Letters in Drug Design & Discovery - Volume 10, Issue 6, 2013

A set of new nitrogen-containing compounds with adamantane and monoterpene frameworks was synthesized. The antiviral activity of the amine products against the influenza virus A/California/07/09 (H1N1)pdm09 was studied. The introduction of a monoterpenoid fragment led to increase of the antiviral activity of adamantylamine derivatives against adamantylamine resistant virus: the selectivity index of the majority of the synthesized amines was higher than that of rimantadine and amantadine.

Some benzimidazole derivatives bearing hydrazone moiety were synthesized and their in vitro antimicrobial activity was determined against various gram-positive and gram-negative bacteria, and fungi using microbroth dilution method. The structures of all new compounds were identified by¹H-NMR, FT-IR, MS spectroscopic techniques and elemental analysis. Sixteen final products were examined for their in vitro antimicrobial activities. When compared to the reference agents, chloramphenicol and ketoconazole, most of the synthesized compounds showed sufficient antibacterial activity against Pseudomonas aeruginosa and antifungal activity against Candida albicans and C. glabrata.

3-Chlorobenzoic acid hydrazide was reacted with different aryl isothiocyanates to give the corresponding 1-(3- chlorobenzoyl)-4-substituted thiosemicarbazides 1-16. Reaction yields ranged from 74 to 96%. Structures of the synthesized compounds were defined on the basis of ¹H NMR and IR spectra. As it was showed the antibacterial activity of the obtained compounds was limited only towards Gram-positive bacteria. As regards B. cereus ATCC 10876, 1-(3- chlorobenzoyl)-4-(3,5-dichlorophenyl)thiosemicarbazide (8) was 16 times more active than ampicillin and 8 times more active than cefuroxime.

In our early study, a series of anthranilic diamides containing acylthiourea linker (C) was reported to display favorable activities. Based on that research, four series of novel pyridylpyrazole derivatives (D-G) derived from C were designed and synthesized. Totally 24 compounds were synthesized and all the compounds were characterized by melting points, 1H NMR, 13C NMR and HRMS. Bioassay results indicated that compounds 5b, 5c and 6b showed 100 % insecticidal activities against oriental armyworm (Mythimna separata) at 200mg/L. Their fungicidal activities against A. solani, F. graminearum, P. capsici, S. sclerotiorum, B. cinerea and R. solani were evaluated and the results indicated that compounds 7a-g which contained acylguanidine linker showed favourable antibacterial activity against B. cinerea, among which 7d and 7f showed 97.5 % inhibitory activities against B. cinerea at 50mg/L. To further explore the comprehensive structure-activity relationship on the basis of insecticidal activity data, comparative molecular field analysis (CoMFA) was performed, and a statistically reliable model with good predictive power (r2 = 0.972, q2 = 0.604) was achieved.

In this study, 15 new 3(2H)-pyridazinone derivatives carrying N'-(4-substitutedphenylmethylidene)acetohydrazide moiety on lactam nitrogen were synthesized and their chemical structures were confirmed by ¹H-NMR, mass, and elemental analysis. Analgesic and anti-inflammatory activities of the synthesized compounds were evaluated in mice. Among the synthesized compounds, compound 11e exhibited the best analgesic and anti-inflammatory activities, without causing any gastric effect in stomachs of tested animals. Additionally, the synthesized compounds were screened for their antibacterial and antifungal activities against some pathogenic strains.

In this study, Saturation Transfer Difference NMR (STD NMR) was employed for the first time to detect the binding epitopes of new inhibitors of the enzyme urease. Inhibition of urease is recognized as an important approach towards the treatment of ulcer, urolithiasis and related diseases. During the current study, STD-NMR was used as a tool for the identification of structural features responsible for inhibition of urease enzyme at the atomic levels. This approach, combined with mechanism-based biochemical assay, is specially suited for the discovery and optimization of potent inhibitors of enzymes. Urease from Jack beans was used for epitope mapping of inhibitors, i.e. flavonoid glycosides, hypoxanthine and benzodioxane derivatives and STD-NMR results were compared with the results of kinetic studies.

Keeping in view the potential of heterocyclic fused quinazolones and arylidene linked heterocycles , hybrid molecules of these functionalities were designed and synthesised. All the synthesised molecules were characterized by spectroscopic techniques and evaluated for antimicrobial activity against 2 Gram positive bacterial strains; Staphylococcus aureus (MTCC 96) and Bacillus subtilis (MTCC 2451), 3 Gram negative bacterial strains; Escherichia coli (MTCC 82), Pseudomonas aeruginosa (MTCC 2642) and Salmonella typhimurium (MTCC 1251) and 2 fungal strains; Saccharomyces cerevisiae (MTCC 2799) and Candida albicans (MTCC 3018). Among the synthesised molecules, arylidene pyrrolo fused quinazolones displayed significant antimicrobial activity in comparison to arylidene pyrido fused quinazolones. The influence of the electronic factors linked with the arylidene ring was also observed on the antimicrobial potential. Thus the present study highlights the potential of such hybrid molecules as a new class of antimicrobials.

A series of substituted cinnamic acid esters were synthesized and their inhibitory effects on the diphenolase activity of mushroom tyrosinase were evaluated. Compound 8 was found to be the most potent inhibitor with IC50 value of 5.60μM. Preliminary structure activity relationships (SARs) were concluded. The inhibition kinetics analyzed by Lineweaver–Burk plots revealed that compound 8 was anti-competitive inhibitor.

Extensive researches within the last decade have supported the anti-inflammatory properties of curcumin. However, the development and clinical application of curcumin have been limited significantly by its instability and poor metabolic property resulting from the β-diketone moiety decomposition and phenolic glucuronides. In this paper, a curcumin derivative (A50) without β-diketone and phenolic hydroxyl groups was designed and reported. The X-ray diffraction analysis showed a more rigid structure of A50 than that of curcumin. A pharmacokinetic study of A50 in rats indicated that its metabolic parameters were significantly improved compared to those of curcumin. Furthermore, A50 exhibited stronger anti-inflammatory activity than curcumin did via the mechanism, at least partly, associated with inhibiting ERK and JNK phosphorylation in macrophages. These results suggest that the structural modification is both pharmacokinetically and pharmacologically beneficial, and A50 may be a promising anti-inflammatory candidate to treat various inflammatory diseases.

A new series of 5-alkylthio-4-phenyl-2,4-dihydro-3H-1,2,4-triazol-3-one derivatives (4a-w) have been synthesized and tested for their anticonvulsant activity using the maximal electroshock (MES) test. The results indicated that all of the target compounds exhibited anticonvulsant activity in the MES test. Of the compounds tested, compound 4g showed the most potent level of activity with an ED50 value of 38.7 mg/kg, a TD50 value of 633.7 mg/kg, and a superior protective index (PI) value of 16.4, revealing the greater margin of safety of compound 4g versus the standard drug carbamazepine (PI = 6.5). In addition, the potency of compound 4g against seizures induced by pentylenetetrazole in the chemical-induced seizure test was also established.

Curcumin ((1E,6E)-1,7-bis(4-hydroxy-3-methoxyphenyl) hepta-1,6-diene-3,5-dione) is a naturally occurring polyphenol. We have investigated effects of curcumin on human erythrocytes membrane naïve and subjected to in vitro oxidative stress by incubating with tert-butylhydroperoxide (t-BHP). Human erythrocytes have been chosen for the study model due to their being the primary target site for the oxidative stress generated by extracellular as well as intracellular metabolic pathway and substances. Acetylcholinesterase (AChE) in the erythrocytes membrane shows many properties similar to those of brain tissues AChE activity may be considered as central cholinergic status. Results show that curcumin (10^-5 M to 10^-8 M) significantly (p<0.001) protects AChE activity in erythrocyte during oxidative stress. AChE activity in naïve membrane was found to be maximum at 10^-6 M of curcumin. Curcumin at 10^-6 M caused decrease in Km of the enzyme Our results signify the potential protective effect of curcumin on the cholinergic system under conditions of oxidative stress.