Медицинская химия

Tuberculosis (TB) is a traditional disease caused by infection with Mycobacterium tuberculosis, it is a serious public health issue due to its risk of person-to-person transmission, and high level of morbidity and humanity. The World Health Organization (WHO) estimates 11.4 million people worldwide are infected with both Mycobacterium tuberculosis (Mtb) and HIV. Currently, there are approximately 8 million new infections and 3 million deaths attributed to M. tuberculosis annually. One of the major problems associated in comprehensive control of TB is that the restart of the disease in patients who carry a latent syndrome, in which the bacteria is in slow budding or non growing state and is refractory to treat with predictable anti-TB drugs. Directly observed treatment (DOT) is presently practicing for standard TB chemotherapy. It is well known that the resistance levels are poor in the areas with a strongly performing DOTS programmes. However, various drugs available in the market cannot be used for prolonged times due to diverse side effects. Therefore, the development of new and safe anti-TB drugs is in high demand. The major investigation on sEH inhibitors focused on urea, amide, amino- heterocycles and carbamate derivatives, but research on new compound structures is limited. Benzoxazolones are widely distributed in plants and are of increasing interest for a variety of pharmacological properties, such as detoxification, antibacterial, anti- HIV, anti-inflammatory, and transequilizers. Since benzoxazolones are active and inexpensive, many structural modification and preliminary bioactivity evaluation studies have been performed based on benzoxazol-ones. In this paper, 3-isopropyl benzo[d]oxazol-2(3H)-one amides and urea analogues were synthesized and evaluated as sEH inhibitors in vitro, and their anti-tuberculosis activities were determined in vivo. The 3-isopropylbenzo[d]oxazol- 2(3H)-one heterocycles has received considerable attention from the medicinal chemists owing to their capacity to mimic a benzamides or a phenyl urea moiety in a metabolically stable template. This class of compounds has led to the discovery of a number of derivatives endowed with antibacterial-antifungal, analgesic-antiinflammatory, anticonvulsant, dopaminergic, HIV-1 reverse transcriptase activity, and normolipenic agents. Usually functionalization of the nitrogen atom is of interest, since the electronic characteristic of this atom can be decisive for the biological activity. Nevertheless, most efforts have focused on N-, 5-, or 6-substituted benzoxazol-ones. Presently, 5-substituted benzoxazolone derivatives have been scarcely prepared, and few reports have described the sEH inhibitory activities or anti-tuberculosis activities. The pronounced biological activity of benzoxazolone derivatives and the lack of structure-bioactivity relationships prompted our investigation on 5-substituted-3- isopropylbenzo[d]oxazol-2(3H)-one.

The study was carried out on the isolation of various micro-organisms, in which various samples of chicken and mutton were collected from different locations of the Dehradun. The process of slaughtering of the chicken and mutton as per the survey was of two types- viz, Jatka and Halal. The isolated micro-organisms from the chicken samples of Jatka type include- Vibrio, Enterobacter species, Clostridium, E. coli, Shigella, whereas the micro-organisms isolated from the chicken samples of Halal type include only Enterobacter species, Clostridium and E. coli. The micro-organisms isolated from the mutton sample of Jatka type include, Shigella, E. coli, Vibrio, Staphylococcus, and the micro-organisms isolated from the mutton samples of Halal type include only E. coli, Vibrio and Staphylococcus. The micro-organisms have been isolated and identified by various biochemical tests. The isolated micro-organisms have been then testified for antimicrobial susceptibility test against various chemical substances which include, Gentamicin, Naphthazarin, Azithromycin, Citric Acid, Amphotericin-B, Clindomycin, Cefixime, Norfloxacin, Streptomycin, Ampicilin. Among the various used chemical substances, Gentamicin have been found effective in inhabiting the growth of all the isolated micro-organisms, followed by Norfloxacin, Streptomycin, Ampicilin, Azithromycin, Citric Acid. Least antimicrobial activity was observed for Naphthazarin, Amphotericin-B, Clindomycin, and Cefixime. Among the isolated micro-organisms shigella species was found to be less proned against the applied anti-microbial drugs, and the most susceptible micro-organism among the isolated micro-organisms includes E. coli. Also from the collected chicken and mutton samples the samples of Halal type have been to be less effective against the growth of micro-organisms as compared to the Jatka type samples, which could be due to different procedure of slaughtering technique.

A series of 2,6-diaryl substituted -4-indolylpyridines have been synthesized from indole-3-carboxaldehyde and acetophenones and all the compounds characterized by spectroscopic techniques. 5-Lipoxygenase enzyme inhibitory activities were performed for all the compounds. Among the 2, 6-diaryl substituted -4-indolylpyridine derivatives 3ad and 3aa showed good activity.

In many tropical areas, infections by Leishmania species are endemic and include visceral leishmaniasis (VL), which is often fatal if untreated. Outside India, VL treatment and control are based on long-term administration of highly toxic pentavalent antimonials. Previously, we described the synthesis and in vitro leishmanicidal activity of a series of nine benzophenone derivatives with low toxicity towards murine macrophages. Here in, we report the in vivo evaluation of the most promising active compounds of that series in an experimental model of established VL by L. (L). infantum chagasi in hamsters. Importantly, parasite DNA (amastigote form) quantification in infected tissues was performed by real time PCR, for improved detection accuracy and speed. Compounds 2-Hydroxy-4- O-(3,3-dimethyl)-allylbenzophenone (LFQM-117 (1)), 4-O-(3,3-Dimethyl)-allylbenzophenone (LFQM-120 (2)) and 4,4′-Di-methoxybenzophenone (LFQM-121 (3)) were administered as oral suspensions (50 mg/kg/day) for 10 days, after 50 days of parasite inoculation, and their efficacy was compared to pentavalent antimonial Glucantime (GLU). Compound 1 significantly reduced the number of parasites in the spleen (1.64 × 102 amastigotes/g, vs. 1.16 × 106 amastigotes/g in the untreated control), while compound 2 significantly reduced (p<0.05) the number of parasites in the liver (1.28 × 104 amastigotes/g, vs. 1.76 × 105 amastigotes/g in the untreated control) of infected animals. Glucantime was the most effective in the treatment of infected animals (1.15 × 101 and 3.20 × 102 amastigotes/g in the spleen and liver, respectively), but with higher toxicity then the most active compounds LFQM-117 (1) and LFQM-120 (2).

Background: The pharmacology activity of corticosteroids, is due to the formation in the blood of the complex Corticosteroid- Protein Glycosylated, that, in this form, after the binding to the cytoplasmic receptor, penetrates in the target cells. This interaction process, also happens, with salivary proteins The aim of this study is, to study this process, that precipitate the salivary proteins, and with them, the salivary secreted mucin.

Materials and methods: In two samples of whole saliva provided by volunteers, are added different concentrations of three corticosteroids, beclometasone, budesonide, fluticasone. The samples are centrifuged, and in surnatant, dosed, the amounts of total salivary proteins and mucins. The results are statistically analyzed with Mann Whitney U Test, Test T, Pearson Correlation Coefficient

Results and discussion: With all dosage, the difference of the proteins and mucins precipitated by the Budesonide, and beclometasone vs fluticasone, are statistically different., p ≤ 0.05. For all three corticosteroids, there is a saturation value, with a good correlation between corticosteroids’s dosage and the amount of the proteinmucins precipitation, (Pearson coefficient of 0.91). The little difference in the precipitation of the mucins, and the proteins, p=0.0334, obtained with the budesonide versus beclometasone, can find an explanation, for the presence in the first, of two hydroxyl groups, (one in beclometasone). The difference of beclometasone and budesonide, versus fluticasone, is due assuming that the parameters, that stabilize the (CCP), type hydrogen bonds and Van der Waals forces, are more influenced by solubility in water, there is nothing for the fluticasone, rather than by the chemical conformation of drugs

A series of 1, 2, 4-triazole derivatives (1-17, Scheme 1) was synthesized and evaluated for their antimicrobial and antioxidant potential. Results of antimicrobial screening of the synthesized compounds indicated that most of the synthesized compounds showed good activity as compare to the norfloxacin as antibacterial and fluconazole as antifungal standard drugs. Compounds 7 and 12 were found to be most effective against various strains used for the antimicrobial activity like S. aureus, B. subtilis, E. coli, Candida albicans and A. niger using tube dilution method having MIC 3.12 μg/ml for S. aureus and 06.25 μg/ml for rest strains. All the synthesized compounds also evaluated for antioxidant activity by DPPH method and results revealed that the compounds 8 and 16 showed antioxidant activity comparable to the positive control ascorbic acid.

The clinical success of cisplatin has stimulated the quest for novel anticancer metallodrugs during the last two decades. A major emphasis has been put on copper due to its selective cytotoxicity toward malignant cells. This selectivity stems from the hypoxic environment of cancer cells that promotes the reduction of Cu(II) to Cu(I), leading a pro-apoptotic oxidative stress. At the current time, two copper complexes have reached clinical assay, which paves the road to the first copper-based anticancer therapeutics.

Background: Total Epimedium-derived flavonoids (EF) were reported to be a group of major bioactive constituents present in genus Epimedium for the treatment of osteonecrosis. The present study aimed to investigate the pharmacokinetics of main bioactive components of EF in rabbit.

Methods: A rapid and sensitive method for the simultaneous determination of icariin, icariside I, icariside II and icaritin in serum was established and validated by ultra-performance liquid chromatography coupled with quadrupole time-of-flight tandem mass spectrometry (UPLC-Q-TOF/MS). Serum samples were pretreated with water-saturated ethyl acetate. Furthermore, sample separation was achieved on an Waters BEH C18 column (50 mm × 2.1 mm, 1.7 μm) by gradient elution with acetonitrile-water (both including 0.1% formic acid) as mobile phase. Finally, pharmacokinetics of EF in rabbit serum was investigated.

Results: All calibration curves displayed excellent linearity (r2>0.99) within 1.2~24 ng/mL. The assay was specific, precise and accurate, as demonstrated with intra-run precisions not more than 12.6%, inter-run precisions less than 9.9% and accuracies between -4.4% and 9.3%. Meanwhile, the matrix effects, extraction recoveries and stabilities were all satisfactory. Moreover, this validated method was successfully applied to analyse the pharmacokinetic of EF in rabbit serum after oral dosage of 80 mg/kg.

Conclusion: These results would enlarge our knowledge about main bioactive components of EF for the treatment of osteonecrosis in rabbit.

Nucleosides take an important place in medicinal chemistry as the structural basis for the development of therapeutic agents. The chemistry of substituted base-modified nucleosides has been an interesting field of study over the last two decades owing to their biological properties. This mini-review summarizes recent efforts on the synthesis of C5- and C8-alkynyl base-modified pyranonucleoside analogues using Sonogashira cross-coupling reaction under microwave irradiation.