Organic and Medicinal Chemistry Letters最新文献

Aryl azides were treated with allenylmagnesium bromide to generate 1,5-disubstituted butynyl 1,2,3-triazoles in a domino fashion, which upon Cu(I) catalyzed 1,3-dipolar cycloaddition with aryl azides afforded novel bis-1,2,3-triazoles in quantitative yields. The final products were analyzed for their antimicrobial activities against a panel of bacterial and fungal strains which revealed the products to be potent antimicrobials.

Background: The classical Paal-Knorr reaction is one of the simplest and most economical methods for the synthesis of biologically important and pharmacologically useful pyrrole derivatives.

Results: Polystyrenesulfonate-catalyzed simple synthesis of substituted pyrroles following Paal-Knorr reaction has been accomplished with an excellent yield in aqueous solution. This method also produces pyrroles with multicyclic polyaromatic amines.

Conclusions: The present procedure for the synthesis of N-polyaromatic substituted pyrroles will find application in the synthesis of potent biologically active molecules.

Annulated benzothiazoloquinazolines have been synthesized by a diversity oriented simple and convenient synthesis involving one-pot three-component reaction of substituted 2-aminobenzothiazoles with α-tetralone and aromatic/heteroaromatic aldehydes in ethanol in the presence of catalytic amount of triethylamine. The synthesized compounds have been characterized by their elemental analyses and spectral data.

Background: Substituted 1,3,4-oxadiazoles are of considerable pharmaceutical interest. 2,5-Substituted diphenyl-1,3,4-oxadiazoles are associated with diverse biological activities by the virtue of -N = C-O- grouping. In the view of wide range of biological properties associated with 1,3,4-oxadiazole, we have synthesized substituted derivatives of 1,3,4-oxadiazole (XIII-XXII), a versatile hydrophobic molecule possessing preliminary CNS properties, with the hope to potentiate the biological activities with lesser or limited amount of toxicities.

Method: The synthesis was based on ester substitution of substituted benzohydrazide in presence of hydrazine hydrate followed by cyclization in presence of phosphorus oxychloride. All the synthesized compounds were evaluated for their potential CNS depressant activities. Statistical analysis of the anticonvulsant, antidepressant, and antianxiety activity of the synthesized compounds on animals was evaluated using one-way analysis of variance (ANOVA).

Results: Two compounds 5-(4-nitrophenyl)-2-(4-chlorophenyl)-1,3,4-oxadiazole (XIV) and 5-(4-nitrophenyl)-2-(4-nitrophenyl)-1,3,4-oxadiazole (XV) were found to be the most promising compounds of the series in antidepressant, anticonvulsant and antianxiety activity with no neurotoxicity when compared with standard.

Conclusions: Among the synthesized compounds, it was found that incorporation of electron withdrawing group at C2 and C5 position of the oxadiazole ring led to high degree of pharmacological activity. Thus compounds 5-(4-nitrophenyl)-2-(4-chlorophenyl)-1,3,4-oxadiazole (XIV) and 5-(4-nitrophenyl)-2-(4-nitrophenyl)-1,3,4-oxadiazole (XV) showed excellent CNS depressant activities. The result of the present investigation may encourage us to develop and/or improve similar other related compounds and it may be assumed that further modifications may produce compounds of better activity with lesser side effects.

Background: AT1 receptor antagonists are clinically effective drugs for the treatment of hypertension, cardiovascular, and related disorders. In an attempt to identify new AT1 receptor antagonists, a pharmacophore-based virtual screening protocol was applied. The pharmacophore models were generated from 30 training set compounds. The best model was chosen on the basis of squared correlation coefficient of training set and internal test set. The validity of the developed model was also ensured using catScramble validation method and external test set prediction.

Results: The final model highlighted the importance of hydrogen bond acceptor, hydrophobic aliphatic, hydrophobic, and ring aromatic features. The model satisfied all the statistical criteria such as cost function analysis and correlation coefficient. The result of estimated activity for internal and external test set compounds reveals that the generated model has high prediction capability. The validated pharmacophore model was further used for mining of 56000 compound database (MiniMaybridge). Total 141 hits were obtained and all the hits were checked for druggability, this led to the identification of two active druggable AT1 receptor antagonists with diverse structure.

Conclusion: A highly validated pharmacophore model generated in this study identified two novel druggable AT1 receptor antagonists. The developed model can also be further used for mining of other virtual database.

The chemical constituents and biological activities of the terrestrial Aspergillus flavipes MM2 isolated from Egyptian rice hulls are reported. Seven bioactive compounds were obtained, of which one sterol: ergosterol (1), four butyrolactones: butyrolactone I (2), aspulvinone H (3), butyrolactone-V (6) and 4,4'-diydroxypulvinone (7), along with 6-methylsalicylic acid (4) and the cyclopentenone analogue; terrien (5). Structures of the isolated compounds were deduced by intensive studies of their 1D & 2D NMR, MS data and comparison with related structures. The strain extract and the isolated compounds (1-7) were biologically studied against number of microbial strains, and brine shrimp for cytotoxicity. In this article, the taxonomical characterization of A. flavipes MM2 along with its upscale fermentation, isolation and structural assignment of the obtained bioactive metabolites, and evaluate their antimicrobial and cytotoxic activities were described.

Eight bioactive pyrone derivatives were identified from the culture of Alternaria alternata strain D2006, isolated from the marine soft coral Denderonephthya hemprichi, which was selected as its profound antimicrobial activities. The compounds were assigned as pyrophen (1), rubrofusarin B (2), fonsecin (3), and fonsecin B (5) beside to the four dimeric naphtho-γ-pyrones; aurasperone A (6), aurasperone B (7), aurasperone C (8), and aurasperone F (9). Structures of the isolated compounds were identified on the basis of 1D and 2D NMR spectroscopy and mass (EI, ESI, HRESI) data, and by comparison with the literature. Configuration of the four dimeric naphtho-γ-pyrones 6-9 was analyzed by CD spectra, exhibiting an identical stereochemistry.

Background: We have identified a series of compounds that inhibit protein synthesis in bacteria. Initial IC50's in aminoacylation/translation (A/T) assays ranged from 3 to14 μM. This series of compounds are variations on a 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-ol scaffold (e.g., 4H-pyridopyrimidine).

Methods: Greater than 80 analogs were prepared to investigate the structure-activity relationship (SAR). Structural modifications included changes in the central ring and substituent modifications in its periphery focusing on the 2- and 6-positions. An A/T system was used to determine IC50 values for activity of the analogs in biochemical assays. Minimum inhibitory concentrations (MIC) were determined for each analog against cultures of Enterococcus faecalis, Moraxella catarrhalis, Haemophilus influenzae, Streptococcus pneumoniae, Staphylococcus aureus, Escherichia coli tolC mutants and E. coli modified with PMBN.

Results: Modifications to the 2-(pyridin-2-yl) ring resulted in complete inactivation of the compounds. However, certain modifications at the 6-position resulted in increased antimicrobial potency. The optimized compounds inhibited the growth of E. faecalis, M. catarrhalis, H. influenzae, S. pneumoniae, S. aureus, E. coli tolC, mutants and E. coli modified with PMBN with MIC values of 4, ≤ 0.12, 1, 2, 4, 1, 1 μg/ml, respectively. IC50 values in biochemical assay were reduced to mid-nanomolar range.

Conclusion: 4H-pyridopyrimidine analogs demonstrate broad-spectrum inhibition of bacterial growth and modification of the compounds establishes SAR.

Background: Adverse antimicrobial activities of thiosemicarbazone (TSC) and Schiff base derivatives have widely been studied by using different kinds of microbes, in addition different methods were used to assay the antioxidant activities using DPPH, peroxids, or ntrosyl methods. However, there are no studies describing the synthesis of TSC derived from creatinine.

Results: In this study, 2-(2-imino-1-methylimidazolidin-4-ylidene)hydrazinecarbothioamide (IMHC) was synthesized by the reaction of creatinine with thiosemicarbazide. The novel molecule was characterized by FT-IR, UV-VIS, and NMR spectra in addition of the elemental analysis. The free radical scavenging ability of the IMHC was determined by it interaction with the stable-free radical 2,2"-diphenyl-1-picrylhydrazyl (or nitric oxide or hydrogen peroxide) and showed encouraging antioxidant activities. Density functional theory calculations of the IMHC performed using molecular structures with optimized geometries. Molecular orbital calculations provide a detailed description of the orbitals, including spatial characteristics, nodal patterns, and the contributions of individual atoms. Highest occupied molecular orbital-lowest unoccupied molecular orbital energies and structures are shown.

Conclusions: IMHC shows considerable antibacterial and antifungal activities. The free radical scavenging activity of synthesized compound was screened for in vitro antioxidant activity.

Background: Herpes simplex virus type-1 (HSV-1) is the primary cause of facial lesions (mouth, lips, and eyes) in humans. The widespread use of acyclovir and nucleoside analogues has led to emergence of HSV strains that are resistant to these drugs. Recently, non-nucleoside anti-HSV compounds have received considerable attention. 1,6-Naphthyridines are a class of heterocyclic compounds that exhibit a broad spectrum of biological activities such as inhibitor of HIV-1 integrase, HCMV, FGF receptor-1 tyrosine kinase, and the enzyme acetylcholinesterase. We previously reported the synthesis, SAR studies, and evaluation anti-HSV-1 activity of 3H-benzo[b]pyrazolo[3,4-h]-1,6-naphthyridines. In the course of our search for new 1,6-naphthyridines derivatives with potential activity against HSV-1, we have synthesized and evaluated new 3H-benzo[b]pyrazolo[3,4-h]-1,6-naphthyridines (1a-k) and 3H-pyrido[2,3-b]pyrazolo[3,4-h]-1,6-naphthyridines (2a-c).

Results: A known synthetic approach was used for preparing new 3H-benzo[b]pyrazolo[3,4-h]-1,6-naphthyridines (1a-k) and 3H-pyrido[2,3-b]pyrazolo[3,4-h]-1,6-naphthyridines (2a-c), starting from ethyl 4-chloro-1-phenyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate (7). All compounds were identified by FTIR, 1H NMR, and mass spectrometry. The antiviral effect on HSV-1 virus replication was determined.

Conclusions: The compounds 1d, 1f, 1g, and 1h exhibited the highest anti-HSV-1 activity. In general, 3H-benzo[b]pyrazolo[3,4-h]-1,6-naphthyridines were more effective inhibitors than their corresponding 3H-pyrido[2,3-b]pyrazolo[3,4-h]-1,6-naphthyridines. The compound 1h reduced the virus yield in 91% at 50 μM and exhibited a low cytotoxicity (CC50 600 μM).