Design,synthesis, characterization,antibacterial and antifungal activities of a novel class of 5,7-diaryl-4,4-dimethyl-4,5,6,7-tetrahydropyridino[3,4-d]-1,2,3-selenadiazoles

Compound 26 is more potent against Escherichia coli. and 24 is more active against Staphylococcus aureus, β-Heamolytic streptococcus, Vibreo cholerae, Salmonella typhii, and Shigella flexneri than the standard drug ciprofloxacin. Moreover, of all the compounds tested, 26 is more effective against Aspergillus flavus and Mucor, than the standard drug fluconazole.     

Design and synthesis of parthenolide-SAHA hybrids for intervention of drug-resistant acute myeloid leukemia

A series of parthenolide-SAHA hybrids were synthesized and evaluated for their anti-AML activities against HL-60 and HL-60/ADR cell lines. The most active compound 26 exhibited high activity against HL-60/ADR cell line with IC₅₀ value of 0.15 μM, which demonstrated 16.8-fold improvement compared to that of the parent compound PTL (IC₅₀ = 2.52 μM). Moreover, it was six times more potent than the reference drug SAHA (IC₅₀ = 0.90 µM) and fifty-one times more potent than ADR (IC₅₀ = 7.72 µM). The preliminary molecular mechanism of 26 indicated that compound 26 could significantly induce apoptosis of HL-60/ADR cells. The effect of compound 26 was mainly through mitochondria pathway. Further investigation revealed that the protein level of HDAC1 and HDAC6 were reduced after the treatment of compound 26 with a dose-dependent manner. Compound 26 could significantly decrease ABCC1 expression, which increased the accumulation of intracellular drug for overcoming the drug resistance. On the base of these results, compound 26 might be considered as a promising candidate for further evaluation as a potential anti-AML drug.     

Three components coupling catalysed by NaHSO(4).Sio(2) - a convenient synthesis, antibacterial and antifungal activities of novel 6-Aryl-1,2,4,5-tetrazinan-3-ones

A novel method has been developed for the synthesis of 6-aryl-1,2,4,5-tetrazinan-3-ones through a one-pot reaction of urea, various substituted aromatic benzaldehyde having electron donating and electron withdrawing groups and ammonium acetate in the presence of reusable NaHSO(4).SiO(2) heterogeneous catalyst in dry media under microwave irradiation. FT-IR, (1)H NMR, D(2)O Exchange, (13)C NMR, Heteronuclear Single Quantum Correlation (HSQC) spectra, MS and elemental analysis characterized all the synthesized compounds. In vitro antibacterial/fungal activities were evaluated for six new compounds. The antibacterial studies revealed that compounds 1-6 had better activity against tested Gram-positive and Gram-negative organisms. Compounds 1 and 5 were more active against beta-Heamolytic streptococcus, a Gram-positive bacteria and Pseudomonas, a Gram-negative bacteria, respectively, than the standard drug ciprofloxacin. Besides, of all the compounds tested, compound 5 was more effective against Aspergillus flavus, a fungal strain than the standard drug fluconazole.     

The temporal dimensions of anticonvulsant action of some newer benzodiazepines against metrazol induced seizures in mice and rats

In a time-distribution study, the anticonvulsant effects of four benzodiazepine compounds were compared with those of three standard antiepileptics against metrazol-induced seizures in mice and rats. Ethosuximide and trimethadione had the shortest duration of action in mice, but protected the rats up to 6 hr. Phenobarbitone, diazepam, flurazepam and nitrazepam protected the mice up to 12 hr, but the rats were effectively protected only up to 3-4 hr. Clonazepam, the most potent and effective agent, protected the mice from clonic-tonic seizures up to 18-20 hr and the rats up to 6-7 hr. Comparison of the PD50 from clonic seizure at the peak-effect hours revealed that the benzodiazepines were 16 to 96 times more potent than phenobarbitone on a molar basis, while phenobarbitone itself was 12 to 26 times more potent than ethosuximide and trimethadione. Tonic seizures and mortality were largely suppressed by all drugs until 18-20 hr in mice and 6-7 hr in rats. Seizure latency and mortality patterns varied from drug to drug but not in a dose-dependent manner.     

Application of multicomponent reactions to antimalarial drug discovery. Part 3: discovery of aminoxazole 4-aminoquinolines with potent antiplasmodial activity in vitro

The synthesis and antimalarial activity of a novel series of first generation 4-aminoquinoline-containing 2,4,5-trisubstituted aminoxazoles against two strains of the Plasmodium falciparum parasite in vitro is described. A number of compounds significantly more potent than the standard drug chloroquine were identified.     

Conventional and microwave assisted synthesis of pyrazolone Mannich bases possessing anti-inflammatory,analgesic, ulcerogenic effect and antimicrobial properties

In the present study, an efficient synthesis of some Mannich base of 5-methyl-2-[(2-oxo-2H-chromen-3-yl)carbonyl]-2,4-dihydro-3H-pyrazol-3-one (4a–j) have been described by using conventional and non-conventional (microwave) techniques. Microwave assisted reactions showed that require shorter reaction time and good yield. The newly synthesized compounds were screened for their anti-inflammatory, analgesic activity, antioxidant, and antibacterial effects were compared with standard drug. Among the compounds studied, compound (4f) showing nearly equipotent anti-inflammatory and analgesic activity than the standard drug (indomethacin), along with minimum ulcerogenic index. Compounds (4b and 4i) showing 1.06 times more active than ciprofloxacin against tested Gram-negative bacteria.     

Efficacy of methyl 5(6)-(alpha-hydroxyphenylmethyl) benzimidazole-2-carbamate, a metabolite of mebendazole, against developing forms of experimental helminth parasites.

Methyl 5(6)-(alpha-hydroxyphenylmethyl) benzimidazole-2- carbamate, a metabolite of mebendazole, was evaluated against metamorphic forms of Ancylostoma ceylanicum in hamsters, Nippostrongylus brasiliensis in rats and cysticercoids of Hymenolepis nana in grain beetles. The test compound offered better action than mebendazole except against H. nana cysticercoids where the activity of the compound and mebendazole was comparable, but was inferior to the standard cestodicidal drug, praziquantel. The results suggest that the action was better by ip route compared to per os route of drug administration.     

Synthesis, antimicrobial and antimycobacterial evaluation of [2-(substituted phenyl)-imidazol-1-yl]-pyridin-3-yl-methanones

A series of [2-(substituted phenyl)-imidazol-1-yl]-pyridin-3-yl-methanones (1-11) were synthesized and screened for their antimicrobial and antimycobacterial activities. Further, a series of [2-(substituted phenyl)-benzimidazol-1-yl]-pyridin-3-yl-methanones (12-20) reported in our earlier study was also screened for their antimycobacterial activity. The antimycobacterial activity results indicated that [2-(4-Nitro-phenyl)-imidazol-1-yl]-pyridin-3-yl-methanone (8, minimum inhibitory concentration [MIC]?=?3.13 μg) was equipotent as standard drug ciprofloxacin and [2-(4-Nitro-phenyl)-benzimidazol-1-yl]-pyridin-3-yl-methanone (16, MIC?=?1.56 μg) was equipotent as standard drug ethambutol. The results of antimicrobial screening demonstrated that 2-[1-(Pyridine-3-carbonyl)-1H-imidazol-2-yl]-benzoic acid (compound 11, MIC?=?0.002 μg) was two times more effective than standard drug ciprofloxacin (MIC?=?0.004 μg) against tested bacterial strains and [2-(2,5-Dimethyl-phenyl)-imidazol-1-yl]-pyridin-3-yl-methanone (compound 3, MIC?=?0.005 μg) was equipotent to the reference compound, fluconazole against tested fungal strains.     

A facile synthesis, antibacterial, and antitubercular studies of some piperidin-4-one and tetrahydropyridine derivatives

The raise in clinical significance of multidrug-resistant bacterial pathogens has directed us to synthesize 2,6-diarylpiperidin-4-one and Delta(3)-tetrahydropyridin-4-ol based benzimidazole and O-arylsulfonyl derivatives. X-ray crystal structure of tetrahydropyridinol (23) confirmed a change in conformation and orientation of substituents upon amide formation. Antibacterial activities evaluated against a wide number of bacterial pathogens (both sensitive and multidrug-resistant) revealed that 19, 27 against Staphylococcus aureus, 27 against Enterococcus faecalis, and 19, 21, 23, and 27 against Enterococcus faecium are significantly good at lowest MIC(90) (16 microg/mL). Inhibitory power noticed by 23 against Vancomycin-Linezolid-resistant E. faecalis and 27 against Vancomycin-resistant E. faecium are onefold better than the standard Linezolid and Trovafloxacin drugs, respectively. Moreover, antitubercular activity for the selected compounds against Mycobacterium tuberculosis H37Rv revealed that compounds 23, 24, and 27 expressed onefold improved potency compared to the standard Rifampicin drug.     

Fluorescence-Labeled Immunomicelles: Preparation, in vivo Biodistribution, and Ability to Cross the Blood-Brain Barrier

Multifunctional hybrid micelles are prepared from amphiphilic mal-PEG-b-PLA and mPEG-b-P(LA-co-DHC/RhB) block copolymers. A specific anti-transferrin receptor antibody, OX26, is linked onto the surface of the micelles. ELISA indicates that the conjugated antibody preserves its activity. OX26 conjugation can increase the uptake efficiency of micelles by target cell lines (C6). Pharmacokinetics and in vivo biodistribution experiments are carried out to investigate the ability of OX26-conjugated micelles (immunomicelles) to cross the blood-brain barrier. The data show that the brain uptake of OX26-conjugated micelles is much more than that of OX26-free ones. Therefore, OX26-conjugated micelles will be promising drug carriers to cross the blood-brain barrier.     

Design,synthesis, and anticancer evaluation of some novel thiourea,carbamimidothioic acid,oxazole, oxazolidine,and 2-amino-1-phenylpropyl-2-chloroacetate derived from L-norephedrine

A novel series of thiourea, carbamimidothioic acid, 4, 5-dihydrooxazole-2-thiol, oxazolidine-2thine, and 2-amino-1-phenylpropyl-2-chloroacetate derivatives was designed and synthesized using 2-amino-1-phenylpropan-1-ol (L-norephedrine) as a strategic starting material. The structures of the newly synthesized compounds were established by elemental analyses, IR, and ¹H NMR and ¹³C NMR spectral data. The compounds were evaluated for their in vitro anticancer activity against various cancer cell lines. The corresponding acetamide, carbamimidothioic acid, and 2-2-amino-1-phenylpropyl-2-chloroacetate derivatives showed almost the same activity as the standard drug doxorubicin against human breast cancer cell line (MCF-7). Also, the acetamide and 2-thioxoimidazolidin-4-one derivatives exhibited higher activity than the reference drug doxorubicin against human colon cancer cell line (HCT 116).     

肠杆菌新解释标准指导临床用药的实用性

采用新旧肠杆菌的2种解释标准,分析肠杆菌的耐药性,比较2种解释标准的临床意义。收集本院2009至2010两年临床分离的912株大肠埃希菌、328株肺炎克雷伯菌,用Kirby-Bauer法作药敏试验,用WO-NET5.4软件先设置CLSI推荐的旧的肠杆菌解释标准,分析耐药性。再设置CLSI推荐的新的肠杆菌解释标准[1]修改头孢曲松、头孢他啶、头孢噻肟、氨曲南和亚胺培南的解释标准,分析其耐药性。用肠杆菌旧的解释标准分析常规检测分离出的大肠埃希菌236株产酶株;肺炎克雷伯66株产酶株;产酶株比非产酶株的耐药率高。用新的头孢菌素和氨曲南的解释标准:对于大肠埃希菌头孢曲松的耐药率提高5.2%;头孢他啶提高10.4%;头孢噻肟提高10.2%;氨曲南提高7.1%;对于肺炎克雷伯菌头孢曲松的耐药率提高6.7%;头孢他啶提高4.3%;头孢噻肟提高10.1%;氨曲南提高2.5%;未向临床报产酶株。采用碳青霉烯类抗生素新的解释标准大肠埃希菌和肺炎克雷伯菌对亚胺培南的耐药分别提高了0.4%和0.6%,对美罗培南的耐药率分别提高了0.2%和0.6%。新的肠杆菌解释标准更能客观分析肠杆菌的耐药性,对指导临床合理用药,控制耐药株的蔓延更具实用价值。     

Synthesis of 2-[3,5-substituted pyrazol-1-yl]-4,6-trisubstituted triazine derivatives as antimalarial agents

A series of 22 compounds were synthesized and screened against Plasmodium falciparum NF-54 strain. Of the screened compounds, 6 compounds showed MIC in the range between 1 and 2 microg/mL. These compounds are 32 times more potent than the cycloguanil which was used as the standard drug.     

Investigations on the structural,vibrational, computational,and molecular docking studies on potential antidiabetic chemical agent Diosmetin

In the present study, the harmonic vibrational frequencies of Diosmetin(5, 7 dihydroxy‐2(3‐hydroxy‐4 methoxyphenyl) chromen‐4‐one) have been investigated by both experimental (FTIR and FT‐Raman) and theoretical (HF and DFT/B3LYP) method. The calculated harmonic vibrational frequencies were compared with experimental data. A detailed interpretation of the vibrational spectra of the compound has been made on the basis of the calculated potential energy distribution (PED). The ¹H, ¹³C NMR chemical shifts and TD‐DFT calculations of the molecule were calculated and compared with the available experimental observations. A study on the molecular electrostatic potential surface (MEP) of the compound was performed, and the electrophilic and nucleophilic reactive sites were identified. Furthermore, the inhibition effect of compound against aldose reductase enzyme has been analyzed by molecular docking method, and the results were compared with the standard drug. The docking study indicates that the investigated compound shows better inhibitory activity toward aldose reductase enzyme than the standard drug, and hence this study may be supportive in the field of drug discovery to design more potential antidiabetic agents.     

Evaluation of hepatoprotective activity of Clerodendrum serratum L

The ethanol extract of C. serratum roots and ursolic acid isolated from it were evaluated for hepatoprotective activity against carbon tetrachloride induced toxicity in male Wistar strain rats. The parameters studied were estimation of liver function serum markers such as serum total bilirubin, total protein, alanine transaminase, aspartate transaminase and alkaline phosphatase activities. The ursolic acid showed more significant hepatoprotective activity than crude extract. The histological profile of the liver tissue of the root extract and ursolic acid treated animal showed the presence of normal hepatic cords, absence of necrosis and fatty infiltration as similar to the controls. The results when compared with the standard drug silymarin, revealed that the hepatoprotective activity of the constituent ursolic acid is significant as similar to the standard drug.     

Synthesis,anticancer activity,and β‐lactoglobulin binding interactions of multitargeted kinase inhibitor sorafenib tosylate (SORt) using spectroscopic and molecular modelling approaches

Sorafenib tosylate (SORt) is an oral multikinase inhibitor used for treatment of advanced renal cell, liver, and thyroid cancers. In this study, this drug was synthesized and its antiproliferative activities against HCT116 and CT26 cells were assessed. The interaction of SORt with β‐lactoglobulin (BLG) was studied using different fluorescence techniques, circular dichroism (CD), zeta potential measurements, and docking simulation. The results of infrared (IR), mass, ^HNMR, and ^CNMR spectra demonstrated that the drug was produced with high quality, purity, and efficiency. SORt showed potent cytotoxicity against HCT116 and CT26 cells with IC₅₀ of 8.12 and 5.42 μM, respectively. For BLG binding of SORt, the results showed that static quenching was the cause of the high affinity drug–protein interaction. Three‐dimensional fluorescence and synchronous spectra indicated that SORt conformation was changed at different levels. CD suggested that the α‐helix content remained almost constant in the BLG–SORt complex, whereas random coil content decreased. Zeta potential values of BLG were more positive after binding with SORt, due to electrostatic interactions between BLG and SORt. Thermodynamic parameters confirmed van der Waals and hydrogen bond interactions in the complex formation. Molecular modelling predicted the presence of hydrogen bonds and electrostatic forces in the BLG–SORt system, which was consistent with the experimental results.     

Anti-coccidial activity of 2-picoline, 6-amino-4-nitro-, 1-oxide

An investigational drug (2-picoline, 6-amino-4-nitro-, 1-oxide) was evaluated to characterize the anti-coccidial spectrum of the compound. Two concentrations of the drug (125 and 250 ppm) were evaluated for bioactivity; weight gain, survival, dropping, and lesion scores were the response variables utilized to ascertain activity. The activities of the picoline derivative were compared with monensin, maduramicin, and a narasin/nicarbazin (1:1) combination. The investigational drug had significant activity against Eimeria tenella and Eimeria necatrix, and the 250-ppm level was significantly more active than 125 ppm. At 250 ppm, the E. tenella activity of the picoline derivative was comparable to both monensin (120 ppm) and the 50-ppm narasin/nicarbazin combination, significantly less effective than maduramicin (6 ppm), and significantly more efficacious than 30 ppm narasin/nicarbazin. At the same level (250 ppm), the picoline derivative had significantly less E. necatrix activity than monensin (120 ppm), maduramicin (6 ppm), and narasin/nicarbazin (50 ppm), and significantly greater activity than 30 ppm narasin/nicarbazin. At best, only extremely weak Eimeria acervulina, Eimeria brunetti, and Eimeria maxima activities were noted with the investigational drug; higher concentrations of the picoline derivative may achieve greater anti-coccidial activity against these species. The efficacy of narasin/nicarbazin compared favorably with monensin and maduramicin; the 50-ppm level of the combination appeared significantly more efficacious than 30-ppm.     

3-Phenyl-5-methyl-2H,5H-furan-2-ones: tuning antifungal activity by varying substituents on the phenyl ring

A series of racemic 3-phenyl-5-methyl-2H,5H-furan-2-ones related to a natural product, (-)incrustoporine, was synthesized, and their antifungal activity evaluated. The key structural feature, furanone ring, was closed via H2SO4-mediated cyclization of 2-phenylpent-4-enoic acids. The compounds displayed antifungal activity, especially against filamentous fungi. Expressed as the minimum inhibition concentration (MIC) in micromol/L, the activity of the most promising derivative against Absidia corymbifera matched that of ketoconazole (31.25 micromol/L). In terms of microg/mL, the substance was more active (7.6 microg/mL) than this standard antifungal drug (16.6 microg/mL).     

Novel water-soluble analogues retaining potent antitumor activity of RA-VII, a cyclic hexapeptide from Rubia plants

Deoxybouvardin (3) was reacted with 2-dialkylaminoethyl chloride salts to produce analogues 4a-h. All analogues retained antitumor activity against P388 leukemia in mice, and analogue 4c showed more promising antitumor activity than RA-VII (1) against the P388 leukemia, B16 melanoma and colon adenocarcinoma 26 murine tumor models. The hydrochloride salt of 4c is soluble in water.     

Synthesis and evaluation of 4′,5′-dihydrospiro[piperidine-4,7′-thieno[2,3-c]pyran] analogues against both active and dormant Mycobacterium tuberculosis

Need for new drugs to fight against tuberculosis (TB) is increasing day by day. In the present work we have taken a spiro compound (GSK 2200150A) reported by GSK as a lead and we modified the structure of the lead to study the antitubercular activity. For structure activity profiling twenty-one molecules have been synthesized, characterized and evaluated for their antimycobacterial potency against both active and dormant TB. Compound 06, 1-((4-methoxyphenyl)sulfonyl)-4′,5′-dihydrospiro[piperidine-4,7′-thieno[2,3-c]pyran] was found to be the most potent compound (MIC: 8.23?µM) in active TB and was less effective than the lead but more potent than standard first line drug ethambutol. It was also found to be more efficacious than Isoniazid and Rifampicin and equipotent as Moxifloxacin against dormant Mycobacterium tuberculosis (MTB). Compound 06 also showed good inhibitory potential against over expressed latent MTB enzyme lysine ε-amino transferase with an IC₅₀ of 1.04?±?0.32?µM. This compound is a good candidate for drug development owing to potential against both active and dormant stages of MTB.