AbstractBedaquiline (BDQ) is a novel and highly potent last-line antituberculosis drug that was approved by the US FDA in 2013. Owing to its stereo-structural complexity, chemical synthesis and compound optimization are rather difficult and expensive. This study describes the structural simplification of bedaquiline while preserving antitubercular activity. The compound's structure was split into fragments and reassembled in various combinations while replacing the two chiral carbon atoms with an achiral linkage instead. Four series of analogues were designed; these candidates retained their potent antitubercular activity at sub-microgram per mL concentrations against both sensitive and multidrug-resistant (MDR) Mycobacterium tuberculosis strains. Six out of the top nine MIC-ranked candidates were found to inhibit mycobacterial ATP synthesis activity with IC50 values between 20 and 40 μm, one had IC50>66 μm, and two showed no inhibition, despite their antitubercular activity. These results provide a basis for the development of chemically less complex, lower-cost bedaquiline derivatives and describe the identification of two derivatives with antitubercular activity against non-ATP synthase related targets.

Cell multinucleation is closely related to chromosomal instability. We report a simple, convenient method to assess cell multinucleation with cytoplasm-localized fluorescent probes (CLFP) which is superior to conventional nuclear staining methods. The CLFP method provides high-resolution images that enable the accurate calculation of the number of nuclear fragments.

SYL927 and SYL930 are selective S1P1 agonists under preclinical development. However, during their pharmacokinetic studies we detected two metabolites in rat blood that were tentatively identified as monohydroxylated metabolites of SYL927 and SYL930 based on LC–MS/MS data. In this study, we designed and synthesized possible monohydroxylated products 6a–e and used them as references to confirm the structures of the two metabolites detected by LC–MS/MS. We also evaluated the in vitro and in vivo biological activities of these two metabolites.

The discovery and development of a general method for the one-pot synthesis of substituted phenanthridines is presented. In the presence of Pd(PPh3)4, accessible precursors undergo a Suzuki cross-coupling reaction with 2-(Boc-amino)benzeneboronic acid pinacol ester and then spontaneously undergo deprotection and intramolecular condensation to form the corresponding phenanthridines in one step. This reaction has a wide range of substrates with various functional groups, and the corresponding products have been obtained in good yields.

The dynamic balance of sphingolipids plays a crucial role in diverse biological processes such as mitogenesis, cell migration and angiogenesis. Sphingosine kinases (SKs) including SK1 and SK2 phosphorylate sphingosine to sphingosine 1-phosphate (S1P), and control the critical balance. SK1 overexpression was reported to increase cell survival and proliferation. Although several SK1 selective inhibitors have been reported, detailed analysis toward their selectivity to understand the molecular mechanism has not been performed to our knowledge. Herein, the crystal structure of SK1 and a homology model of SK2 were used to dock five inhibitors (1, 2, 3, 4 and 5). Protein–ligand complexes were then subjected to a molecular dynamics study and MM-PBSA binding free energy calculations. By analyzing the binding model of these inhibitors, we found that residues ILE170, PHE188 and THR192 in SK1 significantly contribute a favorable binding energy to the selectivity.

A new nucleophilic 1,3-rearrangement is observed when treating 2-methoxyquinolino-3-lithium with an α-C substituted deoxybenzoin, and this rearrangement yielded an unusual 3,4-disubstituted 3,4-dihydroquinoline. Several similar reactions were designed and executed to investigate this novel 1,3-rearrangement, and a mechanism involving a nucleophilic addition and a following 1,3-rearrangement with an unusual dearomatization on the quinoline ring is proposed.A novel nucleophilic 1,3-rearrangement is observed when treating 2-methoxyquinolino-3-lithium with α-C substituted deoxybenzoins, and the reaction mechanism is discussed.

•We discovered the trihydroxybenzohydrazide scaffold as an SphK inhibitor.•51 derivatives were synthesized and evaluated for SAR study.•The most potent compound 33 decreased SphK expression in HCT116.•33 significantly inhibited DSS induced colitis in mice.•33 inhibited IL-6 and COX-2 overexpression induced by DSS.Sphingosine kinase (SphK)-catalyzed production of sphingosine-1-phosphate (S1P) regulates cell growth, survival and proliferation as well as inflammatory status in animals. In recent study we reported the N′-(3-(benzyloxy)benzylidene)-3,4,5-trihydroxybenzohydrazide scaffold as a potent SphK inhibitor. As a continuation of these efforts, 51 derivatives were synthesized and evaluated by SphK1/2 inhibitory activities for structure–activity relationship (SAR) study. Among them, 33 was identified as the most potent SphK inhibitor. Potency of 33 was also observed to efficiently decrease SphK1/2 expression in human colorectal cancer cells (HCT116) and significantly inhibit dextran sodium sulfate (DSS)-induced colitis as well as the decreased expression of interleukin (IL)-6 and cyclooxygenase-2 (COX-2) in mouse models. Collectively, 33 was validated as an effective SphK inhibitor, which can be served as anti-inflammatory agent to probably treat inflammatory bowel diseases in human.

Starting from 7-hydroxyisoflavones, we developed a new class of fluorescent scaffolds, 3-alkyl-6-methoxy-7-hydroxy-chromones (AMHCs, MW ∼ 205.19, λab ∼ 350 nm, λem ∼ 450 nm) via a trial and error process. AMHCs have the advantages of being a small molecular moiety, having strong fluorescence in basic buffers, reasonable solubility and stability, non-toxicity, and are conveniently linked to pharmacophores. AMHCs were successfully used in fluorescence microscopy imaging of cells and tissues.

A tetrahydrofuro[3,2-d]oxazole scaffold was synthesized efficiently and stereoselectively. The tandem ionic hydrogenation, ketalization, and intramolecular cyclization of arene-1,4-diones with a combination of TiCl4/Et3SiH give facile access to tetrahydrofuro[3,2-d]oxazole derivatives in good yields at room temperature.

Sphingosine kinase 1 (SphK1) is an oncogenic lipid kinase, emerging as a novel and promising target for cancer and other diseases. Herein, hierarchical structure-based virtual screening against the sphingosine kinase 1(SphK1) binding pocket was performed. Consequently, three compounds have been identified as dual inhibitors of SphK1 and SphK2. Among them, compound 25 exhibited comparable SphK1 and SphK2 inhibitory activities to the positive control N,N-dimethylsphingosine (DMS) 1, and exerted anti-proliferative effects on U937 cells. Furthermore, molecule dynamic (MD) simulations have been conducted to provide a more detailed insight into the binding model between SphK1 and 25 in a state close to physiological conditions. 25 may serve as a potential novel scaffold for further development of SphK1 inhibitors.

Two series of phenothiazine derivatives were designed and synthesized. All compounds were tested for anti-tuberculosis activities against Mycobacterium tuberculosis H37RV. In comparison with mother compound of chlorpromazine, compound 6e shows promising anti-tuberculosis activity and much less mammalian cell cytotoxicity, compound 6e merits to be further explored as new anti-tuberculosis agents.Two series of phenothiazine derivatives were designed and synthesized. They were evaluated for anti-tuberculosis activity.

The discovery and development of an efficient and versatile method for the synthesis of N-substituted lactams is described. Pyrrolindinones, piperidones, and structurally related heterocycles were formed by Al(OTf)3-catalyzed cascade cyclization and ionic hydrogenation reactions of corresponding nitrogen substituted ketoamides in good yields.

•A highly predictive 3D QSAR pharmacophore model of S1P1 agonists was developed.•35 target compounds were designed and synthesized based on the pharmacophore model.•Click chemistry reaction was used for rapidly assembly of molecules.•Most compounds were identified as potent and selective S1P1 agonists.•Three compounds showed good in vivo activities and favorable PK profiles.We have discovered a series of triazole/oxazole-containing 2-substituted 2-aminopropane-1,3-diol derivatives as potent and selective S1P1 agonists (prodrugs) based on pharmacophore-guided rational design. Most compounds showed high affinity and selectivity for S1P1 receptor. Compounds 19b, 19d and 19p displayed clear dose responsiveness in the lymphocyte reduction model when administered orally at doses of 0.3, 1.0, 3.0 mg/kg with reduced effect on heart rate. These three compounds were also identified to have favorable pharmacokinetic properties.A series of triazole/oxazole-containing 2-substituted 2-aminopropane-1,3-diol derivatives were discovered as potent and selective S1P1 agonists based on pharmacophore-guided rational design.

A facile and versatile synthesis of dihydrobenzoheterocycles via Al(OTf)3-mediated cascade cyclization and ionic hydrogenation has been developed. The reaction is applicable to a wide range of substrates with various functional groups to afford the corresponding products in good yields.

An efficient synthesis of substituted 1,4-diazepines is developed. The accessible intermediates have been obtained via Pd-catalyzed amination. The subsequent hydrogenation and intramolecular condensation sequences could be conducted successively in one pot without special operation. The mild and general strategy enables the synthesis of various substituted 1,4-diazepines in high yields.An efficient synthesis of substituted 1,4-diazepines is developed. The mild and general strategy enables the construction of various substituted 1,4-diazepines in high yields.

Spingosine-1-phosphate receptor 1 (S1P1) has been actively pursued as an important therapeutic target in immune regulation. A series of 2-substituted 2-aminopropane-1,3-diols were designed and synthesized as selective S1P1 agonists. Most of the compounds with a biphenyl ether scaffold showed moderate to excellent S1P1/S1P3 selectivity. Compound 40c is identified as a potent S1P1 agonist with 350-fold S1P1/S1P3 selectivity. 39c, the alcohol form of 40c exerted good lymphopenia activity in vivo but with weak influence on heart rate. To investigate the SARs of 2-substituted 2-aminopropane-1,3-diols in more details, COMFA (q2 = 0.547, r2 = 0.986) and COMSIA (q2 = 0.544, r2 = 0.943) models were established based on molecular docking alignment, which were validated with high reliability in predicting activities of agonists. The 3D-QSAR models will be helpful in the design of novel, potent and selective S1P1 agonists.

An efficient method for mono-phosphorylation of 2 (KRP203) using cbz-protection, dibenzylphosphoryl chloride and TMSI affording 2-P (KRP203-P) was developed. We applied the present method to the synthesis of KRP203 phosphate analogs which were difficult to produce through tradition procedures.A three-step procedure for the preparation of mono-phosphorylation of KRP203 to 2-P has been developed. This method was considered as an effective route to synthesize various analogs of 2-P.

A one pot protocol for the synthesis of dibenzodiazepinones was developed. The substituted ethyl 2-halobenzoates are cross-coupled with o-phenylenediamine utilizing a ligand-free, CuI catalyzed system, which spontaneously undergo an intramolecular N-acylation in ethylene glycol to give the corresponding products in high yields. This synthetic protocol provides a concise and efficient access to a wide variety of dibenzodiazepinone, including biologically active molecules.A one pot protocol for the synthesis of dibenzodiazepinones was developed. The substituted ethyl 2-halobenzoates are cross-coupled with o-phenylenediamine utilizing a ligand-free, CuI catalyzed system, which spontaneously undergo an intramolecular N-acylation in ethylene glycol to give the corresponding products in high yields.

A series of benzimidazole derivatives have been designed, synthesized and evaluated for H1 antihistamine activity. Six compounds have showed potent antihistamine H1 activity. The primary SAR analysis indicated that benzyl or benzylidinyl substituted on the exo-nitrogen atom and C2 of the benzimidazole were significant. Further experiments indicated that compound 17d displayed excellent activity to reduce mast cell degranulation, moderate anti-PAF activity and decreased potency on hERG compared to astermizole. Hence compound 17d could serve as anti-allergic agent for further development.

Two types of sinenxan A derivatives with different side chains at C-5 were synthesized and evaluated for their in vitro multidrug resistant reversal activities. Several derivatives exhibited better activities than the positive control verapamil. The structure–activity relationships of these derivatives suggested that a carbonyl group at C-13 and the length of side chain at C-5 are important for the activity.A series of new taxoids derived from sinenxan A were synthesized and evaluated for their in vitro multidrug resistant reversal activities. Four derivatives exhibited better activities than the positive control verapamil. Structure–activity relationships of these derivatives were explored as well.

Starting from 7-hydroxyisoflavones, we developed a new class of fluorescent scaffolds, 3-alkyl-6-methoxy-7-hydroxy-chromones (AMHCs, MW ∼ 205.19, λab ∼ 350 nm, λem ∼ 450 nm) via a trial and error process. AMHCs have the advantages of being a small molecular moiety, having strong fluorescence in basic buffers, reasonable solubility and stability, non-toxicity, and are conveniently linked to pharmacophores. AMHCs were successfully used in fluorescence microscopy imaging of cells and tissues.

A tetrahydrofuro[3,2-d]oxazole scaffold was synthesized efficiently and stereoselectively. The tandem ionic hydrogenation, ketalization, and intramolecular cyclization of arene-1,4-diones with a combination of TiCl4/Et3SiH give facile access to tetrahydrofuro[3,2-d]oxazole derivatives in good yields at room temperature.