Letters in Drug Design & Discovery - Volume 9, Issue 5, 2012

We previously reported that the phenanthroindolizidine alkaloid 3 and its derivatives had markedly potent in vitro cytotoxicity. However, they had low in vivo antitumor activities and high in vivo toxicities, which was a serious problem for further development. Based on the finding that antitumor activity and toxicity could be improved by acetylation of 3, we synthesized new derivatives of 3, which possessed various acyl groups, and evaluated their antitumor activities and toxicities. We found that derivatives with sterically less bulky acyl groups had improved antitumor activities.

The new series of N-(methylene-4-oxo coumarinyl)anilines 1-13 was synthesised and screening of different solvents led to the discovery of high boiling alcohols as the suitable candidate for one pot efficient three component reaction. Particularly in 2-butanol the product was precipitated out in excellent yields without the hassle of purification. The product distribution of Z and E-isomers was established by 1HNMR. These compounds were screened for their in vitro antibacterial activity against Escherichia Coli, Bacillus Subtilis, Shigella flexenari, Staphylococous aureus, Pseudomonas aeruginosa and Salamonella typhi. Standard drug impenium was used as control.

Several 4H-pyrano[3,2-h]quinoline 3,4,7-9, 7H-pyrimido[4',5':6,5]pyrano[3,2-h]quinoline 10a,b and 14Hpyrimido[ 4',5':6,5]pyrano[3,2-h][1,2,4]triazolo[1,5-c]quinoline 11a-c derivatives were obtained by treatment of (E) 2-(4- chlorostyryl)-8-hydroxyquinoline 1, (E) 2-amino-4-(4-chlorophenyl)-9-(4-chlorostyryl)-4H-pyrano[3,2-h]quinoline-3- carbonitr-ile 3 or (E) 9-amino-7-(4-chlorophenyl)-2-(4-chlorostyryl)-8-imino-8,9-dihydro-7H-pyrimido-[4',5':6,5]pyrano [3,2-h]quinoline 10b with different electrophiles followed by nucleophilic reagents. Structures of these compounds were established on the basis of IR, 1H NMR, 13C NMR, 13C NMR-DEPT, 13C NMR-APT and MS data. The antitumor activity of the synthesized compounds was investigated and compared with that of the standard drug vinblastine, a well-known anticancer drug, using MTT colorimetric assay. Among them, compounds 10b and 3 showed the most potent activity against the human breast tumor cells (MCF-7) and the human lung carcinoma cells (HCT), while compound 10b exhibited the most potent activity against the human hepatocellular carcinoma cells (HepG-2). The structure-activity relationships are discussed.

A new series N-substituted -2-piperidine-4-yl-2H-benzotriazole (6a-6r) have been synthesized from 4-oxopiperidine- 1-carbaxylic acid tert-butyl ester. The new compounds were screened for their antibacterial activity against Gram positive bacteria (Bacillus subtilis, Bacillus megaterium, Bacillus pumilis, Staphylococcus aurius, Enterobactor aerogens and Streptococcus pyrogens) and Gram negative bacteria (Escherichia coli, Proteus vulgaris, Proteus mirabilis and Klebsiella pneumonia). Compounds 6a, 6b, 6g, 6h, 6k, 6q and 6r showed significant anti bacterial activity. The compounds have also been screened for antifungal activity viz Candida albicance, Fusarium oxysporum, Drechslera halodes,and Colletotrichum falcatum. Compounds 6a, 6b, 6d, 6g, 6h and 6r showed significant antifungal activity.

In the present study, a series of chalcone derivatives were designed based on QSAR analysis. The designed compounds were synthesized by Claisen Schmidt condensation and evaluated for anti-inflammatory, antioxidant and antiulcer activities. The results of the best 2D & 3D QSAR models suggested that by introducing electron releasing groups at R2 and introducing heteroatom with increasing bulkiness at R4 in the benzylideneacetophenone nucleus will increase the activity. The structures of the compounds were established by IR, 1H NMR and mass spectral analysis. All the compounds were evaluated for their anti-inflammatory (carrageenan-induced rat paw edema assay), antioxidant (inhibition of lipid peroxidation) and antiulcer activity (indomethacin-induced gastric damage). Of 10 compounds screened, compounds 1e and 1d exhibited promising anti-inflammatory activity with 68-70% inhibition at 100mg/kg , inhibition of lipid peroxidation with IC50 2.47 & 3.1 μg/ml respectively. The Compounds 1e, 1j and 1d exhibited good gastro protective action as indicated by their low ulcer score. Overall, 1e was obtained as lead compound with promising anti-inflammatory, antioxidant and antiulcer activities.

Irritable bowel syndrome is the most common functional gastrointestinal disorder characterized by chronic abdominal pain or discomfort in association with a change in bowel habit. 5-HT receptor modulators have been developed as IBS therapeutic agents and proved to be effective in the treatment of the disease. In this letter, 12 berberine derivatives were designed and synthesized as 5-HT receptor modulators. Preliminary biological tests suggested that the new compounds exhibited promising activity for IBS therapy.

This study focuses on the physico-chemical characterization of surfactant nanovectors according to the evidence that the knowledge of nanocarrier properties is a necessary step to translate their potentiality to nanomedicine applications. In particular, in this investigation we have prepared deformable surfactant vesicles (dSV) and characterized them in terms of dimensions, zeta-potential, deformability index and stability. Also the potential application of analyzed carriers is evaluated in terms of ammonium glycyrrhizinate (AG) entrapment efficiency and in vitro permeation experiments. The obtained results suggest the potential application of dSV in dermal administration of AG, a useful drug for the treatment of various skin diseases, such as dermatitis, eczema and psoriasis.

The five dose comparative CNS Cancer Cell Line cytotoxicity profiles of N9-[4'-Chloro-2'-butynyl-1'-yl]-2,6- dichloropurine 1, Bis- 6,9-[4'-chloro-2'-butynyl-1'-yl]-thioguanine 2, Bis- 6,9-[4'-chloro-2'-butynyl-1'-yl]-mercaptopurine 3, Bis-6,9-[[o-(chloromethyl)phenyl]methyl]-thioguanine 4, Bis-6,9-[[o-(chloromethyl)phenyl]methyl]-mercaptopurine 5, 6-[4'-chloro-2'-butynyl-1'-yl]-thioguanine 6, and N9-[4'-Chloro-2'-butynyl-1'-yl]-6-(4-methoxyphenyl)purine 7 are presented in this communication. These compounds were evaluated for cytotoxic activity against NCI-60 DTP human tumor cell line five dose screen. All the unsaturated highly lipophilic substituents as expected contributed for the excellent CNS cancer cell line cytotoxicity, GI50 values 4-7 μM. Further, the thioguanine, mercaptopurine, and 6-phenylpurine are identified as the potential candidates for the CNS active cancer drug development and to cross the blood brain barrier.

To improve the bioavailability of oleanolic acid (OA), OA-phospholipid complex (OA-PLC) was prepared and evaluated with solubility, differential scanning calorimetry, x-ray powder diffractometry, IR spectroscopy, dissolution study and pharmacokinetic characteristics in rats. Concentrations of OA after oral administration of OA-PLC and OA aqueous suspension in rats were determined by high-performance liquid chromatography/mass spectrometry /mass spectrometry. Solubility of OA-PLC in water and in n-octanol was effectively enhanced by 300 times and 1.2 times, respectively. Spectra of DSC, xRD and IR showed that OA-PLC was formed. Cmax of rats treated with OA and OA-PLC is 0.47 and 1.18 μg/mL, respectively. AUC0→24h and AUC0→∞ values in rats of group OA-PLC were increased significantly (p<0.01) by 2.06 and 2.16 times compared with those of group OA, respectively. This study indicates the superiority of OA-PLC over OA, in terms of enhanced water and lipid solubility and improved bioavailability in rats.

8-(Trifluoromethyl)-1,2,3,4,5-benzopentathiepine-6-amine 1a and its hydrochloride revealed significant analgesic activity in the acetic acid-induced writhing test, and ED50 of the compound 1a was 0.66 mg/kg. In the hot plate pain test, the reliable analgesic activity was found in hydrochloride 1a*HCl, whereas the free base 1a proved to be inactive. Based on the results of the naloxone test, the analgesic effect of the compound 1a*HCl in both tests is mediated with the opioidergic system. Both the free base 1a and its hydrochloride did not show the anti-inflammatory activity. Replacement of the CF3 group for the fluorine atom resulted in complete loss of analgesic activity in the acetic acidinduced writhing test.

Our original aim was to evaluate in vivo nuclear uptake of a conjugate containing the SV40 T Antigen nuclear localization sequence (NLS), 6 aminohexanoic acids alternating with 7 arginines, the fluorescence dye fluorescein isothiocyanate (FITC) and the gadolinium chelator 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA). During the confocal laser scanning microscopy examination of frozen sections of the kidneys of mice injected intravenously with the conjugate we found unexpected conjugate relocation. In the dry frozen sections no nuclear staining was found. After covering the sections with physiological saline and a coverslip, the conjugate was relocated to the cell nuclei. Causation of this effect by FITC and DOTA could be excluded with appropriate controls. In the assumption that other positively charged conjugates behave in the same manner we tested two further conjugates in vivo. An octaarginine coupled to a lysine carrying FITC on the ε-amino-group was found in the cell nuclei of the frozen kidney sections before and after covering the slices with saline. By contrast, a conjugate containing myristoylated HIV-Tat was found not to stain the cell nuclei but only the cytoplasm before and after covering with saline. This demonstrates that not all positively charged conjugates are relocated to the cell nucleus after covering the frozen sections with saline. This was confirmed by direct incubation of frozen sections from untreated kidneys with the same conjugates and additional positively charged FITC conjugates. By coincubating the FITC conjugates with a cytoplasm directed rhodamine conjugate on untreated kidney sections we found that such conjugates could be used as nuclear FITC counterstain. In summary, one should bear in mind that positively charged conjugates applied in vivo can relocate artificially after covering with saline.

Chemometric methods, structure-activity relationships (SAR), molecular modeling, and quantitative structureactivity relationships (QSAR) are some of the in silico methods widely used in medicinal chemistry, and that are found to be appropriate to be employed in food research. Some of these methodologies represent an attempt to correlate structural or property descriptors of compounds to several types of biological activities. The physicochemical traditional descriptors include parameters related to hydrophobicity, topology, electronic properties, and steric effects. Other computational tools, such as density functional theory (DFT) calculations, are used in order to examine the influence of the electronic surfaces of new ingredients. Advances in the development of in silico methods, such as structure similarity searching, have increased the availability of additional resources for safety assessment. This review analyzes some studies in order to show how computational chemistry can be used to predict important chemical structure information and how these techniques can be applied in food research.

Leishmaniasis is caused by protozoan parasites belonging to the genus Leishmania. According to WHO, leishmaniasis occurs in four continents and is considered to be endemic in 88 countries, 72 of which are developing countries. Intensive effort to investigate novel compounds to counter the parasites that are resistant to existing drug molecules is necessary. This review intends to give an outline of the present state of knowledge on antileishmanial drugs along with molecules that are currently under development as promising drug candidate. A brief discussion on some aspects of associated drug resistance is also considered.

The broad and potent activity of 2-thioxo-imidazolidin-4-one (2-thiohydantoin) has established it as one of the biologically important scaffolds. This article highlights the medicinal chemistry investigations in search for novel 2- thioxo-imidazolidin-4-one derivatives with promising biological activities. New 2-thioxo-imidazolidin-4-one derivatives contain diaryl, triaryl, pyrimidine, cycloalkylamines and glucopyranosyl substituents and their aryl and halogen and alkyl derivatives, and other substituent with varied the monocyclic (thiadiazole, sulfadiazole) heterocycles linked directly or through alkyl chain with the imidazolidine nucleus. Recently obtained 2-thioxo-imidazolidin-4-one derivatives exhibit promising antibacterial, antifungal, anticancer, anti-inflammatory and many more biological activities. This review shows current tendency in the 2-thioxo-imidazolidin-4-one synthesis and reveals the 2-thioxo-imidazolidin-4-one core to be potent pharmacophoric moiety.

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