Convergent Assembly of 1,4-Benzothiazide Spiroindolinones via [4 + 2] Spiroannulation Under Open-Air Conditions.

This report discloses a transition-metal-free [4 + 2] spirocyclization of isatin-derived β-silylcarbinols and 2-aminobenzenethiols, providing a facile approach to 1,4-benzothiazide spiroindolinones in decent yields. Control experiments indicate that 3-methylene oxindoles and disulfides are key intermediates in this tandem reaction. Moreover, the resulting products can be facilely converted into pharmaceutically significant sulfone and sulfoxide scaffolds, which further demonstrates the potential utility of this protocol.

Design, synthesis, and biological evaluation of dithiocarbamate derivatives as SARS-CoV-2 M inhibitors.

SARS-CoV-2 continues to mutate, spread, and impact public health and daily life. The main protease (M) is essential for the replication and maturation of SARS-CoV-2, making it an ideal target for anti-coronaviral drug discovery and development due to its high conservation and lack of homologous proteases in humans. Herein, we designed and synthesized a series of dithiocarbamate derivatives as potent SARS-CoV-2 M inhibitors.

Advances in diarylpyrimidines and related analogues as HIV-1 nonnucleoside reverse transcriptase inhibitors (2019-2023).

Nonnucleoside reverse transcriptase inhibitors (NNRTIs) have emerged as a vital cornerstone of highly active antiretroviral therapy (HAART) regimens, owing to their unique antiviral activity, low toxicity and high specificity. Diarylpyrimidines (DAPYs) as the second generation NNRTIs, represented by etravirine and rilpivirine, have attracted extensive attention due to their high anti-HIV potency. However, rapid emergence of resistant mutations, suboptimal pharmacokinetics (PK), and toxicity remain significant challenges.

Regioselective Cleavage and Reconfiguration of C-S Bonds with Diazo Compounds.

A coupling reaction between diazo compounds and phenyl benzyl sulfide catalyzed by TfOH has been reported. This reaction can synthesize important α-arylthio carbonyl compounds via regioselective cleavage and reconfiguration of C-S bonds, and various functional groups were tolerant to the reaction conditions. Mechanistic studies have conclusively established that the pivotal intermediate in the reaction was meticulously investigated through spectroscopic evidence, complemented by rigorous control experiments.

Al(OTf)-Catalyzed Regioselective N-Arylation of Tetrazoles with Diazo Compounds.

Regioselective methods to access alkylated tetrazoles still remain a challenging goal. Herein, we describe a novel regioselective protocol for N-arylation of tetrazoles with diazo compounds using inexpensive Al(OTf). This reaction could be conducted under mild conditions to access a diverse array of alkylated tetrazoles with 2-substituted tetrazoles as the major products, demonstrating a comprehensive range of substrate compatibility and excellent functional group compatibility.

T7 peptide-mediated co-delivery platform overcoming multidrug-resistant breast cancer: In vitro and in vivo evaluation.

P-glycoprotein (P-gp) overexpressed mutidrug resistance (MDR) is currently a key factor limiting the effectiveness of breast cancer chemotherapy. Systemic administration based on P-gp-associated mechanism leads to severe toxic side effects. Here, we designed a T7 peptide-modified mixed liposome (T7-MLP@DTX/SchB) that, by active targeting co-delivering chemotherapeutic agents and P-gp inhibitors, harnessed synergistic effects to improve the treatment of MDR breast cancer.

Non-peptidic inhibitors targeting SARS-CoV-2 main protease: A review.

The COVID-19 pandemic continues to pose a threat to global health, and sounds the alarm for research & development of effective anti-coronavirus drugs, which are crucial for the patients and urgently needed for the current epidemic and future crisis. The main protease (M) stands as an essential enzyme in the maturation process of SARS-CoV-2, playing an irreplaceable role in regulating viral RNA replication and transcription. It has emerged as an ideal target for developing antiviral agents against SARS-CoV-2 due to its high conservation and the absence of homologous proteases in the human body.

Synthesis of 2,4-Disubstituted Oxazoles and Thiazoles via Brønsted Acid-Catalyzed Cyclization of α-diazoketones with Amides.

A novel method is described for the synthesis of 2,4-disubstituted oxazole and thiazole derivates via the coupling of α-diazoketones with (thio)amides or thioureas using trifluoromethanesulfonic acid (TfOH) as a catalyst. This protocol is characterized by mild reaction conditions, metal-free, and simplicity and also features good functional group tolerance, good to excellent yields, and a broad substrate scope with more than 40 examples. Experimental studies suggest a mechanism involving 2-oxo-2-phenylethyl trifluoromethanesulfonate as the key intermediate.

Chemodivergent Synthesis of Sulfonamide and Sulfones from -Tosylhydrazones by Switching Catalyst and Temperature.

A catalyst- and temperature-controlled selective synthesis of sulfonamide and sulfones from -tosylhydrazones and MBH carbonates has been developed. The use of palladium catalysts exclusively leads to sulfonamide products at room temperature, whereas the selective synthesis of sulfones is dominant for a temperature-controlled coupling reaction without palladium catalysis. Importantly, the catalyst- or temperature-controlled reaction exhibits high nucleophilicity rather than carbene reactivity in these transformations.

Quinolines and isoquinolines as HIV-1 inhibitors: Chemical structures, action targets, and biological activities.

Human immunodeficiency virus type 1 (HIV-1), a lentivirus that causes acquired immunodeficiency syndrome (AIDS), poses a serious threat to global public health. Since the advent of the first drug zidovudine, a number of anti-HIV agents acting on different targets have been approved to combat HIV/AIDS. Among the abundant heterocyclic families, quinoline and isoquinoline moieties are recognized as promising scaffolds for HIV inhibition.

Iridium-Catalyzed Intramolecular Asymmetric Allylation of Vinyl Benzoxazinones for the Synthesis of Chiral 4-3,1-Benzoxazines via Kinetic Resolution.

Chiral benzoxazinones and 4-3,1-benzoxazines as important motifs are widely found in abundant pharmaceuticals and biological molecules. We herein successfully developed the first kinetic resolution (KR) process of racemic benzoxazinones through Ir-catalyzed asymmetric intramolecular allylation, furnishing a wide range of chiral benzoxazinones and 4-3,1-benzoxazines with excellent results via outstanding KR performances (with the factor up to 170). This protocol exhibited broad substrate scope generality and good functional group tolerance, and the chiral 4-3,1-benzoxazine products could be readily transformed to other useful optically active heterocycles.

E3 ligase ligand optimization of Clinical PROTACs.

Proteolysis targeting chimeras (PROTACs) technology can realize the development of drugs for non-druggable targets that are difficult to achieve with traditional small molecules, and therefore has attracted extensive attention from both academia and industry. Up to now, there are more than 600 known E3 ubiquitin ligases with different structures and functions, but only a few have developed corresponding E3 ubiquitin ligase ligands, and the ligands used to design PROTAC molecules are limited to a few types such as VHL (Von-Hippel-Lindau), CRBN (Cereblon), MDM2 (Mouse Doubleminute 2 homolog), IAP (Inhibitor of apoptosis proteins), etc. Most of the PROTAC molecules that have entered clinical trials were developed based on CRBN ligands, and only was based on VHL ligand.

Indole derivatives as tubulin polymerization inhibitors for the development of promising anticancer agents.

The α- and β-tubulins are the major polypeptide components of microtubules (MTs), which are attractive targets for anticancer drug development. Indole derivatives display a variety of biological activities including antitumor activity. In recent years, a great number of indole derivatives as tubulin polymerization inhibitors have sprung up, which encourages medicinal chemists to pursue promising inhibitors with improved antitumor activities, excellent physicochemical, pharmacokinetic and pharmacodynamic properties.

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.

Recent discoveries in HIV-1 reverse transcriptase inhibitors.

HIV-1 reverse transcriptase inhibitors (RTIs) are indispensable components of highly active antiretroviral therapy (HAART), which has achieved great success in controlling AIDS epidemic in reducing drastically the morbidity and mortality of HIV-infected patients. RTIs are divided into two categories, nucleoside reverse transcriptase inhibitors (NRTIs) and nonnucleoside reverse transcriptase inhibitors (NNRTIs). In this review, the recent discoveries in NRTIs and NNRTIs, including approved anti-HIV drugs and noteworthy drug candidates in different development stages, are summarized, and their future direction is prospected.

Virtual Screening and Optimization of Novel mTOR Inhibitors for Radiosensitization of Hepatocellular Carcinoma.

Background: Radiotherapy has an ameliorative effect on a wide variety of tumors, but hepatocellular carcinoma (HCC) is insensitive to this treatment. Overactivated mammalian target of rapamycin (mTOR) plays an important part in the resistance of HCC to radiotherapy; thus, mTOR inhibitors have potential as novel radiosensitizers to enhance the efficacy of radiotherapy for HCC.

Methods: A lead compound was found based on pharmacophore modeling and molecular docking, and optimized according to the differences between the ATP-binding pockets of mTOR and PI3K.

Indazolyl-substituted piperidin-4-yl-aminopyrimidines as HIV-1 NNRTIs: Design, synthesis and biological activities.

A series of indazolyl-substituted piperidin-4-yl-aminopyrimidines (IPAPYs) were designed from two potent HIV-1 NNRTIs piperidin-4-yl-aminopyrimidine 3c and diaryl ether 4 as the lead compounds by molecular hybridization strategy. The target molecules 5a-q were synthesized and evaluated for their anti-HIV activities and cytotoxicities in MT-4 cells. 5a-q displayed moderate to excellent activities against wild-type (WT) HIV-1 with EC values ranging from 1.

Recent progress in HIV-1 inhibitors targeting the entrance channel of HIV-1 non-nucleoside reverse transcriptase inhibitor binding pocket.

Since the entrance channel was proposed as a new binding site in non-nucleoside reverse transcriptase inhibitor binding pocket (NNIBP) of HIV-1 reverse transcriptase (RT) in 2012, a huge number of HIV-1 inhibitors acting on this target have sprung up, aiming to discover promising inhibitors with excellent antiviral activities, physicochemical properties, and so on. From 2012 to 2018, many noteworthy compounds have been continuously discovered. In this review, the recent progress in HIV-1 inhibitors targeting the entrance channel of HIV-1 NNIBP was summarized and reviewed, which would provide useful clues and inspiration for further design of HIV-1 inhibitors.

Biphasic Enantioselective Fluorescent Recognition of Amino Acids by a Fluorophilic Probe.

A fluorophilic fluorescent probe based on a perfluoroalkyl-substituted bis(binaphthyl) compound was designed and synthesized. It displayed a highly enantioselective fluorescence response toward structurally diverse amino acids in a biphasic fluorous/aqueous system with enantiomeric fluorescent enhancement ratio (ef; ΔI /ΔI ) values up to 45.2 (histidine).

Free Amino Acid Recognition: A Bisbinaphthyl-Based Fluorescent Probe with High Enantioselectivity.

A novel fluorescent probe based on a bisbinaphthyl structure has been designed and synthesized. This compound in combination with Zn(II) has exhibited highly enantioselective fluorescence enhancement with 13 common free amino acids. For example, its enantiomeric fluorescent enhancement ratios ( ef or Δ I/Δ I) in the presence of the following amino acids are extremely high: 177 for valine, 199 for methionine, 186 for phenylalanine, 118 for leucine, and 89 for alanine.

studies of diarylpyridine derivatives as novel HIV-1 NNRTIs using docking-based 3D-QSAR, molecular dynamics, and pharmacophore modeling approaches.

A series of novel diarylpyridine derivatives has recently been identified as HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs), and most of them exhibited potent activities against HIV-1 strains, with EC values in the low nanomolar range. However, the three-dimensional quantitative structure-activity relationships (3D-QSARs) and pharmacophore characteristics of these compounds remain to be studied. In the present study, forty-two diarylpyridine derivatives were firstly docked into HIV-1 reverse transcriptase, and molecular dynamics (10 ns) simulations were further performed to validate the reliability of the docking results, which indicated that residues Lys101, Tyr181, Tyr188, Phe227, and Trp229 might play important roles in binding with these diarylpyridines.

Advances in diarylpyrimidines and related analogues as HIV-1 nonnucleoside reverse transcriptase inhibitors.

HIV-1 nonnucleoside reverse transcriptase inhibitors (NNRTIs) have been playing an important role in the fight against acquired immunodeficiency syndrome (AIDS). Diarylpyrimidines (DAPYs) as the second generation NNRTIs, represented by etravirine (TMC125) and rilpivirine (TMC278), have attracted extensive attention due to their extraordinary potency, high specificity and low toxicity. However, the rapid emergence of drug-resistant virus strains and dissatisfactory pharmacokinetics of DAPYs present new challenges.

Docking-based 3D-QSAR and pharmacophore studies on diarylpyrimidines as non-nucleoside inhibitors of HIV-1 reverse transcriptase.

Diarylpyrimidines (DAPYs), a type of effective HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs), have been considered as one of the most successful agents for treating AIDS. A number of structurally diverse DAPYs have been designed and synthesized in the past decade, and most of them exhibited potent anti-HIV-1 activities; however, the structure-activity relationships of recently reported DAPYs and their pharmacophore features that interacted with HIV-1 reverse transcriptase (RT) remain to be studied. In the present study, molecular docking studies were first performed on three novel classes of DAPYs to study their binding pattern in the HIV-1 RT.