Conformationally Constrained Analogs of N‐Substituted Piperazinylquinolones: Synthesis and Antibacterial Activity of N‐(2,3‐Dihydro‐4‐hydroxyimino‐4H‐1‐benzopyran‐3‐yl)‐piperazinylquinolones

A series of novel quinolone agents bearing a particular bulky and conformationally constrained bicyclic substituent (2,3‐dihydro‐4‐hydroxyimino‐4H‐1‐benzopyran‐3‐yl‐ moiety) on the piperazine ring of 7‐piperazinyl quinolones (norfloxacin, enoxacin, ciprofloxacin, and levofloxacin) were synthesized and evaluated against a panel of Gram‐positive and Gram‐negative bacteria. Among these derivatives, ciprofloxacin counterpart 9c , highly inhibited the tested Gram‐positive bacteria, superior to that of the reference drugs, and displayed antibacterial activity at non‐cytotoxic concentrations.     

Synthesis,In Vitro Protoporphyrinogen Oxidase Inhibition,and Herbicidal Activity of N‐(Benzothiazol‐5‐yl)hexahydro‐1H‐isoindole‐1,3‐diones and N‐(Benzothiazol‐5‐yl)hexahydro‐1H‐isoindol‐1‐ones

Protoporphyrinogen oxidase ( EC 1.3.3.4 ) is one of the most significant targets for a large family of herbicides. As part of our continuous efforts to search for novel protoporphyrinogen oxidase‐inhibiting herbicides, N‐(benzothiazol‐5‐yl)tetrahydroisoindole‐1,3‐dione was selected as a lead compound for structural optimization, leading to the syntheses of a series of novel N‐(benzothiazol‐5‐yl)hexahydro‐1H‐isoindole‐1,3‐diones ( 1a – o ) and N‐(benzothiazol‐5‐yl)hexahydro‐1H‐isoindol‐1‐ones ( 2a – i ). These newly prepared compounds were characterized by elemental analyses, ¹H NMR, and ESI‐MS, and the structures of 1h and 2h were further confirmed by X‐ray diffraction analyses. The bioassays indicated that some compounds displayed comparable or higher protoporphyrinogen oxidase inhibition activities in comparison with the commercial control. Very promising, compound 2a , ethyl 2‐((6‐fluoro‐5‐(4,5,6,7‐tetrahydro‐1‐oxo‐1H‐isoindol‐2(3H)‐yl)benzo[d]thiazol‐2‐yl)‐sulfanyl)acetate, was recognized as the most potent candidate with K_i value of 0.0091 μm . Further greenhouse screening results demonstrated that some compounds exhibited good herbicidal activity against Chenopodium album at the dosage of 150 g/ha.     

Discovery of Novel 2‐(piperidin‐4‐yl)‐1H‐benzo[d]imidazole Derivatives as Potential Anti‐Inflammatory Agents

A novel 2‐(piperidin‐4‐yl)‐1H‐benzo[d]imidazole derivative 5 with good anti‐inflammatory activity was identified from our in‐house library. Based on hit compound 5 , two series of 2‐(piperidin‐4‐yl)‐1H‐benzo[d]imidazole derivative 6a – g and 7a – h were designed and synthesized as novel anti‐inflammatory agents. Most of synthesized compounds exhibited good inhibitory activity on NO and TNF‐α production in LPS‐stimulated RAW 264.7 macrophages, in which the compound 6e showed most potent inhibitory activity on NO (IC₅₀ = 0.86 μm ) and TNF‐α (IC₅₀ = 1.87 μm ) production. Further evaluation revealed that compound 6e displayed more potent in vivo anti‐inflammatory activity than ibuprofen did on xylene‐induced ear oedema in mice. Additionally, Western blot analysis revealed that compound 6e could restore phosphorylation level of IκBα and protein expression of p65 NF‐κB in LPS‐stimulated RAW 264.7 macrophages.     

Synthesis and Evaluation of 3‐(furo[2,3‐b]pyridin‐3‐yl)‐4‐(1H‐indol‐3‐yl)‐maleimides as Novel GSK‐3β Inhibitors and Anti‐Ischemic Agents

A series of novel 3‐(furo[2,3‐b]pyridin‐3‐yl)‐4‐(1H‐indol‐3‐yl)‐maleimides were designed, synthesized, and biologically evaluated for their GSK‐3β inhibitory activities. Most compounds showed favorable inhibitory activities against GSK‐3β protein. Among them, compounds 5n , 5o , and 5p significantly reduced GSK‐3β substrate tau phosphorylation at Ser396 in primary neurons, indicating inhibition of cellular GSK‐3β activity. In the in vitro neuronal injury models, compounds 5n , 5o , and 5p prevented neuronal death against glutamate, oxygen–glucose deprivation, and nutrient serum deprivation which are closely associated with cerebral ischemic stroke. In the in vivo cerebral ischemia animal model, compound 5o reduced infarct size by 10% and improved the neurological deficit. The results may provide new insights into the development of novel GSK‐3β inhibitors with potential neuroprotective activity against brain ischemic stroke.     

Synthesis and in‐vitro Cytotoxic Evaluation of Novel Pyridazin‐4‐one Derivatives

A new series of N‐aryl‐4‐oxo‐1,4‐dihydro‐pyridazine‐3‐carboxylic acids has been synthesized by condensation of aryldiazonium with 4‐hydroxy‐6‐methyl‐2‐pyrone. Some of these compounds exhibited in‐vitro cytotoxic activity with moderate to excellent growth inhibition against the murine P815 mastocytoma cell line. Compound 5b showed an important cytotoxic activity against cell line P815 (IC₅₀ = 0.40 μg/mL).     

Synthesis and pharmacological evaluation of 3‐(4‐chloro phenyl)‐2‐substituted‐3H‐quinazolin‐4‐ones as analgesic and anti‐inflammatory agents

A new series of 3‐(4‐chloro phenyl)‐2‐substituted‐3H‐quinazolin‐4‐ones were synthesized by reacting the amino group of 2‐hydrazino‐3‐(4‐chloro phenyl)‐3H‐quinazolin‐4‐one with different aldehydes and ketones. The compounds were investigated for their analgesic activity in albino mice, and for their anti‐inflammatory and ulcerogenic activities in Wistar rats. All test compounds exhibited analgesic and anti‐inflammatory activities. Compound VA2 (2‐(1‐ethylpropylidene‐hydrazino)‐3‐(4‐chloro phenyl)‐3H‐quinazolin‐4‐one) showed moderately more potent analgesic activity and compound VA3 (2‐(1‐methylbutylidene‐hydrazino)‐3‐(4‐chlorophenyl)‐3H‐quinazolin‐4‐one) showed moderately more potent anti‐inflammatory activity when compared with the reference standard, diclofenac sodium. The test compounds showed only mild ulcerogenic side effects when compared with aspirin. Drug Dev Res 69: 226–233, 2008 ©2008 Wiley‐Liss, Inc.     

Synthesis,in‐vitro Cytotoxicity,and a Preliminary Structure‐Activity Relationship Investigation of Pyrimido[4,5‐c]quinolin‐1(2H)‐ones

As part of our ongoing research effort to develop new antimitotic agents based on the recently reported pyrimido[4,5‐c]quinoline‐1(2H)‐one ring skeleton, we were interested in identifying structural elements that contribute to the cytotoxicity of this class of compounds. The effect of several quinoline‐ring substituents was examined and the new compounds were evaluated in vitro for cytotoxicity against three human cancer cell lines namely, lung fibrosarcoma HT‐1080, colon adenocarcinoma HT‐29, and breast carcinoma MDA‐MB‐231. Most of the compounds showed cytotoxic activity in the low micromolar and sub‐micromolar range. Structure‐activity relationship information revealed that a combination of electronic and steric factors may be involved. Flow cytometric cell cycle analysis performed on HT‐1080 cells revealed that the most cytotoxic compounds 48 , 50 , 54 , 59 , and 63 inhibit the S‐phase and arrest the cells in the G2/M phase of the cell cycle suggesting an antimitotic action of these compounds.     

2-Amino-3-cyano-4-(5-arylisoxazol-3-yl)-4H-chromenes: synthesis and in vitro cytotoxic activity

A new series of 4-aryl-4H-chromenes bearing a 5-arylisoxazol-3-yl moiety at the C-4 position were prepared as potential anticancer agents. The in vitro cytotoxic activity of the synthesized compounds was investigated against a panel of tumor cell lines including MCF-7 (breast cancer), KB (nasopharyngeal epidermoid carcinoma), Hep-G2 (liver carcinoma), MDA-MB-231 (breast cancer), and SKNMC (human neuroblastoma) using the MTT colorimetric assay. Doxorubicin, a well-known anticancer drug, was used as positive standard drug. Among the synthesized compounds, the 5-(3-methylphenyl)isoxazol-3-yl analog (7j) showed the most potent cytotoxic activity against all five human tumor cell lines.     

Synthesis and Selective Inhibitory Activity Against Human COX‐1 of Novel 1‐(4‐Substituted‐thiazol‐2‐yl)‐3,5‐di(hetero)aryl‐pyrazoline Derivatives

Novel 1‐(4‐ethyl carboxylate‐thiazol‐2‐yl)‐3,5‐di(hetero)aryl‐2‐pyrazoline derivatives were obtained by reacting 3,5‐di(hetero)aryl‐1‐thiocarbamoyl‐2‐pyrazolines with the ethyl ester of α‐bromo‐pyruvic acid. The synthesized compounds were confirmed by spectroscopic data and assayed to evaluate their in vitro ability to inhibit both isoforms of human cyclooxygenase (hCOX). Some derivatives (compounds 5 , 6 , 13 , 16 , and 17 ) displayed promising selectivity against hCOX‐1 in the micromolar range and were shown to have a selectivity index similar or better than the reference drugs (indometacin, diclofenac). The introduction of a phenyl or a 4‐F‐phenyl ring on the C5 associated with a 4‐substituted phenyl or a heteroaryl group on the C3 of (4‐substituted‐thiazol‐2‐yl)pyrazoline derivatives improved the activity against hCOX‐1. Thanks to these preliminary results it could be possible to extend our knowledge of the pharmacophoric requirements for the discovery of new pyrazoline‐based hCOX‐1 inhibitors.     

Synthesis and mode of action studies of novel {2‐(3‐R‐1H‐1,2,4‐triazol‐5‐yl)phenyl}amines to combat pathogenic fungi

Due to their high specificity and efficacy, triazoles have become versatile antifungals to treat fungal infections in human healthcare and to control phytopathogenic fungi in agriculture. However, azole resistance is an emerging problem affecting human health as well as food security. Here we describe the synthesis of 10 novel {2‐(3‐R‐1H‐1,2,4‐triazol‐5‐yl)phenyl}amines. Their structure was ascertained by liquid chromatography–mass spectrometry, ¹H and ¹³C NMR, and elemental analysis data. Applying an in vitro growth assay, these triazoles show moderate to significant antifungal activity against the opportunistic pathogen Aspergillus niger, 12 fungi (Fusarium oxysporum, Fusarium fujikuroi, Colletotrichum higginsianum, Gaeumannomyces graminis, Colletotrichum coccodes, Claviceps purpurea, Alternaria alternata, Mucor indicus, Fusarium graminearum, Verticillium lecanii, Botrytis cinerea, Penicillium digitatum) and three oomycetes (Phytophtora infestans GL‐1, P. infestans 4/91; R+ and 4/91; R?) in the concentration range from 1 to 50 µg/ml (0.003–2.1 μM). Frontier molecular orbital energies were determined to predict their genotoxic potential. Molecular docking calculations taking into account six common fungal enzymes point to 14α‐demethylase (CYP51) and N‐myristoyltransferase as the most probable fungal targets. With respect to effectiveness, structure–activity calculations revealed the strong enhancing impact of adamantyl residues. The shown nonmutagenicity in the Salmonella reverse‐mutagenicity assay and no violations of drug‐likeness parameters suggest the good bioavailability and attractive ecotoxicological profile of the studied triazoles.     

Synthesis and Antiproliferative Activitiy of Novel Diaryl Ureas Possessing a 4H‐Pyrido[1,2‐a]pyrimidin‐4‐one Group

We herein disclose a series of novel diaryl urea derivatives possessing a 4H‐pyrido[1,2‐a]pyrimidin‐4‐one group as novel potent anticancer compounds. The structures were confirmed by IR, ¹H‐NMR, and MS. All the compounds were screened for their antiprofilerative activity agaist the human breast cancer cell line (MDA‐MB‐231). The pharmacological results indicated that most of the compounds showed moderate activity. The best of this series is compound 4c (IC₅₀ = 0.7 μmol/L), with a potency 3.6‐fold higher than Sorafenib (IC₅₀ = 2.5 μmol/L), which was approved in 2005.