Multicomponent reactions in crop protection chemistry

An overview is given of the significance of multicomponent reactions in the synthesis of agrochemicals. The most important applications of multicomponent condensations, such as the Biginelli reaction, Bucherer-Bergs reaction, Hantzsch dihydropyridine synthesis, Kabachnik-Fields reaction, Mannich reaction, Passerini reaction, Petasis reaction, Strecker reaction, Ugi reaction and Willgerodt-Kindler reaction, to the synthesis of herbicidally, fungicidally and insecticidally active compounds are presented. Also the mode of action and biological activity of these multicomponent reaction products are reported.     

Antibiotics and the search for new principles

Originally presented as an Invited Lecture at the 1990 Society for Industrial Microbiology Annual Meeting in Orlando, Florida.     

The evolution of multicomponent mimicry

The relative sizes of phenotypic mutations contributing to evolutionary change has long been the subject of debate. We describe how mimicry research can shed light on this debate, and frame mimicry studies within the general context of macromutationism and micromutationism, and punctuated versus gradual evolution. Balogh and Leimar [Müllerian mimicry: an examination of Fisher's theory of gradual evolutionary change. Proc. Roy. Soc. Lond. B Biol. Sci. 272, 2269-2275] have recently used a model to readdress the question of whether or not mimicry evolves gradually along a single dimension. We extend their approach, and present the first model to consider the effect of predator generalization along multiple components on the evolution of mimicry. We find that the gradual evolution of mimicry becomes increasingly less likely as the number of signal components increases, unless predators generalize widely over all components. However, we show that the contemporary two-step hypothesis (punctuated evolution followed by gradual refinement) can explain the evolution of Müllerian mimicry under all tested conditions. Thus, although the gradual evolution of mimicry is possible, the two-step hypothesis appears more generally applicable.     

Isocyanide-based multicomponent reactions in drug discovery

This review describes recent advances in the application of isocyanide-based multicomponent reactions (IMCRs) in drug discovery and summarizes the various chemotypes used to probe biological targets. In the past couple of years, IMCR-derived ligands have been used to develop agents against infectious diseases and to interfere with protein-protein interactions. Additionally, they were active against a variety of targets such as enzymes, GPCRs and ion channels. The rational for the chemical biologist to apply such diversity generating chemistries is also discussed.     

分枝杆菌核糖体的制备与初步结构研究

核糖体是抗生素的主要靶点,而获得足量高纯度的核糖体是进行结构和药物研究的基础。结核分枝杆菌壁厚且生长缓慢,制备足量高纯度的核糖体具有挑战性。本研究改进并优化了核糖体纯化制备方法,通过大量培养和安全处理致病菌,应用高效破碎厚壁革兰阳性菌的技术,结合传统的蔗糖密度离心分离和蛋白液相色谱纯化技术,经多步纯化和分离,获得了高纯度和较高产率的耻垢分枝杆菌与结核分枝杆菌的核糖体样品,为后续生化实验和结构生物学研究提供了保证。该分枝杆菌核糖体制备方法也可应用于其他革兰阳性致病菌复合物样品的直接提纯,以及复合物特异性的进一步研究,特别是利用晶体学与冷冻电镜结合的高精度复合物结构研究,有助于揭示细菌耐药性机制及用于新型抗生素的研发。     

Prediction of adsorption from multicomponent solutions by activated carbon using single-solute parameters

The adsorption of 3 barbiturates—phenobarbital, mephobarbital, and primidone—from simulated intestinal fluid (SIF), without pancreatin, by activated carbon was studied using the rotating bottle method. The concentrations of each drug remaining in solution at equilibrium were determined with the aid of a high-performance liquid chromatography (HPLC) system employing a reversed-phase column. The competitive Langmuir-like model, the modified competitive Langmuir-like model, and the LeVan-Vermeulen model were each fit to the data. Excellent agreement was obtained between the experimental and predicted data using the modified competitive Langmuir-like model and the LeVan-Vermeulen model. The agreement obtained from the original competitive Langmuir-like model was less satisfactory. These observations are not surprising because the competitive Langmuir-like model assumes that the capacities of the adsorbates are equal, while the other 2 models take into account the differences in the capacities of the components. The results of these studies indicate that the adsorbates employed are competing for the same binding sites on the activated carbon surface. The results also demonstrate that it is possible to accurately predict multicomponent adsorption isotherms using only single-solute isotherm parameters. Such prediction is likely to be useful for improving in vivo/in vitro correlations.     

Towards a quantitative rationalization of multicomponent glass properties by means of molecular dynamics simulations

This review summarizes the achievements obtained by making use of molecular dynamics (MD) simulations in the elucidation of the structure of multicomponent glasses exerting bioactive properties. Emphasis on critical aspects of MD simulations for oxide glasses treatment is given. The potentiality of the quantitative structure–property relationships (QSPR) analysis as a tool for interpretative and predictive purposes is highlighted.     

水稻多组分双向反射模型的研究

利用1999-2000年的水稻田间试验实测光谱数据,对水稻不同生长期特性建立的水稻多组分双向反向模型进行了一些主要因子的敏感性分析及模型模拟值与实测值的比较分析。结果表明,考虑水稻冠层叶、茎干、穗等作用及水稻不同生长期特点的水稻多组分双向反向模型,能较好地反映水稻多组分反向光谱的角度分布特征,较准确地模拟水稻不同条件下水稻的自然方向反向系数和冠层"热点"效应的非对称性分布。得到了薄层水体和土壤背景的一次反向辐射以及在冠层内部、薄层水体和土壤表面相互间的多次反向辐射随水稻各组分平均倾角的变化规律,冠层双向反向率随叶面积指数LAI的变化特征。     

Trans-translation and protein synthesis inhibitors

Trans-translation is a process found in all bacteria, which contributes to the release of ribosomes that are stalled through a variety of causes, for example when the 3' end of a truncated mRNA lacking a stop codon is reached or at internal clusters of rare codons. Trans-translation requires tmRNA. Trans-translation is not essential for cell viability under laboratory conditions, but recently it has been shown that it can contribute to cell viability in the presence of protein synthesis inhibitors. In this minireview, we consider the connection between trans-translation and antibiotics and the potential of using trans-translation as a therapeutic target.     

Kinetic studies on the reactions of HCl with trans-[MoL(CNPh)(Ph2PCH2CH2PPh2)2] (L=N2, H2 or CO)

The kinetics of the reactions between anhydrous HCl and trans-[MoL(CNPh)(Ph₂PCH₂CH₂PPh₂)₂] (L=CO, N₂ or H₂) have been studied in thf at 25.0 °C. When L=CO, the product is [MoH(CO)(CNPh)(Ph₂PCH₂CH₂PPh₂)₂]⁺, and when L=H₂ or N₂ the product is trans-[MoCl(CNHPh)(Ph₂PCH₂CH₂PPh₂)₂]. Using stopped-flow spectrophotometry reveals that the protonation chemistry of trans-[MoL(CNPh)(Ph₂PCH₂CH₂PPh₂)₂] is complicated. It is proposed that in all cases protonation occurs initially at the nitrogen atom of the isonitrile ligand to form trans-[MoL(CNHPh)(Ph₂PCH₂CH₂PPh₂)₂]⁺. Only when L=N₂ is this single protonation sufficient to labilise L to dissociation, and subsequent binding of Cl⁻ gives trans-[MoCl(CNHPh)(Ph₂PCH₂CH₂PPh₂)₂]. At high concentrations of HCl a second protonation occurs which inhibits the substitution. It is proposed that this second proton binds to the dinitrogen ligand. When L=CO or H₂, a second protonation is also observed but in these cases the second protonation is proposed to occur at the carbon atom of the aminocarbyne ligand, generating trans-[MoL(CHNHPh)(Ph₂PCH₂CH₂PPh₂)₂]²⁺. Addition of the second proton labilises the trans-H₂ to dissociation, and subsequent rapid binding of Cl⁻ and dissociation of a proton yields the product trans-[MoCl(CNHPh)(Ph₂PCH₂CH₂PPh₂)₂]. Dissociation of L=CO does not occur from trans-[Mo(CO)(CHNHPh)(Ph₂PCH₂CH₂PPh₂)₂]²⁺, but rather migration of the proton from carbon to molybdenum, and dissociation of the other proton produces [MoH(CO)(CNPh)(Ph₂PCH₂CH₂PPh₂)₂]⁺.     

A multicomponent approach in the discovery of indoleamine 2,3-dioxygenase 1 inhibitors: Synthesis,biological investigation and docking studies

Indoleamine 2,3-dioxygenase plays a crucial role in immune tolerance and has emerged as an attractive target for cancer immunotherapy. In this study, the Passerini and Ugi multicomponent reactions have been employed to assemble a small library of imidazothiazoles that target IDO1. While the p-bromophenyl and the imidazothiazole moieties have been kept fixed, a full SAR study has been performed on the side-chain, leading to the discovery of nine compounds with sub-micromolar IC₅₀ values in the enzyme-based assay. Compound 7d, displaying a α-acyloxyamide substructure, is the most potent compound, with an IC₅₀ value of 0.20?µM, but a low activity in a cell-based assay. Compound 6o, containing a α-acylaminoamide moiety, shows an IC₅₀ value of 0.81?µM in the IDO1-based assay, a full biocompatibility at 10?µM, together with a modest inhibitory activity in A375 cells. Molecular docking studies show that both 7d and 6o display a unique binding mode in the IDO1 active site, with the side-chain protruding in an additional pocket C, where a crucial hydrogen bond is formed with Lys238. Overall, this work describes an isocyanide based-multicomponent approach as a straightforward and versatile tool to rapidly access IDO1 inhibitors, providing a new direction for their future design and development.     

In search of new α-glucosidase inhibitors: Imidazolylpyrazole derivatives

Under three different reaction conditions (conventional heating, microwave irradiations and amino acid catalysis), a series of imidazolylpyrazoles (2a-2k) were synthesized in good to excellent yields from a mixture of three precursors: aryl(hetaryl)pyrazole-4-carbaldehydes (1a-1k), benzil and ammonium acetate. α-Glucosidase inhibition assay revealed a new class of highly potent agents wherein each compound displayed significant inhibitory potentials (in terms of percentage inhibition and relative IC₅₀ values) as compared to that of the reference drug (Acarbose). Moreover, molecular modelling of most potent compounds 2h, 2j and 2k also helped in understanding the structure and activity relationship.     

Click chemistry based multicomponent approach in the synthesis of spirochromenocarbazole tethered 1,2,3-triazoles as potential anticancer agents

A series of spirochromenocarbazole tethered 1,2,3-triazoles were synthesized via click chemistry based one-pot, five component reaction between N-propargyl isatins, malononitrile, 4-hydroxycarbazole, aralkyl halides and sodium azide using cellulose supported CuI nanoparticles (Cell-CuI NPs) as the heterogeneous catalyst. Antiproliferative activity of all the synthesized compounds was investigated against panel of cancer cell lines such as MCF-7, MDA-MB-231, HeLa, PANC-1, A-549, and THP-1. Many of the synthesized compounds exhibited good anti-proliferative activity against breast (MCF-7 and MDA-MB-231) and cervical (HeLa) cancer cells with IC₅₀ values less than 10 μM. In case of MCF-7 cells, among the nine compounds that showed good anti-proliferative activity, compounds 6f and 6j were found to be highly potent (IC₅₀ = 2.13 μM and 4.80 μM, respectively). In case of MDA-MB-231, three compounds (6k, 6j and 6s) showed antiproliferative activity amongst which 6k was the most potent one (IC₅₀ = 3.78 μM). On the other hand, in cervical cancer HeLa cells, compounds 6b, 6g, 6s and 6u showed excellent antiproliferative activity (IC₅₀ = 4.05, 3.54, 3.83, 3.35 μM, respectively). All the compounds were found to be nontoxic to the human umbilical vein endothelial cells (HUVECs). AO and EtBr staining and fluorescence microscopy studies of the active compounds (IC₅₀ < 5 μM) suggested that these compounds induce cell death by apoptosis.     

Synthesis and evaluation of iminocoumaryl and coumaryl derivatized glycosides as galectin antagonists

A collection of iminocoumarylmethyl glycoside derivatives have been prepared by copper-catalyzed multi-component reaction of carbohydrate propargyl derivatives, sulfonyl azides, and salicylaldehyde or o-hydroxy acetophenone. The method is simple, versatile to all three components, and exceptionally high yielding. The carbohydrate N-sulfonyl iminocoumarine hybrid molecules were evaluated for binding galectin-1, -2, -3, -4 N, -4C, -7, -8 N, -9 N, and 9C using a competitive fluorescence polarization assay. Selective compounds were identified against galectin-3, 7, 8 N, and 9 N with up to 40-fold affinity enhancements relative to methyl α-d-galactopyranoside due to the coumarylmethyl moieties.     

Design,synthesis and evaluation of novel pyrazolo-pyrimido[4,5-d]pyrimidine derivatives as potent antibacterial and biofilm inhibitors

An efficient four-component reaction of 6-amino-1,3-dimethyluracil, N,N-dimethylformamide dimethylacetal, 1-phenyl-3-(4-substituted-phenyl)-4-formyl-1H-pyrazoles and aromatic amines was conducted in the presence of [Bmim]FeCl₄ ionic liquid as a promoting medium. This strategy provided a convenient route without any additional catalyst or metal salt under mild conditions. All the synthesized pyrazolo-pyrimido[4,5-d]pyrimidines derivatives were evaluated for their antibacterial, minimum bactericidal concentration (MBC), biofilm inhibition, intracellular ROS accumulation and protein leakage activities. The results revealed that among all the screened derivatives, the compounds 5c, 5i, 5l and 5m were quite promising with MIC values ranging between 3.9 and 15.6 μg/mL, while the MBC values were 2-fold the antibacterial activity values. The biofilm inhibition activity revealed that the compounds 5l and 5 m exhibited promising activity with IC₅₀ values ranging between 1.8 and 8.2 μg/mL. It was observed that at a concentration of 0.5 μg/mL, the compound 5l treated biofilms of Micrococcus luteus showed increased levels of intracellular ROS accumulation. Further, the protein leakage study revealed that the Micrococcus luteus cells treated with compound 5l caused membrane permeability which resulted in protein leakage and subsequent bacterial cell death.     

Chemiluminescent reactions in the Belousov-Zhabotinskii oscillating system

Chemiluminescence (CL) occurs during reactions of several of the components of the CH₂ (COOH)₂? KBrO₃? MnSO₄? H₂SO₄ self-sustained system. In contrast to the kinetics determined using potentiometry and spectrophotometry, the CL intensity kinetic curve during the oxidation of manganese (II) ions by acidic bromate has an extremum. Experimental dependences of the maximum CL intensity value on the initial reagent concentrations have been determined and compared with the results of the numerical simulation based on the commonly accepted Noyes-Field-Thompson mechanism.