4-Fluoro-2-(phenyl-amino)-benzoic acid.

The title compound, C13H10FNO2, was obtained by the reaction of 2-bromo-4-fluoro-benzoic acid with aniline. There are two independent mol-ecules, A and B, in the asymmetric unit, with slight conformational differences: the dihedral angles between the aromatic rings are 55.63 (5) and 52.65 (5)°. Both mol-ecules feature an intra-molecular N-H⋯O hydrogen bond. In the crystal, the mol-ecules are linked by pairwise O-H⋯O hydrogen bonds to form A-B acid-acid dimers and weak C-H⋯F inter-actions further connect the dimers.

5-Bromo-2-(phenyl-amino)-benzoic acid.

The title compound, C13H10BrNO2, was obtained by the reaction of 2,5-di-bromo-benzoic acid and aniline. The mol-ecule is twisted with a dihedral angle between the aromatic rings of 45.74 (11)° and an intr-amolecular N-H⋯O hydrogen bond is seen. In the crystal, pairwise O-H⋯O hydrogen bonds generate carb-oxy-lic acid inversion dimers.

Predicting Drug-Drug Interactions Involving Rifampicin Using a Semi-mechanistic Hepatic Compartmental Model.

AIMS: To develop a semi-mechanistic hepatic compartmental model to predict the effects of rifampicin, a known inducer of CYP3A4 enzyme, on the metabolism of five drugs, in the hope of informing dose adjustments to avoid potential drug-drug interactions. METHODS: A search was conducted for DDI studies on the interactions between rifampicin and CYP substrates that met specific criteria, including the availability of plasma concentration-time profiles, physical and absorption parameters, pharmacokinetic parameters, and the use of healthy subjects at therapeutic doses. The semi-mechanistic model utilized in this study was improved from its predecessors, incorporating additional parameters such as population data (specifically for Chinese and Caucasians), virtual individuals, gender distribution, age range, dosing time points, and coefficients of variation. RESULTS: Optimal parameters were identified for our semi-mechanistic model by validating it with clinical data, resulting in a maximum difference of approximately 2-fold between simulated and observed values. PK data of healthy subjects were used for most CYP3A4 substrates, except for gilteritinib, which showed no significant difference between patients and healthy subjects. Dose adjustment of gilteritinib co-administered with rifampicin required a 3-fold increase of the initial dose, while other substrates were further tuned to achieve the desired drug exposure. CONCLUSIONS: The pharmacokinetic parameters AUCR and CmaxR of drugs metabolized by CYP3A4, when influenced by Rifampicin, were predicted by the semi-mechanistic model to be approximately twice the empirically observed values, which suggests that the semi-mechanistic model was able to reasonably simulate the effect. The doses of four drugs adjusted via simulation to reduce rifampicin interaction.

RNA-binding MSI proteins and their related cancers: A medicinal chemistry perspective.

Musashi1 and Musashi2 are RNA-binding proteins originally found in drosophila, in which they play a crucial developmental role. These proteins are pivotal in the maintenance and differentiation of stem cells in other organisms. Research has confirmed that the Musashi proteins are highly involved in cell signal-transduction pathways such as Notch and TGF-ß. These signaling pathways are related to the induction and development of cancers, such as breast cancer, leukemia, hepatoma and liver cancer. In this review we focus on how Musashi proteins interact with molecules in different signaling pathways in various cancers and how they affect the physiological functions of these pathways. We further illustrate the status quo of Musashi proteins-targeted therapies and predict the target RNA regions that Musashi proteins interact with, in the hope of exploring the prospect of the design of Musashi protein-targeted medicines.

A Peptoid-like Approach Led to Lactam-Lactam Dimer Formation in 2-Hydroxy-N-alkyl-N-phenyl-nicotinamides and Their Polymorphism and Solvatomorphism.

Four 2-hydroxy-N-alkyl-N-phenyl-nicotinamides (1-4) were synthesized, and their crystal structures were analyzed to investigate the effect of substitution on their crystal packing of N-phenyl-2-hydroxynicotinanilides. In these compounds, substituents were introduced on the amide N, leading to a peptoid-like structure. One solvent-free form and two hydrates were harvested for compound 1, and one anhydrous form and one hydrate were obtained for compound 2. Polymorphism was observed in compounds 3 and 4. The molecules were found to be in the keto form rather than the enol tautomer. Because of steric effects, the molecules took on an E configuration, leading to a hairpin-like geometry. A lactam-lactam dimer synthon was formed in all solvent-free structures, and a tetramer motif was observed for the first time. Dehydration of the two hydrates of 1 and the hydrate of 2 led to their respective solvent-free form. Phase transition between the polymorphs was revealed in compound 3. Theoretical calculations, including conformational energy evaluation, hydrate forming propensity assessment, and lattice energy appraisal, were performed to provide a reasonable explanation for the keto tautomer and the formation of the hydrates of compound 1.

4-(3-Chloro-anilino)benzoic acid.

The title compound, C13H10ClNO2, was synthesized by a Buchwald-Hartwig reaction and its crystal structure was investigated for the first time. Crystallization in a variety of solvents led to the discovery of one crystal form. High-quality single crystals were obtained by slow evaporation and the crystal structure was determined by single-crystal X-ray diffraction. The mol-ecules in the crystal structures are highly twisted [the dihedral angle between the aromatic rings is 34.66 (6)°] and pair up to form acid-acid dimers.

4-Oxo-N-phenyl-1,4-di-hydro-pyridine-3-carboxamide.

The title compound, C12H10N2O2, shows a nearly planar conformation. The crystal structure is sustained by hydrogen bonds between the NH and the carbonyl O function of the 4-oxo-1,4-di-hydro-pyridine ring of the mol-ecules, forming infinite chains along the b-axis direction.

3-Methyl-2-(4-methyl-phen-oxy)benzoic acid.

In the title compound, C15H14O3, the dihedral angle between the aromatic rings is 86.7 (9)°. In the crystal, carb-oxy-lic acid inversion dimers linked by pairwise O-H⋯O hydrogen bonds are formed.

4-Methyl-2-(2-methyl-anilino)benzoic acid.

The title compound, C15H15NO2, was obtained by the reaction of 2-chloro-4-methyl-benzoic acid and o-toluidine using 2-eth-oxy-ethanol as solvent. Crystals of the title compounds were obtained from crystallization in acetone. The mol-ecule in the crystal is twisted with a dihedral angle between the aromatic rings of 50.86 (5)°. In the crystal structure, the mol-ecules associate to form acid-acid hydrogen-bonded dimers linked by pairwise O-H⋯O hydrogen bonds.

N-(3-Chloro-2-methyl-phen-yl)-6-oxo-1,6-di-hydro-pyridine-3-carboxamide.

In the crystal structure of the title compound, C13H11ClN2O2, the mol-ecules form a three-dimensional network based on two types of hydrogen bonds between NH groups and the carbonyl oxygen atoms and amides. The mol-ecule is highly twisted, as evidenced by the dihedral angle between the 6-oxo-1,6-di-hydro-pyridine and benzene rings [88.1 (2)°].

N-(2,6-Di-chloro-phen-yl)-2-oxo-1,2-di-hydro-pyridine-3-carboxamide.

Crystals of the title compound, C12H8Cl2N2O2, were obtained by slow evaporation of an ethano-lic solution. An intra-molecular amideN-H⋯O=Clactam hydrogen bond is observed. In the crystal, two mol-ecules pair up to form a centrosymmetric lactam-lactam dimers (LLD) by N-H⋯O=C hydrogen bonds, whereas the O=Camide group of the mol-ecule does not participate in hydrogen bonding.

Recent progress in degradation of membrane proteins by PROTACs and alternative targeted protein degradation techniques.

Targeted protein degradation (TPD) is one of the key strategies of current targeted cancer therapy, and it can eliminate some of the root causes of cancer, and effectively avoid drug resistance caused by traditional drugs. Proteolysis targeting chimera (PROTAC) is a hot branch of the TPD strategy, and it has been shown to induce the degradation of target proteins by activating the inherent ubiquitin-proteasome system (UPS) in tumor cells. PROTACs have been developed for more than two decades, and some of them have been clinically evaluated. Although most of the proteins degraded by PROTACs are intracellular, degradation of some typical membrane proteins has also been reported, such as epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), programmed death ligand 1 (PD-L1), and G-protein-coupled receptor (GPCR). In addition, some other effective membrane protein-degrading strategies have also emerged, such as antibody-based PROTAC (AbTAC), lysosome targeting chimera (LYTAC), molecular glue, and nanoparticle-based PROTAC (Nano-PROTAC). Herein, we discussed the advantages, disadvantages and potential applications of several important membrane protein degradation techniques. These techniques that we have summarized are insightful in paving the way for future development of more general strategies for membrane protein degradation.

Solvatomorphism and first-time observation of acid-acid catemer in 4-phenylamino-benzoic acids.

To investigate the polymorphism in 4-phenylamino-benzoic acids (4-PABAs) in general, and the effect on the polymorphism of these compounds exerted by substitution in particular, a series of 4-PABAs (1-8) varying in the substitution position and pattern were synthesized, and their polymorphic behavior was investigated for the first time. A relatively comprehensive polymorph screening led to the discovery of two forms, one solvent-free and the other solvate, for compounds 1, 3 and 8, and one form for the other compounds. The crystal structures were determined by single-crystal XRD. All the 4-PABAs in the crystal structures are highly twisted, and all the solvent-free crystals are based on the conventional acid-acid dimer motif, except for 2, which has a rarely observed acid-acid catemer motif. Two of the solvates (1-S and 8-S) have pyridine in the lattice while the other (3-S) has dichloromethane. The observation indicates that neither conformational flexibility or substitution alone nor the combination of both leads to polymorphism in these compounds, which is in dramatic contrast to the polymorphism of fenamic acids. The thermal properties of each system were investigated by differential scanning calorimetry and desolvation of the solvates was studied by thermogravimetric analysis. Hirshfeld surface analysis and molecular dynamics simulation were performed to study the mechanism of polymorphism and the intermolecular interactions contributing to the formation and stability of each crystal form.

Recent advances in 1,2,3- and 1,2,4-triazole hybrids as antimicrobials and their SAR: A critical review.

With the widespread use and sometimes even abuse of antibiotics, the problem of bacterial resistance to antibiotics has become very serious, and it is posing a great threat to global health. Therefore, development of new antibiotics is imperative. Triazoles are five-membered, nitrogen-containing aromatic heterocyclic scaffolds, with two isomeric forms, i.e. 1,2,3-triazole and 1,2,4-triazole. Triazole-containing compounds have a wide range of biological activities such as antibacterial, antifungal, anticancer, antioxidant, antitubercular, antimalarial, anti-HIV, anticonvulsant, anti-inflammatory, antiulcer, analgesic, and etc. The bioactivities and the diversity of triazole-containing drugs have attracted wide interest in these heterocycles. Various antibiotic triazole hybrids have been developed, and most of which have shown potent antimicrobial activities. In this review, we summarized the recent advances in triazole hybrids as potential antibacterial agents and their structure-activity relationships (SARs). The information gained through SAR studies will provide further insights into the development of new triazole antimicrobials.

Recent advances in anticancer peptoids.

Since most tumors become resistant to drugs in a gradual and irreversible manner, making treatment less effective over time, anticancer drugs require continuous development. Peptoids are a class of peptidomimetics that can be easily synthesized and optimized. They exhibit a number of unique characteristics, including protease resistance, non-immunogenicity, do not interfere with peptide functionality and skeleton polarity, and can adopt different conformations. They have been studied for their efficacy in different cancer therapies, and can be considered as a promising alternative molecular category for the development of anticancer drugs. Herein, we discuss the extensive recent advances in peptoids and peptoid hybrids in the treatment of cancers such as prostate, breast, lung, and other ones, in the hope of providing a reference for the further development of peptoid anticancer drugs.

An optimization model of tram timetables considering various signal priority strategies.

Modern trams generally operate in a semi-independent Right Of Way that intersects with social vehicles at junctions. Typically, there are two signal priority strategies at junctions: active signal priority strategy and no-signal priority strategy. The active signal priority strategy is applied to improve the efficiency of the tram. However, it inevitably causes delays to social vehicles. The no-signal priority strategy could reduce the influence on social vehicles, but it will increase the tram travel time. Therefore, we develop a Mixed-Integer Linear Programming model to optimize the tram timetable and consider various signal priority strategies. In the model, the signal priority strategies of the tram are a set of decision variables that consider the traffic flow of social vehicles rather than fixed input parameters. The model considers minimizing the overall travel time of the tram and the negative utility of signal priority strategies. A numerical experiment is conducted to demonstrate the validity of the proposed model. The experimental results show that the proposed method can optimize the tram timetable and maximize the overall benefits of the junction. Moreover, we compare the experimental results of the proposed method with the approach of fixing the signal priority strategy for the tram at junctions. On the one hand, our proposed method can improve the operational efficiency of trams, i.e., the travel time decreases by 16.60%. On the other hand, the negative utility of signal priority for the comprehensive scheme proposed in this work reduces by 39.45%.

ROS-cleavable diselenide nanomedicine for NIR-controlled drug release and on-demand synergistic chemo-photodynamic therapy.

Many chemotherapeutic drugs and photosensitizers suffer from poor solubility, unspecific delivery and uncontrollable release, which severely impede their biomedical applications. Herein, we designed a type of ROS-cleavable hydrophilic diselenide nanoparticles through self-assembling of PEG-modified camptothecin (CPT, a hydrophobic drug) and meso­tetra (4-carboxyphenyl) porphine (TCPP, a hydrophobic photosensitizer). The TCPP@SeSe-CPT nanomedicine (particle size: 116.5 ± 1.9 nm) has stability for long-time blood circulation. Near-infrared (NIR) laser-triggered generation of ROS from TCPP can efficiently break the ROS-sensitive diselenide bond, which induces the decomposition of TCPP@SeSe-CPT nanomedicine for concurrent release of CPT and TCPP. Moreover, the released amounts of CPT and TCPP can be regulated by adjusting the NIR laser irradiation time. Such NIR-controlled release of CPT and TCPP can give rise to on-demand synergistic chemo-/photodynamic therapeutic effects for maximized tumor growth suppression with minimized side effects. STATEMENT OF SIGNIFICANCE: In this work, a ROS-cleavable diselenide nanoparticle was designed and successfully self-assembled with the hydrophobic drug camptothecin and photosensitizer TCPP into a hydrophilic TCPP@SeSe-CPT nanomedicine. Compared with traditional drug delivery systems, TCPP@SeSe-CPT nanomicelles could reduce premature drug release and co-deliver hydrophobic chemotherapeutic drugs/photosensitizers to tumors, which yielded a NIR-controlled synergistic chemo-/photodynamic therapeutic effect. Since diselenide bond is more sensitive than the traditional disulfide bond, under the 660 nm laser irradiation (300 mW/cm2), ROS generated from laser-excited TCPP in TCPP@SeSe-CPT nanomicelles could break the diselenium bonds to achieve the light-controlled release of CPT. In addition, the photosensitizer TCPP could also be imaged at the tumor site. Due to the photodynamic therapy from laser-excited TCPP and chemotherapy from photocontrolled release of CPT in TCPP@SeSe-CPT, our designed nanomicelles yielded potent antitumor effects both in vitro and in vivo.

Hybrid molecules based on caffeic acid as potential therapeutics: A focused review.

Caffeic acid-based compounds possess a high degree of structural diversity and show a variety of pharmacological properties, providing a useful framework for the discovery of new therapeutic agents. They are well-known analogues of antioxidants found in many natural products and synthetic compounds. The present review surveys the recent developments in structure-activity relationships (SAR) and mechanism of action (MOA) of various caffeic acid-containing compounds that play important roles in the design and synthesis of new bioactive molecules with antioxidant, antidiabetic, antiviral, antibacterial, anticancer, anti-inflammatory, and other properties. This review should provide inspiration to scientists in the research fields of organic synthesis and medicinal chemistry related to the development of new antioxidants with versatile therapeutic potential.

Synthesis of (2-(Quinolin-2-yl)phenyl)carbamates by a One-Pot Friedel-Crafts Reaction/Oxidative Umpolung Aza-Grob Fragmentation Sequence.

Utilizing the easily available isatin-based propargyl amines prepared from isatins, terminal alkynes, and anilines, (2-(quinolin-2-yl)phenyl)carbamates were prepared by a one-pot reaction in sequence, combining the gold-catalyzed Friedel-Crafts cyclization, oxidative umpolung aza-Grob fragmentation, and nucleophilic addition. In this process, gold-catalyzed cyclization of isatin-based propargyl amines gave 1'H-spiro[indoline-3,2'-quinolin]-2-ones, which were oxidized in situ by hypervalent iodine via the aza-Grob fragmentation to afford isocyano intermediates 2-(2-isocyanatophenyl)quinolines. Followed by the nucleophilic addition with alcohol solvents, (2-(quinolin-2-yl)phenyl)carbamates were synthesized. This procedure features easy operation, a wide substrate scope, and mild conditions.

Molecular Docking and Virtual Screening of an Influenza Virus Inhibitor That Disrupts Protein-Protein Interactions.

Influenza is an acute respiratory infection caused by the influenza virus, but few drugs are available for its treatment. Consequently, researchers have been engaged in efforts to discover new antiviral mechanisms that can lay the foundation for novel anti-influenza drugs. The viral RNA-dependent RNA polymerase (RdRp) is an enzyme that plays an indispensable role in the viral infection process, which is directly linked to the survival of the virus. Methods of inhibiting PB1-PB2 (basic polymerase 1-basic polymerase 2) interactions, which are a key part of RdRp enzyme activity, are integral in the design of novel antiviral drugs, a specific PB1-PB2 interactions inhibitor has not been reported. We have screened Enamine's database and conducted a parallel screening of multiple docking schemes, followed by simulations of molecular dynamics to determine the structure of a stable ligand-PB1 complex. We also calculated the free energy of binding between the screened compounds and PB1 protein. Ultimately, we screened and identified a potential PB1-PB2 inhibitor using the ADMET prediction model.