Synthesis and in vitro antibacterial activity of 7-(4-alkoxyimino-3-amino-3-methylpiperidin-1-yl)fluoroquinolone derivatives

A series of novel 7-(4-alkoxyimino-3-amino-3-methylpiperidin-1-yl)fluoroquinolone derivatives were designed, synthesized and characterized by ¹H NMR, MS and HRMS. These fluoroquinolones were evaluated for in vitro antibacterial activity against representative Gram-positive and Gram-negative strains. All of the title compounds have considerable activity against the twelve strains, and exhibit exceptional potency in inhibiting the growth of Staphylococcus aureus, Staphylococcus epidermidis and Klebsiella pneumoniae (minimum inhibitory concentration (MIC): 0.06–8 μg/mL). The most active compound 17 is 4-fold more potent than levofloxacin against S. aureus and S. epidermidis, 32-fold more potent than levofloxacin against Streptococcus pneumoniae, and 16-fold more potent than IMB against K. pneumoniae.     

Synthesis and antimicrobial activity of some novel derivatives of benzofuran: part 1. Synthesis and antimicrobial activity of (benzofuran-2-yl)(3-phenyl-3-methylcyclobutyl) ketoxime derivatives

The reaction of salicylaldehyde with 1-phenyl-1-methyl-3-(2-chloro-1-oxoethyl) cyclobutane (1) and potassium carbonate was used to prepare (benzofuran-2-yl)(3-methyl-3-phenylcyclobutyl) methanone (2) for the starting reagent purposes. (benzofuran-2-yl)(3-phenyl-3-methyl cyclobutyl) ketoxime (3) was synthesized from the reaction of the compound (2) with hidroxylamine. New derivatives of (benzofuran-2-yl)(3-phenyl-3-methyl cyclobutyl) ketoxime (3) such as, O-glycidylketoxime (4) and O-phenylacylketoxime (5a-c) were obtained very high yields. Alkyl, allyl and aryl substituted N-oxime ethers (6a-e) were obtained from the reaction compound 3 and various halogen contained compounds. The syntheses of the compounds (7a-f) were carried out from the reaction of the compound (4) and different amines such as, isopropyl amine, natrium azide, morpholine and piperazine. All of the synthesized compounds were tested for antimicrobial activity against Staphylococcus aureus ATCC 6538, Staphylococcus epidermidis ATCC 12228, Escherichia coli ATCC 8739, Klebsiella pneumoniae ATCC 4352, Pseudomonas aeruginosa ATCC 1539, Salmonella typhi, Shigella flexneri, Proteus mirabilis ATCC 14153 and Candida albicans ATCC 10231. Among the synthesized compounds (benzofuran-2-yl)(3-phenyl-3-methyl cyclobutyl)-O-[2-hydroxy-3-(N-methylpiperazino)] propylketoxime (7d) was found the most active derivative against S. aureus ATCC 6538. The compounds 2, 5b, 6b, 6c, 7b and 7f showed very strong and the same antimicrobial effect against C. albicans ATCC 10231. Similarly (benzofuran-2-yl)(3-phenyl-3-methylcyclobutyl)-O-benzylketoxime 6a showed good antimicrobial effect against C. albicans ATCC 10231. None of the other compounds exhibited activity against the other test microorganisms.     

Synthesis and studies of novel 2-(4-cyano-3-trifluoromethylphenyl amino)-4-(quinoline-4-yloxy)-6-(piperazinyl/piperidinyl)-s-triazines as potential antimicrobial, antimycobacterial and anticancer agents

A series of novel s-triazine analogs were synthesized and characterized by IR, ¹H NMR, ¹³C NMR, ¹⁹F NMR spectroscopy and elemental analysis. Preliminary screening of target compounds against eight bacteria (Staphylococcus aureus, Bacillus cereus, Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae, Salmonella typhi, Proteus vulgaris, Shigella flexneria), four fungi (Aspergillus niger, Aspergillus fumigatus, Aspergillus clavatus, Candida albicans) and Mycobacterium tuberculosis H37Rv indicated that 5d, 5h, 5n, 5p, 5q, 5r, 5s, 5t and 5u were the most active compounds among twenty one studied. Thus, they were further subjected to in vitro biological evaluation against human prostate cancer cell line (DU-145) and the results indicate that two compounds 5n and 5s were markedly active.     

In vitro and in vivo anticancer activity of 2-deacetoxytaxinine J and synthesis of novel taxoids and their in vitro anticancer activity

The taxane diterpneoid 2-deacetoxytaxinine J (2-DAT-J) 1 has been isolated from the bark of Himalayan yew, Taxus baccata L. spp. wallichiana in a reasonably good yield (0.1%) and its anticancer activity against breast cancer cell lines (MCF-7 and MDA-MB-231) and normal human kidney epithelial cell line (HEK-293) has been studied. 2-DAT-J (1) showed significant in vitro activity against breast cancer cell line at a concentration of 20 μM and 10 μM in MCF-7 and MDA-MB-231 respectively. Few novel taxoids were derived (7, 8 and 10–13) from the naturally occurring 2-DAT-J (1) and screened for their anticancer activity. The structure–activity relationship studies indicated that the cinnamoyl group on C-5 and acetyl group on C-10 are essential for the anticancer activity. 2-DAT-J (1) was also tested for its in vivo activity on DMBA-induced mammary tumors in virgin female Sprague Dawley rats at a dose of 10 mg/kg body weight orally for 30 days and showed significant regression in mammary tumors as compared to vehicle treated group (p < 0.05).     

Synthesis and evaluation of in vitro anti-microbial and anti-tubercular activity of 2-styryl benzimidazoles

A new series of novel 5-(nitro/bromo)-styryl-2-benzimidazoles (1–12) has been synthesized by simple, mild and efficient synthetic protocol by attempted condensation of 5-(nitro/bromo)-o-phenylenediamine with trans-cinnamic acids in ethylene glycol. Screening for in vitro anti-tubercular activity against Mycobacterium tuberculosis H₃₇ Rv, anti-bacterial activity against Staphylococcus aureus, Escherichia coli, Enterococcus faecalis, Klebsiella pneumoniae bacterial strains and anti-fungal activity against Candida albicans and Asperigillus fumigatus fungal strains were carried out. Compounds 5, 7, 8, 9, 11 showed higher anti-tubercular activity and compounds 7, 8, 10, 11, 12 have proved to be effective with MIC (μg/ml) and emerged as lead molecules showing excellent activities against a panel of microorganisms. All synthesized compounds were characterized using IR, ¹H, ¹³C NMR, GC–MS and elemental analysis.     

Synthesis, photochemical E (trans) → Z (cis) isomerization and antimicrobial activity of 2-chloro-5-methylpyridine-3-olefin derivatives

2-Chloro-5-methylpyridine-3-olefin derivatives (3a-e) have been synthesized from 2-chloro-5-methylnicotinaldehyde (1) and studied their photochemical E (trans) → Z (cis) isomerization upon direct irradiation and triplet sensitized excitation for the first time. The triplet sensitized excitations of the compounds yielded high Z (4a–e) isomer composition, whereas the direct excitation results in less Z (4a–e) isomer composition, indicating triplet pathway is very efficient in converting the E (trans) → Z (cis) isomer. Thus synthesized E (3a–c and 3e) and generated Z (4a–c and 4e) isomers were tested for antimicrobial activity. Antifungal activity of these pyridine derivatives are closely comparable to the standard used.     

匹莫齐特对金黄色葡萄球菌的体外和体内抗菌研究

目的 探讨抗精神病类药物匹莫齐特对金黄色葡萄球菌的体外和体内抗菌活性。方法 采用微量肉汤稀释法检测匹莫齐特的最低抑菌浓度(MIC)和最低杀菌浓度(MBC)。通过96孔细胞培养板构建生物膜,利用比浊法检测匹莫齐特的抗生物膜活性,进一步通过激光共聚焦显微镜和SYTO9/PI染色观察匹莫齐特对生物膜的作用。采用棋盘稀释法检测匹莫齐特与抗菌药物联合抗菌效果,CCK-8试剂盒检测匹莫齐特的细胞毒性。构建皮肤脓肿模型,检测匹莫齐特的体内抗菌活性及毒性。结果 匹莫齐特对金黄色葡萄球菌具有明显的剂量依赖抑菌活性,其MIC为8～16μg/mL,能显著抑制金黄色葡萄球菌生物膜的形成并分散已形成的生物膜。匹莫齐特与多西环素联合,体外具有协同抗菌效果,其协同抑菌指数为0.5;体内能显著降低小鼠脓肿组织中的细菌载量,使活菌量从(8.25±0.13)对数值CFU/脓肿减少到(3.31±0.81)对数值CFU/脓肿(q=3.74,P<0.05);匹莫齐特的细胞毒性极低,对细胞的半数抑制浓度>64μg/mL。结论 匹莫齐特毒性低且具有明显的体外和体内抗菌活性,有望成为一种精神病患者合并局部金黄色葡萄球菌相...     

Synthesis, anticonvulsant and CNS depressant activity of some new bioactive 1-(4-substituted-phenyl)-3-(4-oxo-2-phenyl/ethyl-4H-quinazolin-3-yl)-urea

Several new 1-(4-substituted-phenyl)-3-(4-oxo-2-phenyl/ethyl-4H-quinazolin-3-yl)-urea were synthesized and screened for anticonvulsant, CNS depressant and sedative-hypnotic activity in the mice. After i.p. injection to mice at doses of 30, 100, and 300 mg/kg body weight synthesized compounds were examined in the maximal electroshock induced seizures (MES) and subcutaneous pentylenetetrazole (scPTZ) induced seizure models in mice. Spectroscopic data and elemental analysis were consistent with the newly synthesized compounds. The neurotoxicity was assessed using the rotorod method. Compounds E1, E6, E9, E12, P3, P4 and P6 were found to be active in the MES screen whereas E1, P4, P6 and P11 were found to be active in the scPTZ screen. All except E6, E11 and P6 showed more than 50% decrease in locomotor activity at 1 h of compound administration via actophotometer screen. CNS depressant activity screened with the help of the forced swim method resulted into some potent compounds. All the compounds were found to exhibit potent CNS depressants activity as indicated by increased immobility time. It can be concluded that newly synthesized compounds possessed promising CNS activities.     

Synthesis, spectral, crystal structure and in vitro antimicrobial evaluation of imidazole/benzotriazole substituted piperidin-4-one derivatives

Imidazole/benzotriazole analogues substituted piperidin-4-one derivatives (17-26) have been synthesized. Their chemical structures were characterized by IR, ¹H NMR, ¹³C NMR and mass spectral analysis. In addition, single crystal X-ray diffraction has also been recorded for compounds 21 and 23. The synthesized compounds were subjected to their in vitro antibacterial and antifungal activities against pathogenic microbial strains. The results pointed out that compounds 19 & 24 against B. subtilis and 20 & 24 against E. coli were explored superior inhibition activity.     

Design, synthesis and in vitro antibacterial/antifungal evaluation of novel 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7(1-piperazinyl)quinoline-3-carboxylic acid derivatives

A series of 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7(1-piperazinyl)quinoline-3-carboxylic acid (norfloxacin) derivatives were prepared according to the principle of combinating bioactive substructures and tested for their activities against five plant pathogenic bacteria and three fungi in vitro. The preliminary bioassays indicated that almost all synthesized target compounds retained the antibacterial activities of norfloxacin and had some antifungal activities as carboxylic acid amide compounds. The activities of compounds 1 and 22 against Xanthomonas oryzae were better than norfloxacin and all tested compounds had better antibacterial activities as compared to the agricultural streptomycin sulfate (a commercial bactericide) against X. oryzae, Xanthomonas axonopodis and Erwinia aroideae. Additionally, compounds 2 and 20 displayed good antifungal activities against Rhizoctonia solani and their inhibition of growth reached 83% and 94% respectively at the concentration of 200 mg/L.     

Synthesis, stereochemistry, antimicrobial evaluation and QSAR studies of 2,6-diaryltetrahydropyran-4-one thiosemicarbazones

A series of 2,6-diaryltetrahydropyran-4-one thiosemicarbazones (11-27) were synthesized and characterized for evaluation of potential antibacterial activity against Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa, Salmonella typhi, Bacillus subtilis and Klebsiella pneumonia and antifungal activity against Cryptococcus neoformans, Candida albicans, Rhizopus sp., Aspergillus niger and Aspergillus flavus were evaluated. Compounds 21 and 22 showed maximum inhibition potency at low concentration (6.25 μg/ml) against P. aeruginosa. For antifungal activity, 20 and 21 were effective against C. neoformans and 22-24 against C. albicans at minimum concentration. Further, the results of QSAR studies of these synthesized compounds indicated the importance of weakly polar component of surface area, hydrophobicity and ionization potential parameters in defining their antimicrobial activity.     

Synthesis, characterization and pharmacological activity of 4-{[1-substituted aminomethyl-4-arylideneamino-5-sulfanyl-4,5-dihydro-1H-1,2,4-triazol-3-yl]methyl}-2H-1,4-benzothiazin-3(4H)-ones

A new series of Schiff and Mannich bases derivatives (6) of 4-[(4-amino-5-sulfanyl-4H-1,2,4-triazol-3-yl)methyl]-2H-1,4-benzothiazin-3(4H)-one (4), derived from (3-oxo-2,3-dihydro-4H-1,4-benzothiazin-4-yl)acetic acid (3) were synthesized. The structures of all newly synthesized compounds were elucidated by elemental analysis, IR, ¹H NMR and mass spectral data. Synthesized compounds were evaluated for their anti-inflammatory and analgesic activity. Among the tested compounds, the (3-oxo-2,3-dihydro-4H-1,4-benzothiazin-4-yl)acetic acid (3) possess analgesic activity comparable to that of pentazocine; activity decreased on derivatization of the carboxylic acid group. However the anti-inflammatory activity of (3-oxo-2,3-dihydro-4H-1,4-benzothiazin-4-yl)acetic acid (3) increased by derivatization of the carboxylic acid group and some of the compounds showed anti-inflammatory activity comparable to that of indomethacin.     

Synthesis, spectral and biological evaluation of some new thiazolidinones and thiazoles based on t-3-alkyl-r-2,c-6-diarylpiperidin-4-ones

A stereospecific synthesis of some thiazolidinones and thiazoles was achieved conveniently through certain α-halo keto agents and reactivity of chloroacetyl chloride was successfully enhanced by CsF–Celite + CH₃COONa. NMR studies revealed that the configuration of N–N bond is found to be anti with respect to C-3 alkyl group while CN bond in thiazolidinone is trans with respect to N–N bond. Antimycobacterial activity tested against Mycobacterium tuberculosis indicated that compounds 19, 20, 24, 29, 30 and 32 exhibited twofold enhanced potency than Rifampicin. Similarly, antimicrobial screening studies pointed out that compounds 21 and 28 exceptionally noticed promising activities and particularly, 21 against Staphylococcus aureus and, 24 and 32 against Rhizopus sp. exhibited onefold elevated inhibition potency whereas 21 against Klebsiella pneumoniae showed twofold improved potency than Ciprofloxacin and Amphotericin B.     

Synthesis, physicochemical properties and antimicrobial activity of some new benzimidazole derivatives

Some derivatives of benzimidazole were synthesized by nucleophilic substitution of 2-substituted-1H-benzimidazole. The resulting ethyl (2-substituted-1H-benzimidazol-1-yl) acetate on treatment with hydrazine hydrate yielded 2-(2-substituted-1H-benzimidazol-1-yl) acetohydrazide, which on further reaction with one equivalent of different aliphatic or aromatic carboxylic acids in the presence of phosphoryl chloride afforded the corresponding target compounds, 2-substituted-1-[{(5-substituted alkyl/aryl)-1,3,4-oxadiazol-2-yl} methyl]-1H-benzimidazole. The structures of the synthesized compounds were evaluated by spectral and elemental methods of analyses. All the synthesized compounds were screened for their antimicrobial activities. All of the derivatives showed good activity towards Gram-positive bacteria and negligible activity towards Gram-negative bacteria. Some of the synthesized compounds showed moderate activity against tested fungi.     

3-(1,3,4-Thiadiazole-2-yl)quinoline derivatives: synthesis, characterization and anti-microbial activity

A new series of thiadiazoles and intermediate thiosemicarbazones were synthesized from the chloroquinone molecule, with an aim to explore their effect on in vitro growth of microorganisms causing microbial infection. The chemical structures of the compound were elucidated by elemental analysis, FTIR, 1H and 13C NMR and ESI-MS spectral data. In vitro anti-microbial activity was performed against Staphylococcusaureus, Streptococcuspyogenes, Salmonellatyphimurium, and Escherichiacoli. The MIC was detected using the double dilution method. The results were compared by calculating percent inhibit area/μg of the compounds and the standard “amoxicillin”. The selected compounds were tested for cytotoxic results using MTT assay H9c2 cardiac myoblasts cell line and the results showed that all the compounds offered remarkable >80% viability to a concentration of 200 μg/mL.     

Synthesis and structure-activity relationship of 2-thiopyrimidine-4-one analogs as antimicrobial and anticancer agents

Considering that some thiopyrimidines were previously reported as potential therapeutics, the present study achieved novel analogs of bioactive 2-substituted thiopyrimidines-4-(3H)-ones via base catalyzed alkylation reaction of 2-thiouracil using alkyl and aralkyl bromides. The title compounds were 2-(1-butylthio)pyrimidine-4(3H)-one (5a), 2-(2-butylthio)pyrimidine-4(3H)-one (5b), 2-(cyclohexylmethylthio)pyrimidine-4(3H)-one (5c), 2-(benzylthio)pyrimidine-4(3H)-one (5d) and 2-(1-adamantylthio)pyrimidine-4(3H)-one (5e). Bioactivity tests revealed that thiopyrimidines 5a, 5c, 5d and 5e exhibited antimicrobial activity. The thiopyrimidine-4-one (5c) showed complete inhibition against Streptococcus pyogenes and Branhamella catarrhalis as well as antifungal action against Candida albicans. Significantly, the 1-adamantylthiopyrimidine (5e) was shown to be the most potent cytotoxic compound against multidrug-resistant small cell lung cancer (H69AR). Their structure-activity relationships were discussed.     

Novel 4-(morpholin-4-yl)-N′-(arylidene)benzohydrazides: Synthesis, antimycobacterial activity and QSAR investigations

A series of 4-(morpholin-4-yl)-N′-(arylidene)benzohydrazides were synthesized using appropriate synthetic route. Antimycobacterial activity of the synthesized compounds (5a–5j) was carried out and percentage reduction in relative light units (RLU) was calculated using luciferase reporter phages (LRP) assay. Percentage reduction in relative light units (RLU) for isoniazid was also calculated. The test compounds showed significant antitubercular activity against Mycobacterium tuberculosis H37Rv and clinical isolates: S, H, R, and E resistant M. tuberculosis, when tested in vitro.Quantitative structure–activity relationship (QSAR) investigation with 2D-QSAR analysis was applied to find a correlation between different experimental or calculated physicochemical parameters of the compounds studied and 3D-QSAR analysis and to indicate the exact steric and electronic requirements in the ranges at various positions around pharmacophore.In general Schiff bases exhibit antimycobacterial activity and morpholine ring is important for antimicrobial activity. So we have synthesized 10 different 4-(morpholin-4-yl)-N′-(arylidene)benzohydrazides. The structures of new compounds were characterized by TLC, FTIR, ¹H NMR, mass spectral data and elemental analysis.Amongst the compounds tested 5d and 5c were found to be the most potent, while 5i, 5e, and 5j were found to have an average activity against M. tuberculosis H37Rv and 5a, 5f, 5h, 5g, and 5b were found to have a greater activity against clinical isolates: S, H, R, and E resistant M. tuberculosis as compared to M. tuberculosis H37Rv.     

2-Arylidene-4-(4-phenoxy-phenyl)but-3-en-4-olides: synthesis, reactions and biological activity

2-Arylidene-4-(4-phenoxy-phenyl)but-3-en-4-olides (1-17) were prepared from 3-(4-phenoxy-benzoyl)propionic acid and aromatic aldehydes. Some of the selected butenolides were reacted with ammonia and benzylamine to give corresponding 3-arylidene-5-(4-phenoxy-phenyl)-2(3H)-pyrrolones (18-23) and 3-arylidene-5-(4-phenoxy-phenyl)-1-benzyl-2(3H)-pyrrolones (24-29) respectively, which were characterized on the basis of 1H-, 13C-NMR, Mass spectrometric data and elemental analysis results. These compounds were tested for anti-inflammatory and antimicrobial actions. The compounds, which showed significant anti-inflammatory activity, were screened for their analgesic and ulcerogenic activities. Five new compounds (5, 6, 7, 25 and 26), out of 29 showed very good anti-inflammatory activity in the carrageenan induced rat paw edema test, with significant analgesic activity in the acetic acid induced writhing test together with negligible ulcerogenic action. Antibacterial activity against Staphylococcus aureus and Escherichia coli as well as antifungal activity against Candida albicans were expressed as the corresponding minimum inhibitory concentration (MIC) values. Compound 21, 22 and 23 showed excellent activity against C. albicans with MIC-10 microg/ml. Out of the above-mentioned compounds, 22 and 23 also showed good activity against S. aureus with MIC-20 and 15 microg/ml respectively.     

Synthesis and anti-tumor activity of 2-amino-3-cyano-6-(1H-indol-3-yl)-4-phenylpyridine derivatives in vitro

A series of novel 2-amino-3-cyano-6-(1H-indol-3-yl)-4-phenylpyridine derivatives were synthesized and their cytotoxic activity against A549, H460, HT-29 and SMMC-7721 cell lines was evaluated in vitro. Among them, ten compounds (10, 11, 14, 16, 17, 26, 27, 29, 30 and 31) displayed excellent anti-tumor activity against different cell lines. The most promising compound 27 showed strong anti-tumor activity against A549, H460, HT-29 and SMMC-7721 cell lines with IC₅₀ values of 22, 0.23, 0.65 and 0.77 nM, which were 2.6-, 83-, 1.1 × 10³- and 2.0 × 10³- fold more active than MX-58151 (IC₅₀ values of 0.058, 0.019, 0.70 and 1.53 μM), respectively.     

Synthesis of novel bioactive derivatives of 3-(4-chlorophenyl)-2-hydrazino-5,6,7,8-tetrahydrobenzo(b)thieno[2,3-d]pyrimidine-4(3H)-ones

A series of triazolo[4,3-a]tetrahydrobenzo(b)thieno[3,2-e]pyrimidine-5(4H)-ones (12a–n) were synthesized and evaluated for CNS depressant, skeletal muscle relaxant and anticonvulsant activities by photoactometer, Rotarod and pentylenetetrazole induced the convulsions method respectively in Swiss albino mice. Diazepam was used as standard drug. The five derivatives 12b, 12c, 12d, 12i and 12m showed the CNS depressant and skeletal muscle relaxant activities comparable to those of diazepam at a dose of 5 mg/kg. These derivatives also exhibited good activity when tested for anticonvulsant activity in mice at different dose levels. The ED₅₀ values for these derivatives are in the range of 4.40–9.33 mg/kg.