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International audience; The history of antibacterial discovery has revealed that natural products, especially secondary metabolites, represent privileged chemical matters for the antibacterial discovery. Among these metabolites, several natural phthalides exhibit interesting antibacterial activities, such as cytosporone E isolated from endophyte ascomycetes Diaporthe and Cytospora sp. We describe herein the synthesis and the pharmacomulations on the positions 3, 4 and 6 of cytosporone E, then the in vitro antibacterial evaluation of these compounds against Staphylococcus aureus including resistant strains, Escherichia coli and Pseudomonas aeruginosa. The evaluation of the cytotoxicity of the most active compounds against human bronchial epithelial cells was performed in order to check their safety.

3-Alkylidenephthalides represent an important class of natural compounds which are also valuable synthetic precursors for the preparation of phthalides. While recent reviews reported the great interest of the phthalides in the field of medicinal chemistry, few reports are mentioning the recent progress for the synthesis of their unsaturated homologous in the position 3. So, the aim of this report is to present the latest progresses (since 2010 and until 2021) in the synthesis of 3-alkylidenephtalides.

Benzoxazole and benzimidazole are commonly encountered heterocycles in medicinal chemistry and their functionalisation around 1-, 2-, 5-, and/or 6-positions provides a wide range of molecules of biological interest. In this manuscript, a straightforward preparation of diversely and highly substituted benzimidazoles and benzoxazoles on these positions, from a common starting material, a 3,3-dibromoacrolein, is described. Such acrolein derivatives are almost never described in the literature or used as ‘building-block’ for organic synthesis. The double electrophilicity of this substrate was found to be advantageous for condensation with two equivalents of various 1,2-diaminobenzene or 2-aminophenol derivatives. This one-pot reaction performed under metal-free and mild conditions allows the creation of three new carbon–heteroatom bonds and affords the desired heterocycles.

International audience; A total synthesis in four steps of racemic paecilocin A, a natural marine phthalide is reported. The synthetic pathway includes an iodine-magnesium exchange followed by a condensation on an aldehyde and represents a sufficiently flexible approach to allow the synthesis of twelve analogs. The synthesized compounds were investigated for their antibacterial activity against methicillin-sensitive Staphylococcus aureus (MSSA) and methicillin-resistant strain (MRSA). Three analogs were found to have similar or better antibacterial activity than the natural compound on MRSA. (C) 2021 Elsevier Ltd. All rights reserved.

International audience

Several studies have reported that certain psychoactive drugs could have a protective effect against SARS-CoV-2. Herein, we propose that antihistamines (anti-H1) and cationic amphiphilic drugs (CAD), specifically, have the capacity to disrupt virus entry and replication. In addition, several of these molecules have limited side effects and as such could be promising prophylactic candidates against SARS-CoV-2 infection.

SJR 2019 Q3; An increasing body of evidence suggests a protective effect of some psychoactive substances against SARS-CoV-2 (Severe Acute Respiratory Syndrome coronavirus type 2). Recent findings suggest that patients with psychiatric disorders are less affected by SARS-CoV-2 than their caregivers, which may seem surprising given some of the frequent risk factors for an unfavorable course of the disease (e.g., obesity, diabetes, cardiovascular and pulmonary diseases). We propose here a mixed pharmacoepidemiological and pharmacochemical hypothesis to explain these findings. A number of psychotropic drugs exhibit activities against coronaviruses (Middle East Respiratory Syndrome coronavirus (MERS-CoV), the Severe Acute Respiratory Syndrome coronavirus (SARS-CoV-1) and the Infectious Bronchitis Virus (IBV)) and have been put forward as potentially anti-SARS-CoV-2. These treatments include numerous mee-too drugs (chemically and pharmacologically linked to those which have demonstrated anti-SARS-CoV-2 efficacy) which are frequently prescribed in psychiatric settings. Taken alone or in polypharmacy, these drugs could have a prophylactic anti-SARS-CoV-2 effect, explaining the unexpectedly low proportion of patients with psychiatric disorders and COVID-19. Associated factors such as nicotine can also be considered in the context of a broad chemoprophylactic hypothesis in patients with psychiatric disorders taking different psychoactive substances.

β-stannylated propenoates 2 bearing a β-trifluoromethyl group, readily available by hydrostannation of 1, undergo copper(I) catalyzed coupling reactions without any palladium catalyst with allyl, benzyl, alkynyl, acyl and aryl halides. The corresponding adducts were obtained in moderate to good yields with a total retention of the double bond configuration. Interestingly, allyl bromides substituted with a stabilizing group did not led to expected coupling products but to the isomerization products 3. Thus, 31 examples are reported with yields up to 89 %. Finally, a mechanistic study was performed in order to confirm the mechanistic proposal.

The total synthesis of enhygrolide A, a γ-alkylidene butenolide natural product which exhibits antibacterial activities, is reported. The synthetic route features several key transformations, including a copper mediated Sonogashira/oxacyclization 5-exo-dig process to generate the alkylidene butenolide system and a Suzuki cross-coupling to introduce the benzylic unit. The methodology employed for this total synthesis represents a sufficiently flexible route to allow the synthesis of numerous analogs of these enhygrolides.

International audience; A mild, simple method for the regioselective synthesis of thiadiazolo[3,2-a]pyrimidin-7-ones bearing a perfluoroalkyl group is reported. In order to study the core reactivity, various nucleophile substitutions were performed involving the reactive carbon-bromide bond via a one-pot strategy.

International audience; New and efficient methods for the synthesis of 7-substituted-4-trifluoromethylpyrimido[1,2-b]pyridazin-2-one derivatives using either two-step Suzuki/heterocyclization, or two-step heterocyclization/substitution sequences are developed. A variety of substituted products are obtained in good to excellent yields from 3-amino-6-chloropyridazine and ethyl 4,4,4-trifluorobut-2-ynoate.

International audience; An original and convenient domino route to natural nostoclides I and II has been developed using a two-step sequence consisting of a copper-catalyzed tandem reaction associated with Suzuki cross-coupling. The methodology employed for this total synthesis appeared to be an interesting and sufficiently flexible tool to allow the synthesis of numerous analogues of these nostoclides.

How to train your silane: A new family of chiral copper(I) complexes that bear a bifluoride counteranion were prepared and used in the first example of the enantioselective transfer of a silyl group to an aldehyde. This procedure provides fast access to non-racemic α-hydroxysilanes in high enantioselectivities. Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

(Chemical Equation Presented) Asymmetric aldol reaction: A domino silylation-aldol reaction between enoyloxazolidinones and various aldehydes has been developed (see scheme). The process catalysed by a copper complex in the presence of a borosilane led to high diastereoselectivities. Yields between 59 and 90 % and d.r. values between 78:22 to 95:5 were obtained. When methacryloyloxazolidinones were used, a controlled chiral quaternary carbon was generated. BPin=4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl.

Palladium-catalyzed cross coupling reactions (Sonogashira-Hagihara, Suzuki-Miyaura, and Heck) coupling and nickel hydride-mediated tandem isomerization aldolisation have been used for the synthesis of three series of δ-valerolactones substituted in positions 3, 4, 5 and 6 of the lactone ring. The 26 kavaïn-like derivatives were tested against three cell lines and five of them exhibited a weak cytotoxic activity. Reações de acoplamento do tipo Heck, Sonogashira-Hagihara, Suzuki-Miyaura e reação de aldolisação catalizadas por metal foram utilizadas para a obtenção de três séries de δ-valerolactonas substituídas em posições 3, 4, 5 e 6 do anel lactônico. As 26 δ-valerolactonas sintetizadas foram testadas contra três linhagens celulares e cinco delas exibiram uma moderada atividade citotóxica.

A new access to indanones was discovered through a one-step nickel or iron-mediated transposition of 2-hydroxyisobenzofurans. Starting from the corresponding silylenol ethers, a new one-pot tandem isomerisation-Mukaiyama aldol process was also developed. These versatile strategies will be useful for the preparation of various types of indanones and indenones.

From sugars: pentacarbonyl is a cheap and efficient catalyst for a sequence of isomerization, aldol and dehydration, the vinyl sugar converted into cyclopentenones. These compounds are useful intermediates in the total synthesis of various bioactive molecules.

Screening of our chemical library to discover new molecules exhibiting in vitro activity against the invasion of host cells by Eimeria tenella revealed a lead compound with an IC50 of 15μM. Structure-activity relationship studies were conducted with 34 newly synthesized compounds to identify more active molecules and enhance in vitro activity against the parasite. Four compounds were more effective in inhibiting MDBK cell invasion in vitro than the lead compound.

A mild, simple method for the regioselective synthesis of thiadiazolo[3,2- a ]pyrimidin-7-ones bearing a perfluoroalkyl group is reported. In order to study the core reactivity, various nucleophile substitutions were performed involving the reactive carbon–bromide bond via a one-pot strategy.

A new approach to functionalized 1,3 diols, such as 15, is described using as the key step the tandem isomerization–aldolization reaction of allylic alcohols 1. The chiral imidazolidine group is shown to play a key role for the stereocontrol during aldolization and reduction steps.

New and efficient methods for the synthesis of 7-substituted-4-trifluoromethylpyrimido[1,2-b]pyridazin-2-one derivatives using either two-step Suzuki/heterocyclization, or two-step heterocyclization/substitution sequences are developed. A variety of substituted products are obtained in good to excellent yields from 3-amino-6-chloropyridazine and ethyl 4,4,4-trifluorobut-2-ynoate.

The total synthesis is based on a two-step sequence consisting of the Cu-catalyzed tandem reaction associated with the Suzuki cross-coupling reaction.

International audience; Total synthesis of (+/-)-herbaric acid and (+/-)-(4-methoxybenzyl)-5,7-dimethoxyphthalide, two natural phthalide products, was achieved in 8 steps and 5 steps, respectively, starting from commercially available 3,5-dimethoxyaniline. The key step of the sequence included a copper-catalysed tandem cross-coupling and oxacylisation reaction of terminal alkynes and 2-iodobenzok acid derivatives via 5-exo-dig cyclisation with high stereo-, regio- and chemoselectivities. This straightforward method allows the preparation of diverse phthalides, which belong to a group of pharmacologically important compounds.

Newly developed chiral copper(I) complexes bearing a bifluoride counteranion are used in the first example of the enantioselective title reaction.

International audience; A general and efficient Cu(I)-catalyzed cross-coupling reaction of alkynyl bromides and beta-tributylstannyl-alpha, beta-unsaturated ester bearing a trifluoromethyl group in beta-position was developed under very mild conditions. This method provides easy access to a variety of 2,3-enynoate bearing a trifluoromethyl group from good to excellent yields with excellent stereoselectivity. This procedure does not require the use of any expensive supplementary additives and is palladium-free.

International audience; A new one-pot domino process, involving four chemical transformations, for the synthesis of new dipyrido[1,2-a:3',4'-d]imidazole salts in a multicomponent reaction is reported. Various dipyrido[1,2-a:3',4'-d]imidazoles were obtained in moderate to good yields. The scope and limitations of the process and the reaction mechanism are discussed.

International audience

A copper-catalyzed domino silylation—aldol reaction is presented between enoyloxazolidinones (I) and (VII), various aromatic aldehydes and silylboronate (III).

Starting from vinyl pyranoses an iron-catalyzed tandem isomerization-intramolecular aldolization reaction was developed to prepare cyclohexenone derivatives bearing substituents on the double bond, and it has been applied in a short synthesis of 4-epi-gabosines A and B, from d-glucose.

The scope and the limitations of 3-chloro-2-pyridinyl lithium condensation to aldehydes were envisioned de- pending on metallation conditions or condensation time and temperatures. The procedure was applied to various aromatic, aliphatic or functionalized aldehydes to afford a new and efficient access to 2-(polyhydroxyalkyl)pyridines. n Scheme 1. Selective functionalization of 3-chloropyridine induced by (n-BuLi/LiDMAE) superbase. In this previous study, we described the regioselective C- 2 functionalization of 3-chloropyridine (2) performed by a metallation at -60°C for 1h, in hexane as solvent, with super- base (n-BuLi/LiDMAE) (3 eq). Condensation reactions were afforded using various representative electrophiles, one was a carbonyl reagent (tBuCHO, 60% isolated yield). In agree- ment with these results, we reported here a detailed investi- gation to extend the scope of this condensation using a vari- ety of functionalized aldehydes. The best determined condi- tions led us to define an improved protocol for introducing polyhydroxylated moieties on pyridinic ring allowing the synthesis of 1a-b.

The scope and the limitations of 3-chloro-2-pyridinyl lithium condensation to aldehydes were envisioned de- pending on metallation conditions or condensation time and temperatures. The procedure was applied to various aromatic, aliphatic or functionalized aldehydes to afford a new and efficient access to 2-(polyhydroxyalkyl)pyridines. n Scheme 1. Selective functionalization of 3-chloropyridine induced by (n-BuLi/LiDMAE) superbase. In this previous study, we described the regioselective C- 2 functionalization of 3-chloropyridine (2) performed by a metallation at -60°C for 1h, in hexane as solvent, with super- base (n-BuLi/LiDMAE) (3 eq). Condensation reactions were afforded using various representative electrophiles, one was a carbonyl reagent (tBuCHO, 60% isolated yield). In agree- ment with these results, we reported here a detailed investi- gation to extend the scope of this condensation using a vari- ety of functionalized aldehydes. The best determined condi- tions led us to define an improved protocol for introducing polyhydroxylated moieties on pyridinic ring allowing the synthesis of 1a-b.

Nickel hydride type complexes have been successfully developed as catalysts for the tandem isomerization-aldolization reaction of allylic alcohols with aldehydes. Optimization of the reaction conditions has shown that a cocatalyst, such as MgBr2, has a very positive effect on the kinetics of the reaction and in the yields of aldols. Under such optimized conditions {[NiHCl(dppe)] + MgBr(2) at 3-5 mol %)}, this reaction affords the aldols in good to excellent yields. It is a full-atom-economy-type reaction that occurs under mild conditions. Furthermore, it has a broad scope for the allylic alcohols and it is compatible with a wide range of aldehydes, including very bulky derivatives. The reaction is completely regioselective, but it exhibits a low stereoselectivity, except for allylic alcohols with a bulky substituent at the carbinol center. The use of chiral nonracemic catalysts was not successful, affording only racemic compounds. However, it was possible to use asymmetric synthesis for the preparation of optically active aldols. Various mechanistic studies have been performed using, for instance, a deuterated alcohol or a deuterated catalyst. They gave strong support to a mechanism involving first a transition-metal-mediated isomerization of the allylic alcohol into the free enol, followed by the addition of the latter intermediate onto the aldehyde in an "hydroxyl-carbonyl-ene" type reaction. These results confirm that allylic alcohols can be considered as new and useful partners in the development of the aldol reaction.

A series of huprine-tacrine heterodimers has been developed by connection of huprine Y, a compound with one of the highest affinities for the active site of acetylcholinesterase yet reported, with tacrine, a compound with known affinity for the peripheral site of the enzyme, through a linker of appropriate length to allow simultaneous interaction with both binding sites. These compounds exhibit human acetylcholinesterase and butyrylcholinesterase inhibitory activities with IC(50) values in the subnanomolar and low nanomolar range, respectively.