Synthesis and structure-activity relationship of rhodomyrtone derivatives as antibacterial agent

To study structure-activity relationship of rhodomyrtone against Gram-positive bacteria,structural modification of rhodo-myrtone was carried out to afford its 10 analogues.All compounds were assayed for their antibacterial potency using broth microdilution method.The results indicated that rhodomyrtone exhibited higher antibacterial activity against all Gram-positive bacteria than its analogues,with the exception of rhodomyrtone 6,8-diacetate(3) and oxime analogues 6 and 7 which demonstrated similar activity as the parent compound against Bacillus subtilis and Staphylococcus epidermidis with minimum inhibitory concentration and minimum bactericidal concentration ranged from 1 to 4μg/mL and 2 to 4μg/mL,respectively.In contrast,all analogues displayed no activity against Acinetobacter baumannii.Hydroxyl and ketone groups of rhodomyrtone were elucidated to be essential for the antibacterial property.     

Synthesis of ureidomuraymycidine derivatives for structure-activity relationship studies of muraymycins

One of the key constituents of the muraymycins is the 6-membered cyclic guanidine, (2S,3S)-muraymycidine (or epi-capreomycidine). In order to diversify the structure of the oligopeptide moiety of the muraymycins for thorough structure-activity relationship studies, we have developed a highly stereoselective synthesis of ureidomuraymycidine derivatives with the lactone 4a.     

新型血管紧张素转化酶抑制剂: 氮杂三肽类似物的合成及结构活性关系

设计与合成一系列氮杂三肽类似物, 测定了氮杂三肽类似物对血管紧张素转化酶的体外抑制活性, 探讨了它们的结构与抑制活性之间的关系, 结果表明氮杂丙氨酸是丙氨酸很好的替代物。     

Three-dimensional quantitative structure-activity relationship (3D QSAR) and pharmacophore elucidation of tetrahydropyran derivatives as serotonin and norepinephrine transporter inhibitors

Three-dimensional quantitative structure-activity relationship (3D QSAR) using comparative molecular field analysis (CoMFA) was performed on a series of substituted tetrahydropyran (THP) derivatives possessing serotonin (SERT) and norepinephrine (NET) transporter inhibitory activities. The study aimed to rationalize the potency of these inhibitors for SERT and NET as well as the observed selectivity differences for NET over SERT. The dataset consisted of 29 molecules, of which 23 molecules were used as the training set for deriving CoMFA models for SERT and NET uptake inhibitory activities. Superimpositions were performed using atom-based fitting and 3-point pharmacophore-based alignment. Two charge calculation methods, Gasteiger-Hückel and semiempirical PM3, were tried. Both alignment methods were analyzed in terms of their predictive abilities and produced comparable results with high internal and external predictivities. The models obtained using the 3-point pharmacophore-based alignment outperformed the models with atom-based fitting in terms of relevant statistics and interpretability of the generated contour maps. Steric fields dominated electrostatic fields in terms of contribution. The selectivity analysis (NET over SERT), though yielded models with good internal predictivity, showed very poor external test set predictions. The analysis was repeated with 24 molecules after systematically excluding so-called outliers (5 out of 29) from the model derivation process. The resulting CoMFA model using the atom-based fitting exhibited good statistics and was able to explain most of the selectivity (NET over SERT)-discriminating factors. The presence of −OH substituent on the THP ring was found to be one of the most important factors governing the NET selectivity over SERT. Thus, a 4-point NET-selective pharmacophore, after introducing this newly found H-bond donor/acceptor feature in addition to the initial 3-point pharmacophore, was proposed.     

CoMFA and CoMSIA 3D-quantitative structure-activity relationship model on benzodiazepine derivatives, inhibitors of phosphodiesterase IV

Recently, we reported structurally novel PDE4 inhibitors based on 1,4-benzodiazepine derivatives. The main interest in developing bezodiazepine-based PDE4 inhibitors is in their lack of adverse effects of emesis with respect to rolipram-like compounds. A large effort has thus been made toward the structural optimization of this series. In the absence of structural information on the inhibitor binding mode into the PDE4 active site, 2D-QSAR (H-QSAR) and two 3D-QSAR (CoMFA and CoMSIA) methods were applied to improve our understanding of the molecular mechanism controlling the PDE4 affinity of the benzodiazepine derivatives. As expected, the CoMSIA 3D contour maps have provided more information on the benzodiazepine interaction mode with the PDE4 active site whereas CoMFA has built the best tool for activity prediction. The 2D pharmacophoric model derived from CoMSIA fields is consistent with the crystal structure of the PDE4 active site reported recently. The combination of the 2D and 3D-QSAR models was used not only to predict new compounds from the structural optimization process, but also to screen a large library of bezodiazepine derivatives.     

Synthesis of potent beta-secretase inhibitors containing a hydroxyethylamine dipeptide isostere and their structure-activity relationship studies

Several beta-secretase inhibitors were designed based on hydroxyethylamine dipeptide isostere (HDI) structures and were synthesized by a methodology using the aza-Payne rearragement and O,N-acyl transfer reactions to study their structure-activity relationships. Among these pseudopeptides, effective compounds were developed as the first beta-secretase inhibitors containing the HDI transition state mimic with potent enzyme inhibitory activity (IC50 < 100 nM).     

Three-dimensional quantitative structure-activity relationship of 4,5,6,7-tetrahydrothienopyridines analogues as glucose-6-phosphatase inhibitors

A Three-Dimensional Quantitative Structure-activity Relationship (3D-QSAR) model that correlates the biological activities with the chemical structures of a series of Glucose-6-phosphatase inhibitors, exemplified by the 4,5,6,7-tetrahydrothienopyridines derivatives, was established by means of comparative molecular field analysis (CoMFA). The resulting leave-one-out cross-validated value (q²=0.600) and non-cross-validated value (r²=0.956) indicate that the obtained pharmacophore model indeed mimics the steric and electrostatic environment, where inhibitors bind to the enzyme. Furthermore, the developed model also possesses promising predictive ability as discerned by the testing on the external test set. The analysis of the CoMFA contour map, which reveal how steric and electrostatic interactions contribute to inhibitors' bioactivities, provide us with the important information to understand the molecular nature of inhibitor-enzyme interactions and to aid in the design of more potent Glucose-6-phosphatase inhibitors.     

Synthesis,evaluation and docking studies of some 4-thiazolone derivatives as effective lipoxygenase inhibitors

Some promising 4-thiazolone derivatives as lipoxygenase inhibitors were designed, synthesized, characterized and evaluated for anti-inflammatory activity and respective ulcerogenic liabilities. Compounds (1b, 1e, 3b, and 3e) exhibited considerable in vivo anti-inflammatory activity (57.61, 79.35, 75.00, and 79.35%) against carrageenan-induced rat paw edema model, whereas compounds (1e, 3b, and 3e) were found active against the arachidonic acid-induced paw edema model (55.38, 55.38, and 58.46%). The most potent compound (3e) exhibited lesser ulcerogenic liability compared to the standard diclofenac and zileuton. Further, the promising compounds (1e and 3e) were evaluated for in vitro lipoxygenase (LOX; IC₅₀?=?12.98 µM and IC₅₀?=?12.67 µM) and cyclooxygenase (COX) inhibition assay (COX-1; IC₅₀?>?50 µM and, COX-2; IC₅₀?>?50 µM). The enzyme kinetics of compound 3e was evaluated against LOX enzyme and supported by in silico molecular docking and molecular dynamics simulations studies. Overall, the results substantiated that 5-benzylidene-2-phenyl-4-thiazolones are promising pharmacophore for anti-inflammatory activity.     

Synthesis and biological evaluation of triazepane derivatives as DPP-IV inhibitors

A series of triazepane derivatives such as (R)-3-amino-1-(1,2,5-triazepan-1-yl)-4-(2,4,5-trifluorophenyl)butan-1-ones (7, 13a-p) and (R)-3-amino-1-(1,2,5-triazepan-5-yl)-4-(2,4,5-trifluorophenyl)butan-1-ones (17a-e) was synthesized and evaluated for their ability to inhibit dipeptidyl peptidase IV (DPP-IV) enzyme. Compounds with the acid moiety were found to be potent inhibitors of DPP-IV without inhibiting CYP 3A4. Among them, compound 13p ((R)-4-[1-acetyl-2-{3-amino-4-(2,4,5-trifluorophenyl)butanoyl-1,2,5-triazepan-5-carbonyl}benzoic acid]) showed a good in vitro activity without inhibiting CYP.     

Synthesis and biological evaluation of thiophene derivatives as acetylcholinesterase inhibitors

A series of new thiophene derivatives has been synthesized using the Gewald protocol. The acetylcholinesterase inhibition activity was assayed according to Ellman's method using donepezil as reference. Some of the compounds were found to be more potent inhibitors than the reference. 2-(2-(4-(4-Methoxyphenyl)piperazin-1-yl)acetamido)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide (IIId) showed 60% inhibition, compared to only 40% inhibition by donepezil.     

Synthesis of 2-quinolinecarboxamide derivatives as potential HDAC inhibitors

Inhibition of histone deacetylase activity appears as an original and effective approach for the treatment of cancer. A series of novel quinoline-containing derivatives has been synthesized and found that some of these compounds possess nanomolar histone deacetylase inhibitory activity.     

Synthesis of 3-aminorhodanine derivatives as aldose reductase inhibitors

A number of 5-condensated 3-acylaminorhodanines 3 was prepared as potential inhibitors of the aldose reductase by acylation of the amino group of 3-aminorhodanine 1 and subsequent condensation of the 5-methylene function with appropriate aldehydes. Some of these compounds displayed interesting activity.     

Synthesis and structure-activity relationships of o-sulfonamido-arylhydrazides as inhibitors of LL-diaminopimelate aminotransferase (LL-DAP-AT)

Recently, LL-diaminopimelate aminotransferase (LL-DAP-AT), a pyridoxal-5'-phosphate (PLP)-dependent enzyme, was reported to catalyze a key step in the biosynthesis of L-lysine in plants and Chlamydia. Previous screening of a 29,201-compound library against LL-DAP-AT identified an o-sulfonamidoarylhydrazide as a reversible inhibitor with IC(50)～ 5 μM. Structure-activity relationship (SAR) studies based on this lead compound identified key structural features essential for enzyme inhibition and led to slightly improved inhibitors. Preliminary studies on the mode of inhibition of LL-DAP-AT by this class of compounds are also reported.     

Synthesis and structure-activity relationship study of isoglobotrihexosylceramide analogues

Invariant natural killer T (iNKT) cells are innate T lymphocytes that express T cell receptors binding to exogenous and endogenous glycosphingolpid antigens presented by a nonpolymorphic, non-MHC antigen presenting molecule, CD1d. The endogenous glycosphingolipid metabolite, isoglobotrihexosylceramide (iGb3), is the first known natural ligand for both human and mouse iNKT cells, whose activity has been confirmed in a variety of iNKT cell clones generated by different investigators, representing the majority of the iNKT cell population. The signaling pathway mediated by T cell receptor is largely influenced by the structural variation of glycosphingolpid antigens, leading to multiple and varied biological functions of iNKT cells. In order to investigate the structural requirements behind iGb3 triggered iNKT cell activation, the structure-activity relationship (SAR) of iGb3 needs to be characterized. In this study, iGb3 analogues containing 2' ', 3' ', 4' ' and 6' ' deoxy terminal galactose were synthesized for probing the SAR between iGb3 and TCR. The biological assays on the synthetic iGb3 analogues were performed with use of the murine iNKT cell hybridoma DN32.D3. The results showed that the 2' ' and 3' ' hydroxyl groups of terminal galactose play more important roles for the recognition of iGb3 by TCR; while 4' ' and 6' ' hydroxyl groups were not as crucial for this recognition. These studies might help to understand the general structural requirements for natural endogenous ligands recognized by iNKT cells.