaflavin-dependent nitroreductase, chosen as a potential target. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a multifactorial neurodegenerative disease which is still poorly understood. The drugs currently used against AD, mainly acetylcholinesterase inhibitors (AChEI), are considered clinically insufficient and are responsible for deleterious side effects. AChE is, however, currently receiving renewed interest through the discovery of a chaperone role played in the pathogenesis of AD. But AChE could also serve as an activating protein for pleiotropic prodrugs. Indeed, inhibiting central AChE with brain-penetrating designed carbamates which are able to covalently bind to the enzyme and to concomitantly liberate active metabolites in the brain could constitute a clinically more efficient approach which, additionally, is less likely to cause peripheral side effects. We aim in this article to pave the road of this new avenue with an in vitro and in vivo study of pleiotropic prodrugs targeting both the 5-HT4 receptor and AChE, in order to display a neuroprotective activity associated with a sustained restoration of the cholinergic neurotransmission and without the usual peripheral side effects associated with classic AChEI. This plural activity could bring to AD patients effective, relatively safe, symptomatic and disease-modifying therapeutic benefits. [ABSTRACT FROM AUTHOR]

As a joint meeting, the 26th Medicinal Chemistry Conference of GP2A and 32nd Journées Franco-Belges de Pharmacochimie took place between 13th and 15th June at Asnelles sur Mer (Normandie, France), providing a unique opportunity for a wide group of European medicinal chemists to engage. Topics included chemical tools for medicinal chemistry, protein-protein interactions, epigenetics, natural product-inspired molecules, computer-aided drug design, and new strategies for the design and development of drugs. Abstracts of invited lectures, proffered young researcher communications, flash communications and posters presented during the meeting are collected in this report. [ABSTRACT FROM AUTHOR]

Background: During sexual reproduction, pollen grains land on the stigma, rehydrate and produce pollen tubes that grow through the female transmitting-tract tissue allowing the delivery of the two sperm cells to the ovule and the production of healthy seeds. Because pollen tubes are single cells that expand by tip-polarized growth, they represent a good model to study the growth dynamics, cell wall deposition and intracellular machineries. Aiming to understand this complex machinery, we used a low throughput chemical screen approach in order to isolate new tip-growth disruptors. The effect of a chemical inhibitor of monogalactosyldiacylglycerol synthases, galvestine-1, was also investigated. The present work further characterizes their effects on the tip-growth and intracellular dynamics of pollen tubes. Results: Two small compounds among 258 were isolated based on their abilities to perturb pollen tube growth. They were found to disrupt in vitro pollen tube growth of tobacco, tomato and Arabidopsis thaliana. We show that these 3 compounds induced abnormal phenotypes (bulging and/or enlarged pollen tubes) and reduced pollen tube length in a dose dependent manner. Pollen germination was significantly reduced after treatment with the two compounds isolated from the screen. They also affected cell wall material deposition in pollen tubes. The compounds decreased anion superoxide accumulation, disorganized actin filaments and RIC4 dynamics suggesting that they may affect vesicular trafficking at the pollen tube tip. Conclusion: These molecules may alter directly or indirectly ROP1 activity, a key regulator of pollen tube growth and vesicular trafficking and therefore represent good tools to further study cellular dynamics during polarized-cell growth. [ABSTRACT FROM AUTHOR]

Today, treatment of Alzheimer's Disease (AD) mainly involves acetylcholinesterase inhibitors (AChEIs). AChEIs display solely a symptomatic benefit, alleviating the cognitive disorders associated to AD through a temporary restoration of the cholinergic neurotransmission impaired by the neurodegeneration. The gradual loss of efficiency for AChEIs led to associate them to drugs exhibiting potential disease-modifying properties. The "Multi-Target-Directed Ligands" (MTDLs) was used in the recent years with a great potential benefit towards multiple targets implicated in the complex AD,¹ as well as other neurodegenerative syndromes, which involve multiple pathogenic factors. Our contribution to the field led recently to the discovery of Donecopride, the first 5-HT4R partial agonist, which possesses important acetylcholinesterase (AChE) inhibition properties currently under preclinical development.2,3 Based on this experience, we have recently developed a novel pleiotropic prodrugs approach to generate promising in vivo active compounds. Based on the structure of rivastigmine, novel MTDLs were designed, acting as prodrugs, able to temporarily covalently bind and inhibit AChE (for a symptomatic effect). and to secondarily release a drug able to selectively reach another AD target (for a potential disease-modifying effect). This concept was applied to several secondary targets, including different 5-HT receptors of interest4 for the treatment of AD. The concept, the synthetic development, in vitro and in vivo evaluation of these candidates and our undisclosed results will be presented for the first time in this communication. [ABSTRACT FROM AUTHOR]

One common event that is the most detrimental in neurodegenerative disorders, even though they have a complex pathogenesis, is the increased rate of neuronal death. Endogenous neurotrophins consist of the major neuroprotective factors, while brain-derived neurotrophic factor (BDNF) and its high-affinity tyrosine kinase receptor TrkB are described in a number of studies for their important neuronal effects. Normal function of this receptor is crucial for neuronal survival, differentiation, and synaptic function. However, studies have shown that besides direct activation, the TrkB receptor can be transactivated via GPCRs. It has been proven that activation of the 5-HT4 receptor and transactivation of the TrkB receptor have a positive influence on neuronal differentiation (total dendritic length, number of primary dendrites, and branching index). Because of that and based on the main structural characteristics of LM22A-4, a known activator of the TrkB receptor, and RS67333, a partial 5-HT4 receptor agonist, we have designed and synthesized a small data set of novel compounds with potential dual activities in order to not only prevent neuronal death, but also to induce neuronal differentiation in neurodegenerative disorders. [ABSTRACT FROM AUTHOR]

The multifactorial nature of some diseases, particularly neurodegenerative diseases such as Alzheimer's disease, frequently requires the use of several drugs. These drug cocktails are not without drawbacks in terms of increased adverse effects, drug–drug interactions or low adherence to treatment. The use of pleiotropic drugs, which combine, within a single molecule, several activities directed against distinct therapeutic targets, makes it possible to overcome some of these problems. In addition, these pleiotropic drugs generally lead to the expression of a synergy of effects, sometimes greater than that observed with a combination of drugs. This article will review, through recent examples, the different kinds of pleiotropic drugs being studied or already present on the market of medicines, with a focus on the structural aspect of such drug design. [ABSTRACT FROM AUTHOR]

In this work, we exemplified the "copride" family of drug candidates able to both inhibit acetylcholinesterase and to activate 5-HT 4 receptors, with anti-amnesiant and promnesiant activities in mice. Twenty-one analogs of donecopride, the first-in class representative of the series, were synthesized exploring the influence on the biological activities of the substituents (methoxy, amine and chlorine) carried by its phenyl ring. This work was the support of an intensive structure-activity relationship study and allowed to obtain some interesting derivatives of donecopride. In this respect, the replacement of the methoxy group of the latter with a deuterated one led to deudonecopride. On the other hand, the replacement of the chlorine atom of donecopride by various halogen atoms was of particular interest, among which fluorine led to a potent analog, we called flucopride. The latter exhibited promising in vitro activities associated to excellent drugability parameters. Flucopride was consequently involved in in vivo studies such as a scopolamine-induced deficit model of working memory and in a novel object recognition test. Through these evaluations, flucopride demonstrated both its antiamnesiant and promnesiant capacities, which could make it a potential preclinical drug candidate for the treatment of Alzheimer's disease. [Display omitted] • Cholinesterase inhibition and 5-HT 4 R activation can be expressed by a same agent. • Flucopride is a novel Multi-Target-Directed Ligand. • Flucopride exemplifies the copride family of potential anti-Alzheimer agents. • Flucopride exerts both antiamnesiant and promnesiant properties in mice. [ABSTRACT FROM AUTHOR]

Novel multitarget-directed ligands BIGI 4a-d and BIGI 5a-d were designed and synthesized with a simple and cost-efficient procedure via a one-pot three-component Biginelli reaction targeting acetyl-/butyrylcholinesterases inhibition, calcium channel antagonism, and antioxidant ability. Among these multitarget-directed ligands, BIGI 4b, BIGI 4d, and BIGI 5b were identified as promising new hit compounds showing in vitro balanced activities toward the recognized AD targets. In addition, these compounds showed suitable physicochemical properties and a good druglikeness score predicted by Data Warrior software. [ABSTRACT FROM AUTHOR]

Objectives Drug repositioning, that is, the use of a drug in an indication other than the one for which it was initially marketed, is a growing trend. Its origins lie mainly in the attrition experienced in recent years in the field of new drug discovery. Key findings Despite some regulatory and economic challenges, drug repositioning offers many advantages, and a number of recent successes have confirmed both its public health benefits and its commercial value. The first examples of successful drug repositioning mainly came about through serendipity like acetylsalicylic acid, thalidomide, sildenafil or dimethylfumarate. Conclusion The history of great-repositioned drugs has given some solutions to various pathologies. Serendipity is not yet useful to find repositioning drugs. Drug repositioning is of growing interest. Nowadays, a more rational approach to the identification of drug candidates for repositioning is possible, especially using data mining. [ABSTRACT FROM AUTHOR]

Aminothiaindanone heterocycle appears to be a scaffold of interest in medicinal chemistry. To increase the chemical diversity in this series, the introduction of three-point chemical diversity on the cyclopenta[ b ]thiophen-4-one scaffold was explored. About thirty newly functionalized thiophene-containing bicycles were obtained using various chemical reactions, paving the way for novel possibilities in medicinal chemistry projects. [ABSTRACT FROM AUTHOR]

Aims: Drug repositioning aims to propose new indications for marketed drugs. Although several methods exist, the utility of pharmacovigilance databases for this purpose is unclear. We conducted a disproportionality analysis in the World Health Organization pharmacovigilance database VigiBase to identify potential anticholinesterase drug candidates for repositioning in Alzheimer's disease (AD). Methods: Disproportionality analysis is a validated method for detecting significant associations between drugs and adverse events (AEs) in pharmacovigilance databases. We applied this approach in VigiBase to establish the safety profile displayed by the anticholinesterase drugs used in AD and searched the database for drugs with similar safety profiles. The detected drugs with potential activity against acetylcholinesterase and butyrylcholinesterases (BuChEs) were then evaluated to confirm their anticholinesterase potential. Results: We identified 22 drugs with safety profiles similar to AD medicines. Among these drugs, 4 (clozapine, aripiprazole, sertraline and S‐duloxetine) showed a human BuChE inhibition rate of over 70% at 10−5 M. Their human BuChE half maximal inhibitory concentration values were compatible with clinical anticholinesterase action in humans at their normal doses. The most active human BuChE inhibitor in our study was S‐duloxetine, with a half maximal inhibitory concentration of 1.2 μM. Combined with its ability to inhibit serotonin (5‐HT) reuptake, the use of this drug could represent a novel multitarget directed ligand therapeutic strategy for AD. Conclusion: We identified 4 drugs with repositioning potential in AD using drug safety profiles derived from a pharmacovigilance database. This method could be useful for future drug repositioning efforts. [ABSTRACT FROM AUTHOR]

• Drug-drug interactions can be powerful if they are ingeniously exploited. • Drug-drug enhancers are major weapons against resistance in infectiology and oncology. • Drug-drug interactions are widely used therapeutic strategies. Drug–drug interactions are sometimes considered to be detrimental and responsible for adverse effects. In some cases, however, some are stakeholders of the efficiency of the treatment and this combinatorial strategy is exploited by some drug associations, including levodopa (L-Dopa) and dopadecarboxylase inhibitors, β-lactam antibiotics and clavulanic acid, 5-fluorouracil (5-FU) and folinic acid, and penicillin and probenecid. More recently, some drug–drug combinations have been integrated in modern drug design strategies, aiming to enhance the efficiency of already marketed drugs with new compounds acting not only as synergistic associations, but also as real boosters of activity. In this review, we provide an update of examples of such strategies, with a special focus on microbiology and oncology. Using drug–drug interactions to boost the efficiency of a therapeutic treatment appears to be a relevant strategy and is now a modern drug design approach. [ABSTRACT FROM AUTHOR]

RNA viruses are responsible for a large variety of animal infections. Equine Arteritis Virus (EAV) is a positive single-stranded RNA virus member of the family Arteriviridae from the order Nidovirales like the Coronaviridae. EAV causes respiratory and reproductive diseases in equids. Although two vaccines are available, the vaccination coverage of the equine population is largely insufficient to prevent new EAV outbreaks around the world. In this study, we present a high-throughput in vitro assay suitable for testing candidate antiviral molecules on equine dermal cells infected by EAV. Using this assay, we identified three molecules that impair EAV infection in equine cells: the broad-spectrum antiviral and nucleoside analog ribavirin, and two compounds previously described as inhibitors of dihydroorotate dehydrogenase (DHODH), the fourth enzyme of the pyrimidine biosynthesis pathway. These molecules effectively suppressed cytopathic effects associated to EAV infection, and strongly inhibited viral replication and production of infectious particles. Since ribavirin is already approved in human and small animal, and that several DHODH inhibitors are in advanced clinical trials, our results open new perspectives for the management of EAV outbreaks. [ABSTRACT FROM AUTHOR]

Background and Purpose: We recently identified donecopride as a pleiotropic compound able to inhibit AChE and to activate 5-HT4 receptors. Here, we have assessed the potential therapeutic effects of donecopride in treating Alzheimer's disease (AD).Experimental Approach: We used two in vivo animal models of AD, transgenic 5XFAD mice and mice exposed to soluble amyloid-β peptides and, in vitro, primary cultures of rat hippocampal neurons. Pro-cognitive and anti-amnesic effects were evaluated with novel object recognition, Y-maze, and Morris water maze tests. Amyloid load in mouse brain was measured ex vivo and effects of soluble amyloid-β peptides on neuronal survival and neurite formation determined in vitro.Key Results: In vivo, chronic (3 months) administration of donecopride displayed potent anti-amnesic properties in the two mouse models of AD, preserving learning capacities, including working and long-term spatial memories. These behavioural effects were accompanied by decreased amyloid aggregation in the brain of 5XFAD mice and, in cultures of rat hippocampal neurons, reduced tau hyperphosphorylation. In vitro, donecopride increased survival in neuronal cultures exposed to soluble amyloid-β peptides, improved the neurite network and provided neurotrophic benefits, expressed as the formation of new synapses.Conclusions and Implications: Donecopride acts like a Swiss army knife, exhibiting a range of sustainable symptomatic therapeutic effects and potential disease-modifying effects in models of AD. Clinical trials with this promising drug candidate will soon be undertaken to confirm its therapeutic potential in humans. [ABSTRACT FROM AUTHOR]

Alzheimer's Disease is a devastating dementing disease involving amyloid deposits, neurofibrillary tangles, progressive and irreversible cognitive impairment. Today, only symptomatic drugs are available and therapeutic treatments, possibly acting at a multiscale level, are thus urgently needed. To that purpose, we designed multi-effects compounds by synthesizing drug candidates derived by substituting a novel N,N′- disubstituted piperazine anti-amyloid scaffold and adding acetylcholinesterase inhibition property. Two compounds were synthesized and evaluated. The most promising hybrid molecule reduces both the amyloid pathology and the Tau pathology as well as the memory impairments in a preclinical model of Alzheimer's disease. In vitro also, the compound reduces the phosphorylation of Tau and inhibits the release of Aβ peptides while preserving the processing of other metabolites of the amyloid precursor protein. We synthetized and tested the first drug capable of ameliorating both the amyloid and Tau pathology in animal models of AD as well as preventing the major brain lesions and associated memory impairments. This work paves the way for future compound medicines against both Alzheimer's-related brain lesions development and the associated cognitive impairments. • Multi-effect compounds result from disubstituted piperazine anti-amyloid scaffold with acetylcholinesterase inhibitors. • The multi-effect compound improve cholinesterase inhibition and anti-amyloid activity compared to parent compounds. • RPEL compound reduces both amyloid and Tau pathologies in vitro , in vivo and prevents the major brain lesions and associated memory impairments. [ABSTRACT FROM AUTHOR]

Abstract Pleiotropic intervention may be a requirement for effective limitation of the progression of multifactorial diseases such as Alzheimer's Disease. One approach to such intervention is to design a single chemical entity capable of acting on two or more targets of interest, which are accordingly known as Multi-Target Directed Ligands (MTDLs). We recently described donecopride, the first MTDL able to simultaneously inhibit acetylcholinesterase and act as an agonist of the 5-HT 4 receptor, which displays promising activities in vivo. Pharmacomodulation of donecopride allowed us to develop a novel series of indole derivatives possessing interesting in vitro activities toward AChE and the σ 1 receptor. The crystal structures of complexes of the most promising compounds with Torpedo californica AChE were solved in order to further understand their mode of inhibition. Graphical abstract Image 1 Highlights • Novel indolic MTDLs were obtained with good in vitro activities for the σ 1 R and AChE. • Torpedo californica AChE in complex with two indolic derivatives were obtained. • Ligand demonstrates in vivo activity in a dizocilpine-induced impairment model. [ABSTRACT FROM AUTHOR]

Abstract Equid alpha-herpesviruses (EHV) are responsible for different diseases in equine population. EHV-1 causes respiratory diseases, abortions and nervous disorders, EHV-4 causes respiratory diseases and sporadic abortion, while EHV-3 is responsible of equine coital exanthema. In view of the lack of efficacy of vaccines against EHV-1 and EHV-4 and in the absence of vaccines against EHV-3, the use of antiviral treatment is of great interest. In this study, we documented the interest of the Real-Time Cell Analysis (RTCA) technology to monitor the cytopathic effects induced by these viruses on equine dermal cells, and established the efficacy of this method to evaluate the antiviral effect of aciclovir (ACV) and ganciclovir (GCV). In addition, the RTCA technology has also been found appropriate for the high-throughput screening of small molecules against EHV, allowing the identification of spironolactone as a novel antiviral against EHV. Highlights • RTCA system is effective to monitor ECP formation induced by equid alphaherpesviruses on equine dermal cells. • Ganciclovir is ten-fold more effective than aciclovir against EHV-1, EHV-4 and EHV-3 on equine dermal cells. • RTCA system is suitable for high-throughput screening of small antiviral molecules against EHVs. • Spironolactone is identified as a new potential antiviral compound against EHV-1. [ABSTRACT FROM AUTHOR]

Natural or synthetic carbazole derivatives have recently attracted the attention of the scientific world because of their multiple biological activity, leading to an increase of designed, synthesized and studied analogues. In this paper, four 1,4-dimethylcarbazole derivatives, analogues of Ellipticine, have been investigated for their ability to block cancer cells growth, with low effects on the proliferation of normal cells. DNA topoisomerases inhibition assays, docking simulations, stability studies and effects on a membrane model are reported. Particularly, compounds 2 and 3 have been found thermally stable and able to inhibit, strongly and selectively, the human DNA topoisomerase II. These properties confer a good and broad antitumoral activity in vitro, with very low cytotoxic effect on the proliferation of normal cell lines and without damaging, in contrast with Ellipticine, the cell membrane model. The presented outcomes set the most active compounds as good candidates for pre-clinical studies useful in cancer treatment. [ABSTRACT FROM AUTHOR]

5-HT 4 receptor (5-HT 4 R) activation and blockade of the 5-HT 6 receptor (5-HT 6 R) are known to enhance the release of numerous neurotransmitters whose depletion is implicated in Alzheimer’s disease (AD). Furthermore, 5-HT 4 R agonists seem to favor production of the neurotrophic soluble amyloid protein precursor alpha (sAPPα). Consequently, combining 5-HT 4 R agonist/5-HT 6 R antagonist activities in a single chemical compound would constitute a novel approach able to display both a symptomatic and disease-modifying effect in AD. Seventeen novel derivatives of RS67333 ( 1 ) were synthesized and evaluated as potential dual-target compounds. Among them, four agents showed nanomolar and submicromolar affinities toward 5-HT 4 R and 5-HT 6 R, respectively; one of them, 7m , was selected on the basis of its in vitro affinity ( K i5-HT4R = 5.3 nM, K i5-HT6R = 219 nM) for further in vivo experiments, where 7m showed an antiamnesic effect in the mouse at 1 mg/kg ip. [ABSTRACT FROM AUTHOR]

Despite its implication in several physiological and pathological processes the serotonin subtype-4 receptor (5-HT 4 R) has seen limited effort for the development of radiolabeling agent especially concerning single photon emission computed tomography (SPECT). Bearing an ester function, the available ligands are rapidly susceptible to hydrolysis which limits their use in vivo . In this study the synthesis of iodinated benzamide and ketone analogs were described. Their affinity for the 5-HT 4 R and their lipophilicity were evaluated and the most promising derivatives were evaluated ex vivo for their binding to the receptor and for their ability to displace the reference ligand [ 125 I]-SB207710. [ABSTRACT FROM AUTHOR]

This work describes the synthesis and the biological evaluation of novel benzylidenephenylpyrrolizinones as potential antioxidant, metal chelating or amyloid β (βA) aggregation inhibitors. Some derivatives exhibited interesting results in regard to several of the performed evaluations and appear as valuable Multi-Target Directed Ligands with potential therapeutic interest in Alzheimer's disease. Among them, compound 29 particularly appears as a valuable radical and NO scavenger, a Cu(II) and Fe(II) chelating agent and exhibits moderate βA aggregation inhibition properties. These activities, associated to a good predictive bioavailability and a lack of cytotoxicity, design it as a promising hit for further in vivo investigation. [ABSTRACT FROM AUTHOR]

Numerous studies have been published about the implication of the neurotrophin brain-derived neurotrophic factor (BDNF) and its receptor TrkB in the pathogenesis of several neurodegenerative conditions such as Alzheimer's disease, Parkinson's disease, Multiple Sclerosis and motor neuron disease. BDNF activates the TrkB receptor with high potency and specificity, promoting neuronal survival, differentiation and synaptic plasticity. Based on the main structural characteristics of LM22A-4, a previously published small molecule that acts as activator of the TrkB receptor, we have designed and synthesized a small data set of compounds. The lead idea for the design of the new compounds was to modify the third position of the LM22A-4, by introducing different substitutions in order to obtain compounds which will have not only better physicochemical properties but selective activity as well. ADME and toxicity profiles of molecules have been evaluated as well as their biological properties through the TrkB receptor and affinity to promote neurite differentiation. [Display omitted] • The neurotrophin TrkB receptor represents one of the potential targets in neurodegenerative diseases. • New serie of potential TrkB activators was developed from the LM22A-4. • ENT-C225 has better physicochemical profile, higher potency in activating the TrkBR and promising neuroprotective profile. [ABSTRACT FROM AUTHOR]

A series of unknown 3-(alkyl(dialkyl)amino)benzofuro[2,3- f ]quinazolin-1(2 H )-ones 4–17 has been synthesized as new ellipticine analogs, in which the carbazole moiety and the pyridine ring were replaced by a dibenzofuran residue and a pyrimidine ring, respectively. The synthesis of these benzofuroquinazolinones 4–17 was performed in a simple one-pot reaction using 3-aminodibenzofuran or its 2-methoxy derivative, as starting materials. From 3-(dipropylamino)-5-methoxybenzofuro[2,3- f ] quinazolin-1(2 H )-one ( 13 ), we prepared 3-(dipropylamino)-5-hydroxybenzofuro[2,3- f ]quinazolin-1(2 H )-one ( 18 ), referred to as DPA-HBFQ-1 . The cytotoxic activities of all the synthesized compounds, tested in different human breast cancer cell lines, revealed that DPA-HBFQ-1 was the most active compound. In particular, the latter was able to inhibit anchorage-dependent and -independent cell growth and to induce apoptosis in estrogen receptor alpha (ERα)-positive and -negative breast cancer cells. It did not affect proliferation and apoptotic responses in MCF-10A normal breast epithelial cells. The observed effects have been ascribed to an enhanced p21 Cip1/WAF1 expression in a p53-dependent manner of tumor suppressor and to a selective inhibition of human topoisomerase II. In addition, DPA-HBFQ-1 exerted growth inhibitory effects also in other cancer cell lines, even though with a lower cytotoxic activity. Our results indicate DPA-HBFQ-1 as a good candidate to be useful as cancer therapeutic agent, particularly for breast cancer. [ABSTRACT FROM AUTHOR]

5-HT 4 and 5-HT 6 serotonergic receptors are located in brain structures involved in memory processes. Neurochemical and behavioural studies have demonstrated that acute activation of 5-HT 4 receptors (5-HT 4 R) or blockade of 5-HT 6 receptors (5-HT 6 R) improves memory. To evaluate the potential of these two receptors as targets in the treatment of memory disorders encountered in several situations (ageing, Alzheimer’s disease, schizophrenia, etc.), it is necessary to assess whether their beneficial effects occur after chronic administration, and if such treatment induces adverse effects. The goal of this study was to assess the effects of chronic 5-HT 4 R or 5-HT 6 R modulation on recognition memory, and to observe the possible manifestation of side effects (modification of weight gain, locomotor activity or exploratory behaviour, etc.). Mice were treated for 14 days with a 5-HT 4 R partial agonist (RS-67333) or a 5-HT 6 R antagonist (SB-271046) at increasing doses. Memory performances, locomotor activity, and exploration were assessed. Both chronic 5-HT 4 R activation and 5-HT 6 R blockade extended memory traces in an object recognition test, and were not associated with any adverse effects in the parameters assessed. Chronic modulation of one or both of these receptors thus seems promising as a potential strategy for the treatment memory deficits. [ABSTRACT FROM AUTHOR]

A preliminary in vitro screening of compounds belonging to various chemical families from our library revealed the thieno[3,2- d ]pyrimidin-4(3 H )-one scaffold displayed a promising profile against Plasmodium falciparum . Then, 120 new derivatives were synthesized and evaluated in vitro ; compared to drug references, 40 showed good activity toward chloroquine sensitive (IC 50 35–344 nM) and resistant (IC 50 45–800 nM) P. falciparum strains. They were neither cytotoxic (CC 50 15–50 μM) toward HepG2 and CHO cells, nor mutagenic. Structure–activity relationships were defined. The lead-compound also appeared active against the Plasmodium liver stages ( Plasmodium yoelii IC 50 = 35 nM) and a preliminary in vivo evaluation indicated the in vitro activity was preserved (45% reduction in parasitemia compared to untreated infected mice). A mechanistic study demonstrated these molecules do not involve any of the pathways described for commercial drugs and exert a specific activity on the ring and trophozoite stages. [ABSTRACT FROM AUTHOR]

5-HT 6 Receptors are relatively recently discovered receptors that interact with cholinergic, glutamatergic, GABAergic and dopaminergic transmission systems. These receptors have been implicated in the CNS system as therapeutic targets in applications such as psychosis, reduction of body weight or Alzheimer's disease. As part of our efforts to develop 5-HT 6 antagonists, we explored the benzothiazolone scaffold substituted in position 3 or 6 respectively with ethylamino chains and an aromatic ring connected through a sulfonyl linker. Final compounds were evaluated in radioligand binding assays for their ability to interact with 5-HT 6 receptors. Their potential cytotoxic effects were determined on the human neuroblastoma cell line SY5Y. They showed very low cytotoxicity, and one of them has submicromolar affinity for 5-HT 6 receptors. [ABSTRACT FROM AUTHOR]

This paper reports the synthesis and cardiac activity of new β-blockers derived from (Z/E)- indeno[1,2- c ]pyrazol-4(1 H )-one oximes ( 5a,b ). The latter compounds were allowed to react with epichlorohydrin, followed by reacting the oxiranyl derivatives formed ( 6a,b ) with some aliphatic amines to give the target compounds (Z/E)- 1-phenyl-1 H- indeno[1,2 -c ]pyrazol-4-one O -((2-hydroxy-3-(substituted amino)propyl)oxime ( 7a–c ) and (Z/E)- 1-methyl-1 H- indeno[1,2 -c ]pyrazol-4-one O -((2-hydroxy-3-(substituted amino)propyl)oxime ( 8a–c ). These final products 7a–c and 8a–c were evaluated for their ability to modulate the cardiac performance of a prototype mammalian heart. The results showed that, out of these molecules tested, 7b elicits a more potent depressant effect on contractility and relaxation, and competitively antagonizes β 1 -adrenergic receptors. [ABSTRACT FROM AUTHOR]

Thanks to a preliminary in vitro screening of several CCl3-substituted-nitrogen containing heterocycles belonging to our chemical library, the 2-trichloromethylquinoxaline scaffold appeared to be of potential interest for developing new antiplasmodial agents. Then, combining these experimental results to the antimalarial properties reported for various pyrrolo[1,2-a]quinoxaline derivatives, an original series of fifteen 7-substituted-4-trichoromethylpyrrolo[1,2-a]quinoxalines was synthesized in a 4 to 5 reaction steps pathway. All molecules were evaluated in vitro toward both their antiplasmodial activity on the K1 multi-resistant Plasmodium falciparum strain and their cytotoxicity on the HepG2 human cell line. Thus, 3 hit molecules were identified, displaying IC50 values in the micromolar range and low cytotoxicity values, reaching good selectivity indexes, in comparison with the reference drugs chloroquine and doxycycline. Structure-activity relationship studies showed that the pyrrolo[1,2-a]quinoxaline scaffold can support selective antiplasmodial activity when substituted at position 4 by a CCl3 group. However, substitution at position 7 of the same scaffold is neither beneficial for cytotoxicity nor favourable for the solubility in the biological media. [ABSTRACT FROM AUTHOR]

Abstract: Several new alkylguanidines derived from carbazole have been synthesized in a simple one-pot reaction starting from 3-aminocarbazole derivatives. The aminocarbazoles were reacted with ethoxycarbonylisothiocyanate, to give thiourea intermediates, followed by the addition of an alkylamine and HgCl2 to give ethoxycarbonylguanidine intermediates. The reaction mixture was then heated at 160°C to give the N-(1,4-dimethyl-9H-carbazol-3-yl)-N′-alkylguanidines. The cytotoxic activity of all the synthesized guanidines was evaluated against different cell lines. [Copyright &y& Elsevier]

Nine new 17-(piperazin-1-yl)pyridin-5-yl)steroids as abiraterone analogues were synthesized. Compounds 5d and 5g showed selective activities against 17α-hydroxylase/C17,20-lyase (CYP17A1) and aromatase (CYP19), respectively. IC50 values of 5d were 5.09 and >50 μ m, whereas these values for 5g were >50 μ m and 7.40 μ m, respectively, for CYP17A1 and CYP19. Molecular modelling highlighted that the inhibitor designed to bind cytochrome P450 haem iron is a necessary condition but not the only rationale to explain inhibitory activity. These abiraterone analogues were then evaluated on hormone-independent prostate cancer cell lines DU-145 and PC-3 and on hormone-dependent breast and prostate cancer cell lines MCF-7 and LNCaP, respectively. Compounds 5e, 5g and 5i have showed potent activities only on hormone-independent prostate cancer cell lines DU-145 and PC-3 with 60-85% inhibition of both cell viability and growth at 10 n m with pro-apoptotic mechanism as illustrated in PC-3 cells by DNA ladder assay and Western blotting of Bax, Casp-3 and its substrate, the poly (ADP-ribose) polymerase. We conclude that hybrid heterocycle steroids could be good lead compounds in the drug design especially against hormone-independent prostate cancer. [ABSTRACT FROM AUTHOR]