Zhu-Ping Xiao

Synthesis, molecular docking and evaluation of thiazolyl-pyrazoline derivatives as EGFR TK inhibitors and potential anticancer agents.

Fourty-two thiazolyl-pyrazoline derivatives were synthesized to screen for their EGFR kinase inhibitory activity. Compound 4-(4-chlorophenyl)-2-(3-(3,4-dimethylphenyl)-5-p-tolyl-4,5-dihydro-1H-pyrazol-1-yl)thiazole (11) displayed the most potent EGFR TK inhibitory activity with IC(50) of 0.06 μM, which was comparable to the positive control. Molecular docking results indicated that compound 11 was nicely bound to the EGFR kinase. Compound 11 also showed significant antiproliferative activity against MCF-7 with IC(50) of 0.07 μM, which would be a potential anticancer agent.

Tyrosyl-tRNA synthetase inhibitors as antibacterial agents: Synthesis, molecular docking and structure–activity relationship analysis of 3-aryl-4-arylaminofuran-2(5H)-ones

Thirty-five 3-aryl-4-arylaminofuran-2(5H)-one derivatives were designed, prepared and tested for their inhibitory activity against tyrosyl-tRNA synthetase. Out of these compounds, 3-(3-bromophenyl)-4-(3,5-dichlorophenylamino)furan-2(5H)-one (35) was the most active with IC(50) of 0.09 ± 0.02 μM. The structure-activity relationship revealed that introduction of chlorine atoms at both meta positions of aniline moiety significantly increased the enzyme inhibitory activity. The results of antibacterial assay revealed that the tested compounds showed good activity against Gram-positive bacteria, with 35 being the most potent with MIC(50) of 0.06 μg/mL against Staphylococcus aureus ATCC 25923. Molecular docking of 35 into S. aureus tyrosyl-tRNA synthetase active site was also performed. The inhibitor snugly fitting the active site may well explain its excellent inhibitory activity.

Amines and oximes derived from deoxybenzoins as Helicobacter pylori urease inhibitors

Twenty amines and oximes from deoxybenzoins were prepared and evaluated for their inhibitory activity against Helicobacter pylori urease. Among these compounds, high inhibitory activities were observed in amines and oximes, especially amines 1b (IC(50)=0.011 mM) and 6b (IC(50)=0.047 mM) exhibited good in vitro activities, and were comparable to acetohydroxamic acid (AHA). The hydroxyl groups on deoxybenzoin skeleton may be responsible for the inhibitory activity and coordinate with the nickel (active site) on enzyme. A direct interaction may exist between the OH group of hydroxylamines or NH group of amines and His alpha323 of H. pylori urease, which is on the flap of the enzyme active site.

Design, synthesis, and evaluation of novel fluoroquinolone–flavonoid hybrids as potent antibiotics against drug-resistant microorganisms

Based on a rationally conceived pharmacophore model to build a multi-target bacterial topoisomerase inhibitor, twenty-one fluoroquinolone-flavonoid hybrids were synthesized. Some obtained hybrids show excellent antibacterial activity against drug-resistant microorganisms with narigenin-ciprofloxacin being the most active, showing 8, 43, 23 and 88 times better activity than ciprofloxacin against Escherichia coli ATCC 35218, Bacillus subtilis ATCC 6633, Staphylococcus aureus ATCC 25923 and Candida albicans ATCC 90873, respectively. Drug accumulation and DNA supercoiling assays of two active analogues revealed potent inhibition of both the DNA gyrase and efflux pump, confirming the desired dual mode of action. Molecular docking study disclosed that the introduced flavonoid moiety not only provides several additional interactions but also does not disturb the binding mode of the floxacin moiety. Our data also demonstrated that development of antifungals is possible from fluoroquinolones modified at C-7 position.

Synthesis, Characterization, and Antibacterial and Cytotoxic Study of Metal Complexes with Schiff Base Ligands

The synthesis of 16 metal complexes from four Schiff bases prepared from 5-chloro-2-hydroxybenzaldehyde and primary amines has been described. The synthesized Schiff base ligands and their complexes were characterized by elemental analyses, spectroscopic (UV, IR, 1H and 13C NMR, electrospray ionization-mass spectrometry) methods, and magnetic and conductance measurements. Furthermore, complexes 1a, 1b, 3d, 4a, and 4d were characterized by X-ray diffraction analysis. After the structural characterization, all the compounds were tested in vitro for their antibacterial (Bacillus subtilis, Escherichia coli, Pseudomonas fluorescens, and Staphylococcus aureus) activities. The cytotoxic activities of the synthesized compounds were evaluated in vitro against human chronic myeloid leukaemia cells (K562) and a human nasopharyngeal epidermoid tumour cell line. The results indicated that most of the complexes showed good cytotoxic activity against human cancer cell lines but weak cytotoxic activity against a human normal cell line (L02). Among the compounds tested, the cobalt complexes 1a, 2a, 3a, and 4a showed the most favourable antibacterial and cytotoxic activities.

Synthesis, structure, molecular docking, and structure-activity relationship analysis of enamines: 3-aryl-4-alkylaminofuran-2(5H)-ones as potential antibacterials.

Thirty-one 3-aryl-4-alkylaminofuran-2(5H)-ones were designed, prepared and tested for their antibacterial activity. Some of them showed significant antibacterial activity against Gram-positive organisms, especially against Staphylococcus aureus ATCC 25923, but all were inactive against Gram-negative organisms. Out of these compounds, 3-(4-bromophenyl)-4-(2-(4-nitrophenyl)hydrazinyl)furan-2(5H)-one (4a11) showed the most potent antibacterial activity against S. aureus ATCC 25923 with MIC(50) of 0.42 μg/mL. The enzyme assay revealed that the possible antibacterial mechanism of the synthetic compounds might be due to their inhibitory activity against tyrosyl-tRNA synthetase. Molecular dockings of 4a11 into S. aureus tyrosyl-tRNA synthetase active site were also performed. This inhibitor snugly fitting the active site might well explain its excellent inhibitory activity. Meanwhile, this modeling disclosed that a more suitable optimization strategy might be to modify the benzene ring at 3-position of furanone with hydrophilic groups.

Synthesis, structure and structure-activity relationship analysis of 3-tert-butoxycarbonyl-2-arylthiazolidine-4-carboxylic acid derivatives as potential antibacterial agents.

Nine 2-arylthiazolidine-4-carboxylic acid derivatives and nine 3-tert-butoxycarbonyl-2-arylthiazolidine-4-carboxylic acid derivatives were synthesized to screen for their antibacterial activities. Compounds 5, 14-18 were first reported. Their chemical structures were clearly determined by (1)H NMR, (13)C NMR, ESI mass spectra and elemental analyses, coupled with one selected single-crystal structure. All the compounds were assayed for antibacterial activities against two Gram-positive bacterial strains (Bacillus subtilis ATCC 6633 and Staphylococcus aureus ATCC 6538) and two Gram-negative bacterial strains (Escherichia coli ATCC 35218 and Pseudomonas aeruginosa ATCC 13525) by MTT method. Most of the 3-tert-butoxycarbonyl-2-arylthiazolidine-4-carboxylic acid derivatives exhibited better antibacterial activities against the four bacterial strains than relative 2-arylthiazolidine-4-carboxylic acid derivatives. Compound (2RS,4R)-3-(tert-butoxycarbonyl)-2-(5-fluoro-2-hydroxyphenyl)thiazolidine-4-carboxylic acid (14) showed powerful antibacterial activities against P. aeruginosa with IC(50) value of 0.195 microg/mL, which was superior to the positive controls Penicillin G and Kanamycin B, respectively. On the basis of the biological results, structure-activity relationships were discussed.

Enamines as novel antibacterials and their structure-activity relationships.

Twenty-six enamines were synthesized to screen for the antimicrobial activity. Out of the compounds, 22 were reported for the first time. Their chemical structures including E/Z-configurations were clearly determined by 1H NMR, ESI mass spectra and elemental analyses, coupled with three selected single-crystal structures. In general, these synthetic compounds were shown to be more effective to inhibit growth of bacteria than fungi. The most active compound, (E)-ethyl 3-(4-hydroxyphenylamino)-2-(4-chlorophenyl)acrylate (1b), showed considerable antibacterial activities against Staphylococcus aureus ATCC 6538 with MIC of 0.5 microg/mL and against Pseudomonas fluorescens ATCC 13525 with MIC of 1.5 microg/mL, which was superior to the positive controls penicillin and kanamycin, respectively. Structure-activity relationship analysis revealed: as for A-ring, the compounds substituted at 3,5-positions were more active than 2,4-position-substituted derivatives, and halo-substituted analogs at 2-position had essentially same activities as the 4-position-substituted derivatives. Increase of steric hindrance around the nitrogen atom led to an inactive compound.

4-Alkoxy-3-arylfuran-2(5H)-ones as inhibitors of tyrosyl-tRNA synthetase: Synthesis, molecular docking and antibacterial evaluation

A series of novel 4-alkoxy-3-arylfuran-2(5H)-ones as tyrosyl-tRNA synthetase inhibitors were synthesized. Of these compounds, 3-(4-hydroxyphenyl)-4-(2-morpholinoethoxy)furan-2(5H)-one (27) was the most potent. The binding model and structure-activity relationship indicate that replacement of morpholine-ring in the side chain of 27 with a substituent containing more hydrophilic groups would be more suitable for further modification. Antibacterial assay revealed that the synthetic compounds are effective against growth of Gram-positive organisms, and 27 is the most potent agent against Staphylococcus aureus ATCC 25923 with MIC(50) value of 0.23 μg/mL.

Synthesis, Antiproliferative Activity, and Structure–Activity Relationships of 3-Aryl-1H-quinolin-4-ones

The antiproliferative activities of 36 3‐aryl‐1H‐quinolin‐4‐ones were determined against two cancer cell lines (Hep G2 and KB) in vitro. The results indicate that most of these compounds show good cytotoxic activity against human cancer cell lines, but no cytotoxicity against a human normal cell line (L02). The positive control compounds genistein and 5‐fluorouracil show no selectivity at inhibiting the growth of the above three cell lines. Generally, compounds that bear a halogen atom at the 8 position and a methoxy group at the 3′ position exhibited remarkable cytotoxicity toward human cancer cell lines. Electron‐withdrawing substituents at the 6 position decrease the antiproliferative activity significantly. We also put forward a pharmacophore model for 3‐aryl‐4‐quinolinones binding with epidermal growth factor receptor protein tyrosine kinases (EGFR PTK). Out of the 36 synthetic compounds, 34 are reported for the first time.