Uncovering One-Dimensional Reaction Coordinate that Underlies Structure-Function Relationship of Proteins

Understanding the mechanism of functional protein dynamics is critical to understanding protein functions. Reaction coordinates is a central topic in protein dynamics and the grail is to find the one-dimensional reaction coordinate that can fully determine the value of committor (i.e. the reaction probability in configuration space) for any protein configuration. We present a powerful new method that can, for the first time, identify the rigorous one-dimensional reaction coordinate in complex molecules. This one-dimensional reaction coordinate is determined by a fundamental mechanical operator--the generalized work functional. This method only requires modest computational cost and can be readily applied to large molecules. Most importantly, the generalized work functional is the physical origin of the collectivity in functional protein dynamics and provides a tentative roadmap that connects the structure of a protein to its function.

6’-Amino-5,7-Dibromo-2-Oxo-3’-(Trifluoromethyl)-1’H-Spiro[Indoline-3,4’-Pyrano[2,3-c]Pyrazole]-5’-Carbonitrile

The multicomponent reactions are environmentally benign synthetic methods of building-up of complex molecules and several levels of structural diversity for diverse applications. Spirooxindoles are an important synthetic target possessing extended biological activity and drug discovery applications. In this communication, the multicomponent transformation of 5,7-dibromoisatin, malononitrile, and 5-(trifluoromethyl)-2,4-dihydro-3H-pyrazol-3-one in EtOH at reflux in the presence of sodium acetate was carefully investigated to give 6’-amino-5,7-dibromo-2-oxo-3’-(trifluoromethyl)-1’H-spiro[indoline-3,4’-pyrano[2,3-c]pyrazole]-5’-carbonitrile in excellent yield. The structure of the new compound was established by means of elemental analysis, mass and nuclear magnetic resonance, and infrared spectroscopy.

Unsymmetrical Growth Synthesis of Nontraditional Dendrimers

Developing highly complex molecules is of great significance in science and technology. Here we present an unprecedented type of dendrimer assembled from linear ABB-type monomer. The construction of this nontraditional ramified architecture was facilely achieved through one simple convergent strategy established on the iridium-catalyzed cycloaddition of organic azides with internal 1-thioalkynes (IrAAC). By virtue of the unsymmetrically growing fashion in this process, diverse functional groups could be conveniently distributed on both of its exterior and interior layers. Syntheses of two dendrons from the cooperation of one linear alkyne motif with different azides were presented to demonstrate the efficiency and fidelity of this protocol. Post-modifications on their core or periphery were further conducted, resulting in diverse newly functionalized dendrimers with up to ~16.0 kDa molecular weight. The identity and purity of these unsymmetrical dendritic macromolecules were well confirmed by 1H NMR, MS and SEC analysis.

Green Multi-Component Synthesis of Fused heterocyclic derivatives: An atom economic ecofriendly approach for complex molecules

Background: The construction of fused heterocyclic compounds is always fascinating on the strength of their applications as novel pharmaceuticals. Multi-component reactions (MCRs) are atom economical, beneficial, straightforward and ecofriendly approach for synthesis of complex heterocycles in a single step with higher selectivity. Methods: The review mainly focused on the synthesis of fused heterocycles such as pyrimidine - chromene, Pyrrolo - pyrazine, Pyrazolo - pyrimidine, pyran - imidazole and pyrazole- imidazole - pyrimidine, pyran - pyridmidone, pyrrolo - chromene, pyridine-pyrimidinone, fused indole derivatives, furano - pyran along with some simple MCRs discussed, which published in in the period of 2019 and 2020. A table of summary about 50 heterocycles with product, catalysts and cited literature for are given at end. Conclusions: From this review we understand that MCRs can deliver an effortless access to molecular targets of our interest with wide choice of reactants and their combinations. Thus, the creativity and choice of reactants are pushing the development in MCRs towards more atom economical and eco-friendly approach Objective: Understanding recent trends in the development of MCRs is a requisite for anyone, who wish to synthesise simple and fused heterocycles. By keeping this as primary objective, the present review provides an overview of latest developments in fused heterocyclic synthesis via green multicomponent reactions in the period of 2019 and 2020.

Transaminase Catalysis for Enantiopure Saturated Heterocycles as Potential Drug Scaffolds

As efforts in rational drug design are driving the pharmaceutical industry towards more complex molecules, the synthesis and production of these new drugs can benefit from new reaction routes. In addition to the introduction of new centers of asymmetry, complexity can be also increased by ring saturation, which also provides improved developability measures. Therefore, in this report, our aim was to develop transaminase (TA)-catalyzed asymmetric synthesis of a new group of potential chiral drug scaffolds comprising a saturated amine heterocycle backbone and an asymmetric primary amine sidechain (55a–g). We screened the Codex® Amine Transaminase Kit of 24 transaminases with the morpholine containing ketone 57a, resulting in one (R)-selective TA and three (S)-selective TAs operating at 100 mM substrate concentration and 25 v/v% isopropylamine (IPA) content. The optimized reaction conditions were than applied for asymmetric transamination of further six ketones (57b–g) containing various amine heterocycles, in which a strong effect of the substitution pattern of the γ-position relative to the substituted N-atom could be observed. Mediated by the most enantiotope selective (S)-TAs in scaled-up process, the (S)-amines [(S)-55a–g] were isolated with moderate-to-excellent yields (47–94%) in enantiopure form (>99% ee).

Bioremediation of Cutting Pits by Autochtonous Bacteria-Fungi Consortia

The aim of this work is to verify the potential of a consortium of autochthonous bacteria and fungi, isolated from samples of contaminated soils and water collected in a site containing cutting pits muds, in order to evaluate enhancing in biodegradation of hydrocarbons content. This innovative technique would take advantage of the synergistic effect of bacteria and fungi. In addition, this technique would allow to avoid the introduction of commercial allochthonous microflora for soil remediation and the use of chemical products for tool cleaning. Samples retrieved from a production site were used to isolate bacterial and unicellular fungal species able to grow on hydrocarbons were demonstrated to be able to degrade light and "diesel-like" hydrocarbons under laboratory conditions and in liquid cultures in less than a month. The activity of the consortium was also tested on crude oil, showing an overall degradation of the analyzable fraction greater of sixty percent after a 14-day incubation. Low C number linear hydrocarbons were the preferred substrate, but also cycloalkanes and mono- and di-aromatics seemed to be a good growth substrate. Probably, the action of enzymes secreted by fungal strains could enhance the degradation of complex molecules such as polycyclic aromatic hydrocarbons. Lab tests of consortium efficiency on mud samples are ongoing and an on-site pilot test is foreseen, to prove the activity of the consortium under the challenging field conditions. The development of fungal and bacterial consortia for degradation of complex hydrocarbon mixtures will represent an innovative approach that combines the action of enzymes secreted by fungi followed by the bacterial breakdown, a synergistic effect which could potentially increase the rate and effectiveness of hydrocarbons decontamination.

Pyrrolotriazinone as an Underexplored Scaffold in Drug Discovery

Heterocyclic amino derivatives have been extensively synthesized and validated as potent bioactive compounds, and nowadays, numerous marketed drugs share these scaffolds, from very simple structures (monoamino, monocyclic compounds) to much more complex molecules (polycyclic derivatives with two or more nitrogen atoms within the (fused) rings). In a constant quest for new chemical entities in drug discovery, a few novel heterocycles have emerged in recent years as promising building blocks for the obtainment of bioactive modulators. In this context, pyrrolotriazinones have attracted attention, and some show promising biological activities. Here, we offer an extensive review of pyrrolo[2,1-f][1,2,4]triazin-4(1H)-one and pyrrolo[1,2-d][1,2,4]triazin-4(3H)-one, describing their biological properties en route to drug discovery.

Dichlorido(η6-p-cymene)[tris(4-methoxyphenyl)phosphane]ruthenium(II)

The title compound, [RuCl2(C10H14)(C21H21O3P)], crystallizes with two complex molecules in the asymmetric unit. The RuII atom has a classical three-legged piano-stool environment being coordinated by a cymene ligand [Ru—centroid = 1.707 (2)/1.704 (2) Å], a tris(4-methoxyphenyl)phosphane ligand [Ru—P = 2.3629 (15)/2.3665 (15) Å] and two chloride atoms with the Ru—Cl bonds adopting two distinct values of 2.4068 (16)/2.4167 (16) and 2.4016 (15)/2.4244 (16) Å. The effective cone and solid angles for the phosphane ligands were calculated to be 149.5/150.2° and 25.3/25.6°, respectively. In the crystal, weak C—H...Cl/O/π interactions are observed. The crystal was refined as a two-component twin.