Quinoline derivatives are valuable scaffolds in medicinal and synthetic organic chemistry. In this work, a series of 3-formyl-2-allyloxyquinolines were synthesized from 2-chloro-3-formylquinolines prepared via the Meth-Cohn protocol, followed by acetal protection and alkoxide substitution. The Baylis-Hillman reaction of these quinolinic aldehydes with methyl acrylate in the presence of DABCO afforded the corresponding beta-hydroxy acrylate adducts in good yields. To prevent undesired transformations of the hydroxyl functionality, these adducts were protected as tert-butyldimethylsilyl ethers. However, reduction of the silylated Baylis-Hillman adducts with LiAlH4 did not furnish the anticipated allylic alcohols. Instead, the reaction proceeded through a competing reduction-elimination pathway, leading to mixtures of unsaturated esters and primary alcohols. The product distribution was influenced by the substitution pattern of the quinoline framework.

Quinoline derivatives are significant in organic and medicinal chemistry due to their versatile applications, especially in pharmacology. In this work, we report the synthetic pathways and structural characterization of four new quinoline epoxides derived from 2-chloro-3-formylquinoline, namely 2-chloro-3-(oxiran-2-yl)quinoline (4a), 2-chloro-6-methoxy-3-(oxiran-2-yl)quinoline (4b), 2-chloro-5,8-dimethyl-3(oxiran-2-yl)quinoline (4c) and 2-chloro-6,8-dimethyl-3(oxiran-2-yl)quinoline (4d), by using a stepwise approach involving the preparation of acetanilides, their transformation into quinoline derivatives and subsequent epoxidation. These compounds were characterized by spectroscopic FT-IR, 1HNMR , 13CNMR , 1H/1HCOSY, HSQC, high-resolution mass spectrometry (HRMS) and powder X-ray diffraction (PXRD) techniques. We have provided herein insights into the structural features of the studied compounds by analyzing their Hirshfeld surfaces and most prominent intermolecular interactions. Furthermore, we have investigated their in vitro biological implications as antioxidant agents and highlighted their in silico binding modes by carrying out molecular docking calculations against human peroxiredoxin (3MNG).

Herein, we report a visible-light-mediated, transition-metal-free strategy for the synthesis of E-configured bi-aryl imines and 2-phenylquinazolin-4(3H)-ones via insertion of siloxycarbenes, generated in situ from acylsilanes, into aniline N-H bonds. This operationally simple C-N bond formation transformation proceeds under mild, oxidant-free conditions and exhibits broad compatibility with both aromatic acylsilanes and diverse 2-cyano-anilines. In addition, under basic conditions, the reaction can further be directed toward the efficient construction of complex quinazolinone frameworks.

A protocol for the ortho C-H alkenylation of aromatic and heterocyclic esters under ruthenium catalysis has been developed. Herein, we report a Cp*-free ruthenium-catalyzed direct mono-alkenylation of arene esters with cyclic enediones. The reaction proceeds through initial cyclometalation via weak chelation-assisted C-H bond activation, followed by coordination of the activated alkene, insertion into the Ru-C bond, and β-hydride elimination. Additionally, regioselective dual ortho C-H alkenylation was realized, which not only broadens the synthetic utility of the arene esters as directing groups but also enables the construction of structurally diverse, symmetrically, and unsymmetrically alkenylated aromatic frameworks in a straightforward manner.

Diaryl pyrimidines (DAPYs) are privileged structures for Non-Nucleosidic Reverse Transcriptase Inhibitors (NNRTIs), and they are considered as one of the fundamental scaffolds of existing anti-HIV agents. In this study, we designed novel molecules by the addition of a N-acyl group to the C4-position of Rilpivirine/Etravirine basic scaffold, a well-known class of DAPYs, in order to provide more interactions with K103 and E138 in Reverse Transcriptase. This was leading, as expected, to better in vitro RT inhibition, and the compounds 12c (56 %) and 12 k (49 %) demonstrated three-fold higher potency than Doravirine (17 %). Additionally, compound 12c was identified as a strong and 12k as a moderate HIV reverse transcriptase enzyme inhibitor in the in vitro experiments. DAPYs are also crucial in the development of novel anti-cancer agents targeting several kinases, and our compounds, 12d and 12j, exhibited moderate cytotoxicity with IC50 values of 14.21 and 10.16 μM, respectively, against PC-3 cells and caused cell cycle arrest at G2/M checkpoint. The compound 12d induced apoptosis and reduced angiogenesis in PC-3 cells. Additionally, preliminary kinase screening against a panel of eight human kinases demonstrated only low PIM1 inhibition. However, the absence of correlation with cytotoxicity advocates an alternative mode of action that ought to be determined. Altogether, these studies indicate that the C4-position of diaryl pyrimidines could be important and warrants further investigated towards optimization of potential reverse transcriptase inhibitors.

The insertion of carbene into secondary amide N-H bonds remains underexplored in organic synthesis. In this work, we discovered the visible-light-induced insertion of siloxycarbene into amide N-H bonds. This metal-free, facile reaction proceeds with atom economy under mild conditions with a broad range of secondary N-H amides, including benzanilide, acetanilide, oxindole, isatin, quinolinone, and maleimide, affording stable N- and O-acetals in excellent isolated yields. In addition, the chemoselective insertion reveals the robustness of this chemical transformation.

Herein, a novel synthesis of different indolopyrido-quinazolinones by the reaction of easily accessible 2-indolyl quinazolinone with propargylic alcohols has been developed. This [4 + 2] annulation proceeds through sequential acid-catalyzed C-propargylation and base-promoted aza-annulation by forming C-C and C-N bonds in a one-pot operation. Interestingly, the reagent-controlled regiodivergent annulations were observed leading to diversely fused N1-C2 or C2-N3 indolopyrido-quinazolinones. This approach demonstrates access to 7,8-substituted dehydrorutaecarpine alkaloids and their unique structural isomers.

Research on new and potent inhibitors of anti-apoptotic proteins is a very active and promising topic in bioorganic and medicinal chemistry. MIM1 is a small molecule that was among the first reported inhibitors of the anti-apoptotic protein Mcl-1. We recently corrected its structure and developed a focused library of analogues to obtain new dual Bcl-xL/Mcl-1 inhibitors as well as selective Mcl-1 inhibitors. All the corresponding molecules contained a triphenol core, established by molecular modelling as the key component to anchor these products to the binding site of these proteins. Thus, as a next step, we designed and synthesized novel analogues in which this labile core was replaced by a meta carboxylic acid. A focused library of such molecules was submitted to a set of in cellulo biological studies, which allowed new potent and selective inhibitors of Mcl-1 to be identified. Preliminary structure-activity relationships were elucidated, and molecular modelling studies allowed us to propose a rationale for the biological activity of this series of new inhibitors, in particular for the inhibition of the anti-apoptotic protein Mcl-1.

A facile Rh(III)-catalyzed spiro-cyclization and ortho-(proximal) aromatic C-H activation reaction of amides with maleimides has been established via a weakly coordinating amide carbonyl acting as the directing group. This protocol features high competence, functional group tolerance, and wide-ranging substrate scope and, by slight adjustments of the reaction conditions, affords either a variety of spiropyrrolidinetrione or substituted 8-membered unsaturated lactams known as azocines in moderate yields. Additionally, the reaction is highly regioselective, furnishing mono-ortho-spiro and mono-ortho-8-membered annulated products.

Herein, we reveal an approach for the synthesis of a unique structural framework, dihydrofluoren-3-one, from the reaction of propargylic alcohol with alkynyl silyl enol ether. The transformation proceeds through acid-catalyzed propargylation of silyl enol ether leading to alkynyl-alkynones and subsequent intramolecular annulation (3+2 cycloaddition) in the presence of PPh3AuNTf2 (2 mol %). This novel dihydrofluoren-3-one motif was found to be a versatile precursor to provide diverse functionalized fluorenes.

In this paper, we report a short and efficient synthesis of novel N-arylbenzo[h]quinazoline-2-amines. We have prepared a focused library of nineteen representative examples which have been submitted to cytotoxicity assays against a representative panel of eight cancer cell lines and several molecules gave attractive results in this area.

The first sequential acid-catalyzed propargylation/base-mediated aza-cycloisomerization between indolyl-benzimidazoles and propargylic alcohols is described. This protocol enables the one-pot construction of N-fused benzimidazo-β-carbolines in good yields. The synthetic utility of this approach is demonstrated by the assembly of an aza-helicene and also by a gram-scale reaction.

Herein, we present an efficient strategy for the synthesis of spiro(indenyl)cyclohexadienones through radical-promoted reaction of 2-alkynyl biaryls with sodium sulfinates under electrochemical conditions. The reaction involves sulfonylation and dearomative ipso-cyclisation in a domino fashion. This approach features the use of readily accessible precursors, wide functional group tolerance and external oxidant-free reaction conditions. The practicality of the method was also illustrated by scale-up reaction and further diversification of the product.

A well-ordered strategy of sulfoxonium ylides as a directing group as well as carbene source for the Ru-catalysed [4+2] and Rh-catalysed [4+1] carbo-annulations with maleimides has been described. These novel methodologies have been successfully established for the synthesis of complex spiroindanones and benzoisoindoles containing compounds by the transition metal-mediated C-H activation/functionalization reactions. Further, Rh-catalysed [4+1] annulated compounds were obtained in the absence of any oxidant. A possible rationale for the remarkable divergent selectivity between the two catalysts has been proposed.

We herein demonstrate the acylsilane-directed Rh-catalyzed arene C-H bond alkylation with maleimides. The resulting derivatives were utilized in visible-light-induced intramolecular siloxycarbene-amide cyclization for the synthesis of new tricyclic γ-lactams. In parallel, we also harnessed the same acylsilane and maleimide units through [3 + 2] carbo-annulation by using Ru-catalysis. A wide range of maleimides and aroylsilanes were used to establish the broadness of these transformations.

Benzofuran and 2,3-dihydrobenzofuran scaffolds are heterocycles of high value in medicinal chemistry and drug synthesis. Targeting inflammation in cancer associated with chronic inflammation is a promising therapy. In the present study, we investigated the anti-inflammatory effects of fluorinated benzofuran and dihydrobenzofuran derivatives in macrophages and in the air pouch model of inflammation, as well as their anticancer effects in the human colorectal adenocarcinoma cell line HCT116. Six of the nine compounds suppressed lipopolysaccharide-stimulated inflammation by inhibiting the expression of cyclooxygenase-2 and nitric oxide synthase 2 and decreased the secretion of the tested inflammatory mediators. Their IC50 values ranged from 1.2 to 9.04 µM for interleukin-6; from 1.5 to 19.3 µM for Chemokine (C-C) Ligand 2; from 2.4 to 5.2 µM for nitric oxide; and from 1.1 to 20.5 µM for prostaglandin E2. Three novel synthesized benzofuran compounds significantly inhibited cyclooxygenase activity. Most of these compounds showed anti-inflammatory effects in the zymosan-induced air pouch model. Because inflammation may lead to tumorigenesis, we tested the effects of these compounds on the proliferation and apoptosis of HCT116. Two compounds with difluorine, bromine, and ester or carboxylic acid groups inhibited the proliferation by approximately 70%. Inhibition of the expression of the antiapoptotic protein Bcl-2 and concentration-dependent cleavage of PARP-1, as well as DNA fragmentation by approximately 80%, were described. Analysis of the structure–activity relationship suggested that the biological effects of benzofuran derivatives are enhanced in the presence of fluorine, bromine, hydroxyl, and/or carboxyl groups. In conclusion, the designed fluorinated benzofuran and dihydrobenzofuran derivatives are efficient anti-inflammatory agents, with a promising anticancer effect and a combinatory treatment in inflammation and tumorigenesis in cancer microenvironments.

An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.

The Meyer-Schuster Rearrangement (MSR) is a challenging process for propargylic alcohols bearing fluorine atom(s) on their chains. Most classical reagents/catalysts failed to perform the MSR but, after extensive screening, we demonstrated that phosphomolybdic acid was the first efficient catalyst for the MSR with such derivatives. The scope and limitations have been studied, affording fluorine-containing enones as useful intermediates for the synthesis of targets with fluorine(s) on their side chains. It was exemplified by the preparation of a 2-piperidino-pyrimidine and a pyrazole. New enones with mono-, gem-difluoro- or trifluoro chains are easily obtained through the Meyer-Schuster Rearrangement (MSR), using phosphomolybdic acid as the catalyst selected after extensive screening.image

The development of inhibitors of anti-apoptotic proteins, such as Mcl-1, is currently a very active area in the field of cancer research. One of the very first reported inhibitors of Mcl-1 was the MIM1 molecule, but we have recently demonstrated that the structure of this compound had to be revised from 2 to the derivative 1 (FJ-809). In this paper we first develop a strategy to unambiguously prepare molecules such as 1 with a thiazol-3(2H)-yl)imino core, instead of the [2(3H)-thiazolylidene]hydrazine previously found in MIM1 (2). Next a series of biological studies have been performed on 1, using IGROV1-R10 ovarian cancer cells as models, and they have been complemented by fluorescence polarisation assays. These studies demonstrated that the new compound FJ-809(1) was devoid of any significant activity on Mcl-1, in contrast to 2. Then molecular modelling and molecular dynamics studies have been performed in order to elucidate the differences between FJ-809 and MIM1 in their interaction with the Mcl-1 protein.

The development of inhibitors of anti-apoptotic proteins, such as Mcl-1, is currently a very active area in the field of cancer research.