Terminal Rings Research Articles

4-Aryl Pyrrolidines as a Novel Class of Orally Efficacious Antimalarial Agents. Part 1: Evaluation of 4-Aryl- N-benzylpyrrolidine-3-carboxamides.

Identification of novel chemotypes with antimalarial efficacy is imperative to combat the rise of Plasmodium species resistant to current antimalarial drugs. We have used a hybrid target-phenotype approach to identify and evaluate novel chemotypes for malaria. In our search for drug-like aspartic protease inhibitors in publicly available phenotypic antimalarial databases, we identified GNF-Pf-4691, a 4-aryl- N-benzylpyrrolidine-3-carboxamide, as having a structure reminiscent of known inhibitors of aspartic proteases. Extensive profiling of the two terminal aryl rings revealed a structure-activity relationship in which relatively few substituents are tolerated at the benzylic position, but the 3-aryl position tolerates a range of hydrophobic groups and some heterocycles. Out of this effort, we identified (+)-54b (CWHM-1008) as a lead compound. 54b has EC50 values of 46 and 21 nM against drug-sensitive Plasmodium falciparum 3D7 and drug-resistant Dd2 strains, respectively. Furthermore, 54b has a long half-life in mice (4.4 h) and is orally efficacious in a mouse model of malaria (qd; ED99 ∼ 30 mg/kg/day). Thus, the 4-aryl- N-benzylpyrrolidine-3-carboxamide chemotype is a promising novel chemotype for malaria drug discovery.

Schiff base/ester liquid crystals with different lateral substituents: mesophase behaviour and DFT calculations

ABSTRACTFour new groups of 4-((2ʹ-substitutedphenylimino)methyl)phenyl-4”-alkoxy benzoates, Ina-d, of Schiff base ester liquid crystals, were prepared and investigated for their mesophase formation and stability. Each group constitutes four homologous series that differ from each other by the lateral attached polar group X in the ortho position for the imine mesogen at terminal benzene ring that alternatively changed from F, Br, NO2 and lateral benzene ring. Within each homologous series, the number (n) of carbons in the alkoxy chain varies between 6, 8, 10 and 12. Molecular structures of the prepared compounds were confirmed via elemental analysis, FT-IR, and 1H NMR spectroscopy. Mesomorphic properties were investigated by differential scanning calorimetry (DSC) and the phase identified by polarised light microscopy (PLM). A comparative study was made between the investigated compounds and their previously prepared laterally neat, 4-((4ʹ-phenylimino)methyl)phenyl-4”-alkoxy benzoates (IIn); the result revealed that all lateral substituents not only decrease the melting temperature but also the mesophase stability and shown only nematic phase. Density functional theory (DFT) calculations for new lateral derivatives were discussed.

Theoretical Study on Second Hyperpolarizabilities of Intramolecular Pancake-Bonded Diradicaloids with Helical Scaffolds

Using the spin-unrestricted density functional theory method, we have investigated a novel class of open-shell singlet fused-ring molecules with helical scaffolds toward the development of highly efficient third-order nonlinear optical (NLO) systems. It turns out that the helical molecules possess pancake bonding with intermediate diradical character and thereby exhibit large enhancement of orientationally-averaged second hyperpolarizability γs values (third-order NLO properties at the molecular scale) as compared to their closed-shell analogues. It is also found that the asymmetric charge distribution between the cofacial radical sites located on both the terminal rings of the helical scaffold leads to further enhancement of the γ value in the intermediate open-shell character region as compared to the open-shell analogues without asymmetric charge distributions. These results indicate that the helical systems with intermediate diradical character are potential candidates for the building block of highly...

Synthesis of benzoylbenzamide derivatives of 17α-E-vinyl estradiol and evaluation as ligands for the estrogen receptor-α ligand binding domain

A series consisting of substituted benzoylbenzamide derivatives of 17α-E-vinyl estradiol 6a-i and 7a-d was prepared in good overall yields from the corresponding novel iodinated benzoylbenzamide precursors using Pd(0)-catalyzed Stille coupling. Biological evaluation using competitive binding assays indicated that all compounds were effective ligands for the ERα- and ERβ-LBD (RBA = 0.5–10.0% of estradiol). Most of the compounds expressed lower stimulatory (agonist) potency (RSA <0.2–0.5%) compared to their binding affinity, however, the meta-substituted isomer 6h demonstrated a level of efficacy (RSA = 5.7%) comparable to its affinity (RBA = 9.5%). Docking studies of 6b, 6h, and 6i with the 2YAT crystal structure suggested that higher affinity and efficacy of 6h are due to an effective set of interactions with exposed receptor sidechains not observed with the ortho- and para- isomers. In this binding model, the terminal ring of the ligand is exposed to the solvent space, which would explain both the small variation in RBA values and the narrow SAR for the diverse structural features.

Insights into photocatalytic inactivation mechanism of the hypertoxic site in aflatoxin B1 over clew-like WO3 decorated with CdS nanoparticles

Aflatoxin B1 (AFB1) is regarded as a main biological pollutant with high toxicity, carcinogenicity and teratogenicity, and the double bond (C8C9) of its terminal furan ring is the key hypertoxic site. Although semiconductor photocatalysis has been proposed to be a potential way of reducing or inactivating the toxicity of AFB1, the reaction mechanism of reactive oxygen species with the hypertoxic site has not been defined so far. Herein, a kind of all-solid-state Z-schematic composite was fabricated by depositing CdS on the surface of clew-like WO3, which can sharply reduce the toxicity of aflatoxin B1 in aqueous solution under visible light irradiation according to the cytotoxicity test result. On the bases of high resolution mass spectrum (HRMS), radical trapping test and 18O isotope-labeling studies, it can be concluded that the preferentially inactivating the C8C9 site by the addition reaction of hydroxyl radical was the main pathway for the detoxification of aflatoxin B1. Furthermore, density functional theory (DFT) calculations were applied to reveal the reaction mechanism and verify that the hydroxyl radicals were most likely to react with the C9 site, and then form AFB1-9-hydroxy. This work provides in-depth insights into the inactivation mechanism of hypertoxic site in AFB1, and the design of efficient photocatalysts for alleviating the risk of toxic pollutants.

Enantioselective Synthesis and Epimerization Behavior of a Chiral S‐Shaped [11]Helicene‐Like Molecule Having Collision between Terminal Benzene Rings

It has been established that a chiral S‐shaped [11]helicene‐like molecule can be synthesized with high ee value along with a meso form by the rhodium(I)/(R)‐difluorphos complex‐mediated enantioselective intramolecular double [2+2+2] cycloaddition of a 2‐naphthol‐linked hexayne, even though this chiral helicene has the collision between the terminal benzene rings. Epimerization behavior of the chiral and meso [11]helicene‐like molecules have also been disclosed.

Preparation and Physicochemical Properties of [6]Helicenes Fluorinated at Terminal Rings.

The first racemization-stable helicene derivatives fluorinated at terminal rings, 1,2,3,4-tetrafluoro[6]helicene (6) and 1,2,3,4,13,14,15,16-octafluoro[6]helicene (15), were synthesized via the Wittig reaction followed by oxidative photocyclization in an overall yield of 41% of 6 and 76% of 15. The changed electronic structure in fluorinated helicenes was reflected in a slight shift of UV-vis absorption, fluorescence excitation, and emission spectra maxima when compared to unsubstituted [6]helicene. Cyclic voltammetry revealed a moderate decrease in the HOMO-LUMO gap with increasing fluorination. The specific rotation of tetrafluoro[6]helicene 6 enantiomers was found to be approximately 25% lower than that of unsubstituted [6]helicene. The theoretical study of the racemization barrier suggested a reasonable shift toward higher energy with increasing fluorination. The increasing fluorination also significantly affected the intermolecular interactions in the crystal lattice. The observed CH···F interactions led to the formation of 1D-molecular chains in the crystal structures of both fluorinated helicenes.

The Effective Conjugation Length Is Responsible for the Red/Green Spectral Tuning in the Cyanobacteriochrome Slr1393g3.

The origin of the spectral shift from a red- to a green-absorbing form in a cyanobacteriochrome, Slr1393g3, was identified by combined quantum mechanics/molecular mechanics simulations. This protein, related to classical phytochromes, carries the open-chain tetrapyrrole chromophore phycocyanobilin. Our calculations reveal that the effective conjugation length in the chromophore becomes shorter upon conversion from the red to the green form. This is related to the planarity of the entire chromophore. A large distortion was found for the terminal pyrrole rings A and D; however, the D ring contributes more strongly to the photoproduct tuning, despite a larger change in the twist of the A ring. Our findings implicate that the D ring twist can be exploited to regulate the absorption of the photoproduct. Hence, mutations that affect the D ring twist can lead to rational tuning of the photoproduct absorption, allowing the tailoring of cyanobacteriochromes for biotechnological applications such as optogenetics and bioimaging.

Crystal structure of 2-[(2E)-2-methyl-3-phenyl-prop-2-en-1-yl-idene]-N-phenyl-hydrazinecarboxamide.

The title compound, C17H17N3O, crystallizes with two independent mol-ecules in the asymmetric unit. The semicarbazone moieties of these independent mol-ecules (I and II) are essentially planar [maximum deviation of 0.042 (1) Å in mol-ecule I and 0.041 (1) Å in mol-ecule II], with the terminal phenyl rings twisted away from the mean plane of the semicarbazone moiety, making dihedral angles of 60.26 (8) and 28.76 (9)° in mol-ecule I and 31.07 (9) and 35.45 (8)° in mol-ecule II. The mol-ecules both exhibit an E configuration with respect to the C=C and azomethine C=N bonds. In the crystal, two classical N-H⋯O hydrogen-bonding inter-actions are present between the two mol-ecules, forming a centrosymmetric dimer, while a weak C-H⋯O non-classical hydrogen-bonding inter-action, with a donor-acceptor distance of 3.476 (2) Å, inter-connects two neighbouring centrosymmetric dimers to form a cage-like structure. These cage structures are inter-connected by weak C-H⋯π inter-actions with an H⋯π distance of 2.790 Å, forming supra-molecular chains along the c-axis direction.

Five-ring-fused asymmetric thienoacenes for high mobility organic thin-film transistors: the influence of the position of the S atom in the terminal thiophene ring

Two isomeric asymmetric thienoacenes are designed and synthesized; the syn-isomer demonstrates both μsat and μlin above 10 cm2 V−1 s−1.

Two non-identical twins in one unit cell: characterization of 34π aromatic core-modified octaphyrins, their structural isomers and anion bound complexes.

Four different core-modified planar 34π octaphyrins (10, 11, 13, and 15) which exhibit rotational isomerism have been synthesized and characterized both in solution and solid states. Octaphyrins 10, 11 and 13 show two inseparable isomers A and B which crystallize in the same unit cell. However, 15 forms two identical isomers of A. Structurally, the two isomers in 10, 11 and 13 (A and B) are different only in the ring inversion of one of the thiophene or selenophene rings present in the terthiophene subunit of the macrocycle. In isomer A, the middle thiophene or selenophene rings are inverted, while in isomer B, the terminal thiophene rings are inverted. The 1H NMR spectrum of these macrocycles shows peaks assignable to protons of both the isomers in toluene D8. The single crystal structure analysis of 10 reveals the presence of both isomers 10A and 10B in a single unit cell with the P21/n space group. Both the isomers exhibit aromatic behaviour in the freebase form. Protonation of pyrrole nitrogens leads to exclusive formation of isomer B for 10 and 11. However, both the isomers are present upon protonation of 13 where the central heterocyclic ring of terthiophene subunits has thiophene and selenophene rings. Octaphyrin 15 crystallizes in the P21/c space group and exclusively isomer A was formed in the reaction. Protonation of pyrrole nitrogens leads to significant increases in aromaticity as revealed by 1H NMR chemical shift data. The NICS values calculated for the individual heterocyclic rings before and after protonation support such a conclusion. The AICD plots exhibit clockwise orientation of current density vectors suggesting the presence of diatropic ring current in the octaphyrins. Energy calculations at the M06L/CC-pVTZ//M06L/6-31G** level qualitatively account for exclusive stabilization of a particular isomer relative to the other upon protonation. To the best of our knowledge 10 represents the first example in expanded porphyrin chemistry where two different structural isomers crystallize in a single unit cell.

Hydrosilylation of Diene Derivatives Catalyzed by Fe-Iminobipyridine Complexes Aiming at Syntheses of Organosilane Compounds Containing a Terminal Olefin Portion

Abstract The catalytic ability of Fe-iminobipyridine complexes ((BPI)FeBr2, BPI = iminobipyridine) for hydrosilylation of both a non-conjugated diene and a conjugated diene was investigated aiming at the production of organosilane compounds bearing a terminal olefin portion. Steric effects of (BPI)FeBr2 were controlled by the substituents at the terminal pyridine ring (R1), the imino carbon (R2), and the imino nitrogen (Ar) of the BPI ligand. As regards a non-conjugated diene, hydrosilylation of 1,7-octadiene with diphenylsilane (Ph2SiH2) produced a mixture of mono- and di-hydrosilylated compounds. To obtain the mono-hydrosilylated compound preferably in the 1:1 reaction of non-conjugated diene and silane, the substituent effect of the BPI ligand was investigated. As a result, larger steric hindrance of (BPI)FeBr2 based on substituents slowed the hydrosilylation, instead the selectivity of the mono-hydrosilylated compound was substantially improved. The 6′-Me group on a terminal pyridine was most effective. Finally, production of the mono-hydrosilylated compound from 1,7-octadiene and Ph2SiH2 reached 77% yield and 0.94 selectivity. In the case of a conjugated diene, (BPI)FeBr2 with any substituents selectively generated 1,4-hydrosilylated compound in hydrosilylation of 2,3-dimethyl-1,3-butadiene with Ph2SiH2. In this case, higher steric hindrance of (BPI)FeBr2 simply decreased the yield of the product.

Sum frequency generation spectroscopy probing of formation of self-assembled monolayers from thiols with terminal phenylalanine ring and intrachain amide groups

Formation of a self-assembled monolayer onto the polycrystalline gold substrate from thiols containing a terminal phenylalanine (Phe) ring and intrachain amide groups (HS-(CH2)7-CONH-(CH2)2-C6H5) was characterized by vibrational sum frequency generation (SFG) spectroscopy. The temporal evolution of the characteristic Phe ring stretching vibration ν(=C–H) near 3069 cm–1 and the Amide A mode were monitored by nonlinear vibrational spectroscopy. The SFG data revealed the complete ordering of the terminal Phe rings after about 60 min of adsorption. Formation of a strong hydrogen bonding between the adjacent chains of adsorbed molecules was evident by appearance of the Amide A mode at the relative low frequency (3280–3308 cm–1). The well-ordered and strongly hydrogen bonded SAM with the terminal Phe ring functionality is a promising platform for the analysis of interactions and the function of aromatic rings in biomolecular processes.

Computational conformational analysis of α-thrombin inhibitors possessing distinct scaffolds in aqueous solution and on Ala-sheet

Recent computational simulations on protein-ligand binding/unbinding have precisely been uncovering the ligand-binding process at the atomic level. In the process, the non-specific binding of ligands to the target site is suggested to occur before binding to the target. We in this study analyzed the conformations of ligands under the non-specific binding on a protein surface to figure out the differences in the conformational characteristics in aqueous solution using the 55-ns molecular dynamic simulation. As for the protein surface, we constructed an artificial β-sheet, composed of poly-alanine residues (Ala-sheet). For the ligands, the four α-thrombin inhibitors possessing two scaffolds with distinct hydrophobicity profiles were used.During the simulation, all the inhibitors kept interaction with Ala-sheet and had the limited conformational fluctuations compared with in aqueous solution. The representative conformations obtained from the cluster analysis showed that two of hydrophobic inhibitors adopted the extended conformations in aqueous solution and also on Ala-sheet. For the other two hydrophilic inhibitors, the conformations in aqueous solution adopted the bent conformation with two terminal hydrophobic rings closely packed. On Ala-sheet, contrarily, the two hydrophobic rings were open and took the extended conformations, which were placed on the sheet as a foothold. The charged moieties in the hydrophilic inhibitors were protruded into aqueous environment with the extended conformation.The conformational characteristics of the inhibitors in aqueous solution and Ala-sheet varied likely by chemical features or structures of the inhibitors, but each was considered to be physicochemically reasonable.

Molecular dynamics of the interaction of l-tryptophan with polypyrrole oligomers

There is a current interest in the fabrication of electrochemical sensors based on conducting polymers, such as polypyrrole, (Py)n, for the highly selective sensing of amino acids, for instance, tryptophan, Trp. When (Py)n and other polymers grow in the presence of a target analyte, the material develops cavities that are complementary in size and shape to the analyte. These materials, called molecularly imprinted polymers, MIPs, are very useful for the selective detection of many compounds of biomedical interest. The detailed structure of the MIP complementary cavities is not known. For the design and fabrication of highly selective sensors, information about the structure of such cavities in MIPs is highly desirable. However, this kind of information is not accessible through experimental methods. As a first approach to study the interaction between (Py)n and Trp, in this paper, we use molecular dynamics simulations of Trp and small oligomers of (Py)n (where n = 1, 2, 3, 5) in aqueous solutions. The most significant interactions occur between the indole ring of Trp and the pyrrole pentamer. Attractions occur mainly between the nitrogens of the oligomer chain and the Trp heterocycle, causing the amino acid to walk on the oligomer surface. This process starts with the attraction of Trp by one of the terminal rings in the chain, then, in a concerted way, the nitrogens of the subsequent rings can make a sequence of dipole dipole interactions with the amino acid. Further simulations will address the interaction of Trp with several (Py)n chains simultaneously.

Revealing structural involvement of chromophores in algal light harvesting complexes using symmetry-adapted perturbation theory

The attribution of quantum beats observed in the time-resolved spectroscopy of photosynthetic light-harvesting antennae to nontrivial quantum coherences has sparked a flurry of research activity beginning a decade ago. Even though investigations into the functional aspects of photosynthetic light-harvesting were supported by X-ray crystal structures, the non-covalent interactions between pigments and their local protein environment that drive such function has yet to be comprehensively explored. Using symmetry-adapted perturbation theory (SAPT), we have comprehensively determined the magnitude and compositions of these non-covalent interactions involving light-harvesting chromophores in two quintessential photosynthetic pigment-protein complexes — peridinin chlorophyll-a protein (PCP) from dinoflagellate Amphidinium carterae and phycocyanin 645 (PC645) from cryptophyte Chroomonas mesostigmatica. In PCP, the chlorophylls are dispersion-bound to the peridinins, which in turn are electrostatically anchored to the protein scaffold via their polar terminal rings. This might be an evolutionary design principle in which the relative orientation of the carotenoids towards the aqueous environment determines the arrangement of the other chromophores in carotenoid-based antennas. On the other hand, electrostatics dominate the non-covalent interactions in PC645. Our ab initio simulations also suggest full protonation of the PC645 chromophores in physiological conditions, and that changes to their protonation states result in their participation as switches between folded and unfolded conformations.

Structural and Hirshfeld surfaces of thiophene based isoxazole derivatives: 3-(3-Methylthiophen-2-yl)-5-(3,4,5-trimethoxyphenyl)isoxazole and 5-(3-Methylthiophen-2-yl)-3-(3,4,5-trimethoxyphenyl)isoxazole

Abstract The title compounds C17H17NO4S (I) and C17H17NO4S(II) crystallized in the monoclinic system with the space group of P21/c. The dihedral angles of 8.88(2)˚ and 10.54(13)˚ are observed between their terminal rings for I and II, respectively. Intramolecular hydrogen bonds form a pair of S(6) ring motifs in (I) and three S(6) ring motifs in (II). The crystal structure is stabilized by short intermolecular hydrogen bonds generating ring motifs of the type R22(12) (I) and R12(5) (II). Overall packing form a 3D supramolecular network in (I) and layer stacking along b axis in (II). The intermolecular interactions and their percentage of contributions were quantified for both the compounds using Hirshfeld surfaces.

Antiproliferative, antioxidant and binding mechanism analysis of prodigiosin from newly isolated radio-resistant Streptomyces sp. strain WMA-LM31.

Streptomyces genus are filamentous Gram positive bacteria, of great intrest, producing biologically active compounds. Recent market and consumer curiosity in natural products have forced scientist and industry for the development of new products with therapeutic potential. This study focuses on evaluation of antioxidant and anticancerous properties of prodigiosin from radio-resistant Streptomyces sp. strain WMA-LM31. A molecular docking approach was adopted to understand theoretical binding mechanism and affinity for anticancer targets. A radio-resistant bacterium, labelled as strain WMA-LM31, was isolated from desert soil and screened for its radio-resistant potential and prodigiosin production. 16S rRNA gene sequencing showed that the bacterium clusters to genus Streptomyces and found resistant to ultraviolet radiation (dosage of 2 × 103J/m2). Strain WMA-LM31 produced a red color pigment in tryptone glucose yeast (TGY) medium.The LC-MS analysis of the purified compound showed a molar mass of 324 [m/z]+ matched the chemical formula C20H25N3O, identified as prodigiosin. The compound showed strong antioxidant (62.51%) activities along with significant inhibitory action against oxidative damages to bovine serum albumin (BSA) and mice liver lipids in comparison to standard ascorbic acid. IC50 values of HepG2 and HeLa cell lines was found at 12.66 and 14.83µg/mL of prodigiosin concentration, respectively. Furthermore, molecular docking was performed with two different cancers macromolecular targets: [2O2F (Bcl-2) and 1DI8 (CDK-2)], and BSA (PDB id: 3V03). The results indicated that the binding affinity of prodigiosin to its target molecules is due to the presence of terminal pyrrole rings. It is concluded from the results that prodigiosin from Streptomyces sp. strain WMA-LM31 has strong antioxidant, anticancer and apoptotic properties. The knowledge of binding mechanisms and interactions of prodigiosin could provide future directions in designing potent target specifc drugs.

Crystal Structure of Tetrakis(2,2�-bithiophene-5-yl)silane

The crystal structure of tetrakis(2,2�-bithiophene-5-yl)silane, C16H10S4Si0.5, has been determined at 293K in the Monoclinic (I2) symmetry. The Si atom has quasi-perfect tetrahedral geometry and bithiophene unit are quasi-planar. Comparison of Si-C bond lengths with literature data indicates an electron donating effect of the terminal thienyl ring on the first C linked to the Si central atom. The study of C-C bond lengths reveals a much more aromatic character for the four thienyl rings directly linked to the Si atom. The molecular packing arrangement shows that each molecule presents eight intermolecular contacts.

Hemozoin inhibiting 2-phenylbenzimidazoles active against malaria parasites

The 2-phenylbenzimidazole scaffold has recently been discovered to inhibit β-hematin (synthetic hemozoin) formation by high throughput screening. Here, a library of 325,728 N-4-(1H-benzo[d]imidazol-2-yl)aryl)benzamides was enumerated, and Bayesian statistics used to predict β-hematin and Plasmodium falciparum growth inhibition. Filtering predicted inactives and compounds with negligible aqueous solubility reduced the library to 35,124. Further narrowing to compounds with terminal aryl ring substituents only, reduced the library to 18, 83% of which were found to inhibit β-hematin formation <100 μM and 50% parasite growth <2 μM. Four compounds showed nanomolar parasite growth inhibition activities, no cross-resistance in a chloroquine resistant strain and low cytotoxicity. QSAR analysis showed a strong association of parasite growth inhibition with inhibition of β-hematin formation and the most active compound inhibited hemozoin formation in P. falciparum, with consequent increasing exchangeable heme. Pioneering use of molecular docking for this system demonstrated predictive ability and could rationalize observed structure activity trends.