Identification of CH2-linked quinolone-aminopyrimidine hybrids as potent anti-MRSA agents: Low resistance potential and lack of cross-resistance with fluoroquinolone antibiotics.

The structural optimization of B14, an antibacterial agent we previously obtained, has led to the discovery of a new class of CH2-linked quinolone-aminopyrimidine hybrids with potent anti-MRSA activities. Surprisingly, the hybrids lacking a C-6 fluoro atom at the quinolone nucleus showed equal or even stronger anti-MRSA activities than their corresponding 6-fluoro counterparts, despite the well-established structure-activity relationships (SARs) indicating that the 6-fluoro substituent enhances the antibacterial activity in conventional fluoroquinolone antibiotics. Moreover, these new hybrids, albeit structurally related to conventional fluoroquinolones, showed no cross-resistance with fluoroquinolone drugs. The most active compound, 15m, exhibited excellent activities with a MIC value of 0.39 µg/mL against both fluoroquinolone-sensitive strain USA500 and -resistant MRSA isolate Mu50. Further resistance development studies indicated MRSA is unlikely to acquire resistance against 15m. Moreover, 15m displayed favorable in vivo half-life and safety profiles. These findings suggest a rationale for further evolution of quinolone antibiotics with a high barrier to resistance.

Cascade alkyl migration in 2-alkynylanilines for the synthesis of benzenoid ring multi-functionalized indoles.

Cascade alkyl migration of 2-alkynylanilines via an aromaticity destruction and reconstruction process is reported. The first alkyl migration is triggered by generation of a dearomatized arenium species via oxidation and cyclization, and the second is driven by the force to restore the aromaticity of rearrangement products. The reaction gave rise to a range of multi-functionalized indoles.

Anodic dearomatization of 2-alkynylanilines for the synthesis of multi-functionalized indoles.

An anodic oxidative dearomatization reaction of 2-alkynylanilines was developed. The formed dearomatized compounds were used as versatile precursors in the synthesis of a variety of benzenoid ring multi-functionalized indoles through simple conversions.

Synthesis of C7-Functionalized Indoles through an Aromaticity Destruction-Reconstruction Process.

A process for the synthesis of C7-functionalized indoles using para-substituted 2-alkynylanilines as starting materials was reported. The process involves a dearomatization, an 1,2-addition by organic lithium or Grignard reagents, an aromatization-driven allylic rearrangement, and a cyclization. A variety of groups including alkyl, aryl, alkenyl, or alkynyl groups were selectively installed at the C7 site of indoles leading to the formation of 2,5,7-trisubstituted indoles.

Stereoselective Synthesis of Acyclic Tetrasubstituted Alkenes from Anilines by Dearomatization and Trimethylenemethane Cycloaddition.

A method for stereoselective construction of acyclic all-carbon tetrasubstituted alkenes through insertion of nitrile-substituted trimethylenemethane into the aryl C-N bond in anilines via an aromaticity destruction-reconstruction process is reported. The process involves dearomatization, azo-[3 + 2] TMM cycloaddition and aromatization-triggered rearrangement.

Advances in the development of HIV integrase strand transfer inhibitors.

HIV-1 integrase (IN) is a key enzyme in viral replication that catalyzes the covalent integration of viral cDNA into the host genome. Currently, five HIV-1 IN strand transfer inhibitors (INSTIs) are approved for clinical use. These drugs represent an important addition to the armamentarium for antiretroviral therapy. This review briefly illustrates the development history of INSTIs. The characteristics of the currently approved INSTIs, as well as their future perspectives, are critically discussed.

Synthesis of 15N-labeled heterocycles via the cleavage of C-N bonds of anilines and glycine-15N.

A nitrogen replacement process that directly incorporates the 15N atom of glycine-15N into anilines was reported. The process involves a Csp2-N bond cleavage of anilines driven by dearomatization and a Csp3-N bond cleavage of glycine-15N driven by aromatization. A variety of 15N-labeled aromatic heterocycles can be prepared via this process.

Synthesis of 4-Alkylindoles from 2-Alkynylanilines via Dearomatization- and Aromatization-Triggered Alkyl Migration.

A simple method for rapid synthesis of 4-alkylindoles from 2-alkynylanilines was reported. The protocol involves an oxidative dearomatization and an aromatization triggered regioselective alkyl migration. A range of alkyl groups including linear, branched, or cycloalkyl groups can be introduced into the C4 position of indole.

Conversion of anilines to chiral benzylic amines via formal one-carbon insertion into aromatic C-N bonds.

Insertion of atoms into aromatic carbon-nitrogen bonds is an appealing method for the synthesis of nitrogen-containing molecules and it has the advantage of the availability and abundance of anilines. However, the direct cleavage of aromatic carbon-nitrogen bonds is challenging due to the particularly inert and stable nature of these bonds. Here we report a formal, enantioselective one-carbon insertion into an aromatic carbon-nitrogen bond via an aromaticity dissembly-reconstruction process to directly convert anilines to chiral α-branched benzylic amines. The process involves oxidative dearomatization of para-substituted anilines, chiral sulfur ylide-mediated asymmetric aziridination, and subsequent rearrangement. Chiral sulfur ylides serve as one-carbon insertion units.

Design and synthesis of novel desfluoroquinolone-aminopyrimidine hybrids as potent anti-MRSA agents with low hERG activity.

Despite the fact that the introduction of a fluorine atom at the C-6 position has resulted in the evolution of fluoroquinolones, fluoroquinolone-induced cardiac toxicity has drawn considerable attention. In this context, desfluoroquinolone-based hybrids with involvement of C-7 aminopyrimidine functional group were designed and synthesized. The biological results showed majority of these hybrids still demonstrated potent anti-MRSA activity with MIC values between 0.38 and 1.5 µg/mL, despite the lack of the typical C-6 fluorine atom. Particularly, the most active B14 exhibited activities at submicromolar concentrations against a panel of MRSA strains including vancomycin-intermediate strains, levofloxacin-resistant isolates, and linezolid-resistant isolates, etc. As expected, it also displayed highly selective toxicity toward bacterial cells and low hERG inhibition. Further resistance development study indicated MRSA is unlikely to acquire resistance against B14. The docking study revealed that two hydrogen bonds were formed between the C-7 substituent and the surrounding DNA bases, which might contribute to overcome resistance by reducing the dependence on the magnesium-water bridge interactions with topoisomerase IV. These results indicate a promising strategy for developing new antibiotic quinolones to combat multidrug resistance and cardiotoxicity.

Synthesis of 4,7-Difunctionalized Indoles via Imino Exchange and Sulfinyl Migration.

A process that rapidly assembles 4,7-difunctionalized indoles from 2-alkynycyclohexadienimines, sulfinamides, and nucleophiles (amines or alcohols) was developed. The process involves imino exchange, cascade cyclization/1,4-nucleophilic addition/aromatization, and 1,3-migration of the sulfinyl group. The 7-sulfinyl group is easy to convert into the sulfonyl or the thioether group through a simple oxidation and reduction reaction.

Formal group insertion into aryl C‒N bonds through an aromaticity destruction-reconstruction process.

Given the abundance and the ready availability of anilines, the selective insertion of atoms into the aryl carbon-nitrogen bonds will be an appealing route for the synthesis of nitrogen-containing aromatic molecules. However, because aryl carbon-nitrogen bonds are particularly inert, anilines are normally activated by conversion to more reactive intermediates such as aryldiazonium salts to achieve functionalization of the aryl carbon-nitrogen bonds, but the nitrogen atom is usually not incorporated into products, instead being discarded. The selective insertion of groups into aryl carbon-nitrogen bonds remains an elusive challenge and an unmet need in reaction design. Here we show an aromaticity destruction-reconstruction process that selectively inserts a trimethylenemethane (TMM) group into the aromatic carbon-nitrogen bond of anilines concomitant with a benzylic carbon-hydrogen bond functionalization. This process provides a transformative mode for anilines, and the insertion products are versatile precursor to various nitrogen-containing aromatic molecules through simple conversions.

Iodobenzene-Catalyzed Ortho-Dearomatization and Aromatization-Triggered Rearrangement of 2-Allylanilines: Construction of Indolin-3-ylmethanols with High Diastereoselectivities.

An iodobenzene-catalyzed oxidative rearrangement of 2-allylanilines was developed. This process involves an ortho-oxidative dearomatization mediated by the in situ generated iodine(III) compound and a subsequent aromatization-triggered rearrangement reaction, leading to the formation of functionalized indolin-3-ylmethanols with high diastereoselectivities.

Amine-Mediated Transimination and Aromatization-Triggered Domino Reaction in the Synthesis of Polyfunctionalized 4-Aminoquinolines.

Dearomatization provides numerous possibilities for the development of new transformative modes of aromatic compounds. A conceptually novel metal-free multicomponent domino reaction of the dearomatized products of 2-alkynylanilines is developed. The reaction involves the secondary amine-mediated transimination with α-amino nitriles and subsequent aromatization-triggered cascade rearrangement, nucleophilic cyclization, and retro-Strecker reaction. This process provided a new practical method for the rapid synthesis of polyfunctionalized 4-aminoquinolines from readily available starting materials.

Dearomatization-Induced Cycloaddition and Aromatization-Triggered Rearrangement: Synthesis of Vertically Expanded Five-Ring Fused Benzofurans.

A dearomatization strategy has been developed for the efficient construction of vertically expanded five-ring fused benzofurans from ortho-alkynylphenols and ortho-alkynylarylaldimines. The stepwise procedure comprises a dearomatization-induced silver-catalyzed [3 + 2] cycloaddition followed by an aromatization-triggered ytterbium-catalyzed rearrangement.

Impaired NK cells' activity and increased numbers of CD4 + CD25+ regulatory T cells in multidrug-resistant Mycobacterium tuberculosis patients.

Multidrug-resistant tuberculosis (MDR-TB) often causes persistent infection and chemotherapy failure, which brings heavy burden of society and family. Many immune cell subsets and regulatory mechanisms may operate throughout the various stages of infection. The presence of regulatory T cells (Tregs) is thought to be an important mechanism that TB successfully evades the immune system. Tregs play a central role in the prevention of autoimmunity and in the control of immune responses. The role of Tregs in MDR-TB infection and persistence is inadequately documented. The current study was designed to determine whether CD4 + CD25+ regulatory T cells may modulate innate immunity (such as NK cells) against human tuberculosis. Our results indicated that the numbers of CD4 + CD25+ Treg cells increased in MDR-TB patients' blood, and the cytokine production of IL-10 increased from MDR-patients compared with healthy subjects, along with the lower activity and low CD69 expression of NK cells in patients. These results suggested that immunity to MDR-TB patients induced circulating CD4 + CD25+ T regulatory cells expansion, which may be related to the persistence of Mycobacterium tuberculosis (M. tb) infection, and to the balance between effectors immune responses and suppression immune responses.

Destruction and Construction: Application of Dearomatization Strategy in Aromatic Carbon-Nitrogen Bond Functionalization.

The formation of carbon-carbon bonds through the functionalization of aromatic carbon-nitrogen bonds is a highly attractive synthetic strategy in the synthesis of aromatic molecules. In this paper, we report a novel aromatic carbon-nitrogen bond functionalization reaction by using a simple dearomatization strategy. Through this process para-substituted anilines serve as a potential aryl source in the construction of a range of functionalized aromatic molecules, such as quaternary carbon centers, α-keto esters, and aldehydes.

Aniline Dearomatization and Silver-Catalyzed [3+3] Dipolar Cycloaddition: Efficient Construction of Oxocino[4,3,2-cd]indoles from 2-Alkynylanilines and 2-Alkynylbenzaldoximes.

2-Alkynylanilines are attractive starting materials in indole synthesis because of their ready availability. Herein, a one-pot stepwise procedure is reported for efficient construction of multisubstituted oxocino[4,3,2-cd]indoles from 2-alkynylanilines and 2-alkynylbenzaldoximes. The method comprises the oxidative dearomatization of 2-alkynylanilines, the silver-catalyzed [3+3] cycloaddition with 2-alkynylbenzaldoximes, and subsequent thermal radical skeletal rearrangement and aromatization.

Iodine(III)-mediated oxidative cross-coupling of enamines and propargylamines under metal-free conditions: an alternative way to prepare highly substituted 3-pyrrolines.

A PhIO/Bu4NI-mediated oxidative cross-coupling reaction between enamines and propargylamines under metal-free conditions has been developed. Bu4NI works as an activator of PhIO. The resulting coupling products are ready to undergo copper(II)-mediated electrophilic cyclization to form highly substituted 3-pyrrolines.

Oxidative nucleophilic cyclization of 2-alkynylanilines with thiophenols under metal-free conditions.

An oxidative nucleophilic cyclization of 2-alkynylanilines with thiophenols under metal-free conditions was developed. The one-pot two-step reaction involves a PhI(OAc)2-mediated oxidative dearomatization and a Brønsted acid promoted nucleophilic cyclization. DFT calculations were performed to understand the reaction pathway.