Juxian Wang

Microwave-Assisted Improved Synthesis of Pyrrolo(2,3,4-kl)acridine and Dihydropyrrolo(2,3,4-kl)acridine Derivatives Catalyzed by Silica Sulfuric Acid

An improved synthesis of multifunctionalized pyrrolo[2,3,4-kl]acridine derivatives with different substituted patterns using silica sulfuric acid (SSA) as a heterogeneous catalyst under microwave irradiation conditions was developed. The reaction could be conducted by using readily available and inexpensive substrates within short periods of 12–15 min. under microwave irradiation. Compared with the conventional methods, the remarkable advantages of this method are milder reaction conditions, operational simplicity, higher yields, short reaction times, and an environmentally friendly procedure.

An Efficient Synthesis of Novel Dispirooxindole Derivatives via One-Pot Three-Component 1,3-Dipolar Cycloaddition Reactions

A series of novel dispirooxindoles have been synthesized through three-component 1,3-dipolar cycloaddition of azomethine ylides generated in situ by the decarboxylative condensation of isatin and an α-amino acid with the dipolarophile 5-benzylidene-1,3-dimethylpyrimidine-2,4,6-trione. This method has the advantages of mild reaction conditions, high atom economy, excellent yields, and high regio- and stereo-selectivity.

Ultrasound-Promoted One-Pot, Four-Component Synthesis of Pyridin-2(1H)-One Derivatives

An efficient one-pot synthesis of 1,6-diamino-2-oxo-1,2,3,4-tetrahydro- pyridine-3,5-dicarbonitrile derivatives by four-component piperidine-catalyzed reactions of a ketone, malononitrile, ethyl cyanoacetate and hydrazine hydrate under ultrasound irradiation is described. This method provides several advantages such as shorter reaction times, excellent yields, and a simple workup procedure.

Preliminary SAR and biological evaluation of antitubercular triazolothiadiazine derivatives against drug-susceptible and drug-resistant Mtb strains.

Following up the SAR study of triazolothiadiazoles for their antitubercular activities targeting Mt SD in our previous study, on the principle of scaffold hopping, the C3 and C6 positions of triazolothiadiazine were examined systematically to define a preliminary structure-activity relationship (SAR) with respect to biological activity. This study herein highlights the potential of two highly potent advanced leads 6c-3, 6g-3 and several other compounds with comparable potencies as promising new candidates for the treatment of TB (6c-3, MIC-H37Rv=0.25μg/mL; MIC-MDRTB=2.0μg/mL; MIC-RDRTB=0.25μg/mL; Mt SD-IC50=86.39μg/mL; and 6g-3, MIC-H37Rv=1.0μg/mL; MIC-MDRTB=4.0μg/mL; MIC-RDRTB=2.0μg/mL; Mt SD-IC50=73.57μg/mL). Compounds 6c-3 and 6g-3 possessed a para-nitro phenyl at the 6 position showed low Vero and HepG2 cells toxicity, turning out to be two excellent lead candidates for preclinical trials. In addition, in vitro Mt SD inhibitory assay indicates that Mt SD is at least one of the targets for their antitubercular activity. Thus, they may turn out to be promising multidrug-resistance-reversing agents.

SAR studies on 1,2,4-triazolo[3,4-b][1,3,4]thiadiazoles as inhibitors of Mtb shikimate dehydrogenase for the development of novel antitubercular agents

Shikimate dehydrogenase, an essential protein for the biosynthesis of the chorismate end product, is a highly promising therapeutic target, especially for the discovery and development of new-generation anti-TB agents. Following up the identification of one lead 3,6-disubstituted 1,2,4-triazolo[3,4-b][1,3,4]thiadiazole (1), targeting Mt SD in our previous study, an extensive SAR study for optimization of the lead compound was performed through systematic modification of the 3 and 6 positions. This study has successfully led to the discovery of two highly potent advanced leads 6d-4, 6c-4 and several other compounds with comparable potencies (6d-4, MIC-H37Rv = 0.5 μg mL−1; MIC-MDRTB = 4.0 μg mL−1; MIC-RDRTB = 0.5 μg mL−1; Mt SD-IC50 = 14.20 μg mL−1; and 6c-4, MIC-H37Rv = 0.5 μg mL−1; MIC-MDRTB = 4.0 μg mL−1; MIC-RDRTB = 1.0 μg mL−1; Mt SD-IC50 = 6.82 μg mL−1). These advanced lead compounds possess a para-halogen phenyl at the 3 position. In vitro Mt SD inhibitory assay indicates that Mt SD is the target for their antitubercular activity. Moreover, the BacT/ALERT 3D liquid culture technology and in vitro Mt SD inhibitory assay were initially applied.

Design, synthesis and anticancer activity of 1-acyl-3-amino-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole derivatives

A series of novel 1-acyl-3-amino-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole derivatives were designed and synthesized. These derivatives were initially evaluated for their in vitro anticancer activity against human colon carcinoma HCT-116 cell line, and compounds 11a, b were chosen for further evaluation their in vitro activity against other five human cancer cell lines. These results indicate that most of the target compounds have considerable in vitro anticancer activity. The most active compound 11a was found to be 4- to 28-fold more potent than (R)-roscovitine against six human cancer cell lines. In addition, compound 11a was assessed for its activity against 12 kinases, and then evaluated for its interaction mode by docking experiments with cyclin-dependent kinase 5 (CDK5) and glycogen synthase kinase-3β (GSK3β).

Synthesis and antitumor activity of ATB-429 derivatives containing a nitric oxide-releasing moiety

A series of novel ATB-429 (an anti-inflammatory candidate) derivatives containing a nitric oxide (NO)-releasing moiety were designed, synthesized and evaluated for their in vitro activity against six human cancer cell lines. Our results reveal that phenylsulfonylfuroxan-based derivatives have considerable antitumor activity, and compounds 7-9 (IC50s: 0.256-3.024 μM) against HT-29 and PANC-1, 8a,b (IC50s: 2.677-3.051 μM) against MCF-7 and 8a (IC50: 1.270 μM) against DU145 are more active than Vandetanib (IC50s: 1.925-4.107 μM).

Arylsulfonylamino-benzanilides as inhibitors of the apical sodium-dependent bile salt transporter (SLC10A2).

The apical sodium-dependent bile salt transporter (ASBT) plays a pivotal role in maintaining bile acid homeostasis. Inhibition of ASBT would reduce bile acid pool size and lower cholesterol levels. In this report, a series of novel arylsulfonylaminobenzanilides were designed and synthesized as potential inhibitors of ASBT. Most of them demonstrated great potency against ASBT’s bile acid transport activity. In particular, compound 5g2 inhibited ASBT activity with an IC50 value of 0.11 μM. These compounds represent potential cholesterol-lowering drugs.

5-tert-Butyl 1-ethyl 3-amino-1,4,5,6-tetra-hydro-pyrrolo-[3,4-c]pyrazole-1,5-dicarboxyl-ate.

The asymmetric unit of the title compound, C13H20N4O4, contains two crystallographically independent molecules in which the dihedral angles between the fused pyrrole and pyrazole rings are 5.06 (8) and 1.12 (8)°. In the crystal, molecules are linked by intermolecular N—H⋯O and N—H⋯N hydrogen bonds into chains parallel to the b axis.

One-Pot Synthesis of 3-Functionalized 4-Hydroxycoumarin under Catalyst-Free Conditions

A concise and efficient one-pot synthesis of 3-functionalized 4-hydroxycoumarin derivatives via a three-component domino reaction of 4-hydroxycoumarin, phenylglyoxal and 3-arylaminocyclopent-2-enone or 4-arylaminofuran-2(5H)-one under catalyst-free and microwave irradiation conditions is described. This synthesis involves a group-assisted purification process, which avoids traditional recrystallization and chromatographic purification methods.