Synthesis and in vitro antibacterial activity of quinolone/naphthyridone derivatives containing 3-alkoxyimino-4-(methyl)aminopiperidine scaffolds

We report herein the synthesis of a series of 7-[3-alkoxyimino-4-(methyl)aminopiperidin-1-yl]quinolone/naphthyridone derivatives. In vitro antibacterial activity of these derivatives was evaluated against representative strains, and compared with ciprofloxacin (CPFX), levofloxacin (LVFX) and gemifloxacin (GMFX). The results reveal that all of the target compounds 19a–c and 20 have considerable Gram-positive activity, although they are generally less active than the reference drugs against the Gram-negative strains with some exceptions. Especially, novel compounds 19a2, 19a4 and 19a5 were found to show strong antibacterial activity (MICs: <0.008–0.5 μg/mL) against all of the tested 15 Gram-positive strains including MRSA, LVFX- and GMFX-resistant MRSE, and CPFX-, LVFX- and GMFX-resistant MSSA.     

Internal heavy atom effect of Au(III) and Pt(IV) on hypocrellin A for enhanced in vitro photodynamic therapy of cancer

Hypocrellin A (HA), an a natural perylene quinine photosensitizers (PSs), can chelate with heavy metal ions, including Au(III) and Pt(IV), to form a 1:2 complex, which exhibits enhanced ¹O₂ generation quantum yield through the increased intersystem crossing efficiency mediated by internal heavy atom effect. Besides, the chelate process greatly improved the water solubility of HA. Comparative studies with HA and complexes have demonstrated that the heavy-atom effect on HA molecules enhances the efficiency of in vitro photodynamic (PDT) efficacy.     

Discovery and structure–activity relationships of 6-(benzoylamino)benzoxaboroles as orally active anti-inflammatory agents

Structure–activity relationships of 6-(benzoylamino)benzoxaborole analogs were investigated for the inhibition of TNF-α, IL-1β, and IL-6 from lipopolysaccharide stimulated peripheral blood mononuclear cells. Compound 1q showed potent activity against all three cytokines with IC₅₀ values between 0.19 and 0.50 μM, inhibited LPS-induced TNF-α and IL-6 elevation in mice and improved collagen-induced arthritis in mice. Compound 1q (AN4161) is considered to be a promising lead for novel anti-inflammatory agent with an excellent pharmacokinetic profile.     

Design,synthesis, and biological evaluation of novel 3-pyrrolo[b]cyclohexylene-2-dihydroindolinone derivatives as potent receptor tyrosine kinase inhibitors

A novel series of 3-pyrrolo[b]cyclohexylene-2-dihydroindolinone derivatives targeting VEGFR-2, PDGFR-β and c-Kit kinases were designed and synthesized. The molecular design was based on the SAR features of indolin-2-ones as kinase inhibitors. SAR study of the series allowed us to identify compounds possessing more potent inhibitory activities against the three kinases than sunitinb with IC₅₀ values in the low nanomolar range in vitro. Additionally, some compounds also showed favorable antiproliferative activities against a panel of cancer cell lines (BXPC-3, T24, BGC, HEPG2 and HT29).     

1-(4-Phenylpiperazin-1-yl)-2-(1H-pyrazol-1-yl)ethanones as novel CCR1 antagonists

A novel series of CCR1 antagonists based on the 1-(4-phenylpiperazin-1-yl)-2-(1H-pyrazol-1-yl)ethanone scaffold was identified by screening a compound library utilizing CCR1-expressing human THP-1 cells. SAR studies led to the discovery of the highly potent and selective CCR1 antagonist 14 (CCR1 binding IC₅₀ = 4 nM using [¹²⁵I]-CCL3 as the chemokine ligand). Compound 14 displayed promising pharmacokinetic and toxicological profiles in preclinical species.     

Synthesis and antibacterial activity of 9-oxime ether non-ketolides,and novel binding mode of alkylides with bacterial rRNA

We report a series of new 9-oxime ether non-ketolides, including 3-hydroxyl, 3-O-acyl and 3-O-alkyl clarithromycin derivatives, and thiophene-containing ketolides 1b–1d. Unlike previously reported ketolide 1a, none of them is comparable to telithromycin. A molecular modeling study was performed to gain insight into the binding mode of alkylides 17–20 with bacterial rRNA and to rationalize the great disparity of their SAR. The 3-O-sidechains of 19 and 20 point to the so-called hydrophilic side of the macrolide ring, as seen in clarithromycin. In contrast, the 3-O-sidechains of 17 and 18 bend to the backside, the so-called hydrophobic side of the macrolide ring. The results clearly indicated the alkylides with improved antibacterial activity might possess a novel binding mode, which is different from clarithromycin and the alkylides with poor activity.     

Nonbenzamidine acylsulfonamide tissue factor–factor VIIa inhibitors

Aminoisoquinoline and isoquinoline groups have successfully replaced the more basic P1 benzamidine group of an acylsulfonamide factor VIIa inhibitor. Inhibitory activity was optimized by the identification of additional hydrophobic and hydrophilic P′ binding interactions. The molecular details of these interactions were elucidated by X-ray crystallography and molecular modeling. We also show that decreasing the basicity of the P1 group results in improved oral bioavailability in this chemotype.     

Improved inhibitory activities against tumor-cell migration and invasion by 15-benzylidene substitution derivatives of andrographolide

In the present study, andrographolide (Andro, 1) derivatives were screened to identify potent inhibitors against tumor-cell migration and invasion, and associated structure–activity relationships were studied. Compared to 1, compounds 8a–8d exhibited more potent activities against migration in SGC-7901, PC-3, A549, HT-29 and Ec109 cell lines. Improved activities against tumor-cell migration and invasion were proved to be associated with the down-regulation of MMPs.     

Synthesis and acrosin inhibitory activities of 5-phenyl-1H-pyrazole-3-carboxylic acid amide derivatives

A series of novel 5-phenyl-1H-pyrazole-3-carboxylic acid amide derivatives were designed, synthesized, and their acrosin inhibitory activities in vitro were evaluated. The results of the acrosin inhibitory activity showed that all target compounds were more potent than control TLCK. Compounds AQ-A1, AQ-D3, AQ-D4, AQ-E4 and AQ-E5 exhibited stronger acrosin inhibitory activities than control ISO-1. Especially, compound AQ-E5 displayed the most potent acrosin inhibitory activity in all the compounds, with an IC₅₀ of 0.01 μmol/mL. This study provided a new structural class for the development of novel acrosin inhibitory agents.     

Discovery of 2,5-diarylnicotinamides as selective orexin-2 receptor antagonists (2-SORAs)

The orexin (or hypocretin) system has been identified as a novel target for the treatment of insomnia due to the wealth of biological and genetic data discovered over the past decade. Recently, clinical proof-of-concept was achieved for the treatment of primary insomnia using dual (OX₁R/OX₂R) orexin receptor antagonists. However, elucidation of the pharmacology associated with selective orexin-2 receptor antagonists (2-SORAs) has been hampered by the lack of orally bioavailable, highly selective small molecule probes. Herein, the discovery and optimization of a novel series of 2,5-diarylnicotinamides as potent and orally bioavailable orexin-2 receptor selective antagonists is described. A compound from this series demonstrated potent sleep promotion when dosed orally to EEG telemetrized rats.