Modification Of Substituents Research Articles

1,2,4,6-Thiatriazinyl Radicals and Dimers: Structural and Electronic Tuning through Heteroaromatic Substituent Modification

The functionalization of thiatriazinyl (TTA) radicals with pyridyl and thienyl moieties is described, and their influence at both the molecular and solid-state level has been investigated. Comparative electron paramagnetic resonance studies of 3,5-bis-(2-pyridyl)-1,2,4,6-thiatriazinyl (Py2TTA) and 3,5-bis-(2-thienyl)-1,2,4,6-thiatriazinyl (Th2TTA) reveal the impact of heteroaromatic substitution on the electronic structure, which is supported by density functional theory calculations. Single crystal X-ray analysis emphasizes the importance of intermolecular contacts on the crystal packing and demonstrates the potential for structural control through S---N′ and N---HC′ interactions, which are enhanced in Py2TTA and Th2TTA by the presence of the pyridyl and thienyl groups, respectively. This work represents a fundamental study of heterocyclic aromatic substitution in thiazyl-based radicals and investigates how varying these functional groups influences the molecular properties and long-range order within the supramolecular structure.

Structure-activity analysis of thiourea analogs as inhibitors of UT-A and UT-B urea transporters

Small-molecule inhibitors of urea transporter (UT) proteins in kidney have potential application as novel salt-sparing diuretics. The urea analog dimethylthiourea (DMTU) was recently found to inhibit the UT isoforms UT-A1 (expressed in kidney tubule epithelium) and UT-B (expressed in kidney vasa recta endothelium) with IC50 of 2-3mM, and was shown to have diuretic action when administered to rats. Here, we measured UT-A1 and UT-B inhibition activity of 36 thiourea analogs, with the goal of identifying more potent and isoform-selective inhibitors, and establishing structure-activity relationships. The analog set systematically explored modifications of substituents on the thiourea including alkyl, heterocycles and phenyl rings, with different steric and electronic features. The analogs had a wide range of inhibition activities and selectivities. The most potent inhibitor, 3-nitrophenyl-thiourea, had an IC50 of ~0.2mM for inhibition of both UT-A1 and UT-B. Some analogs such as 4-nitrophenyl-thiourea were relatively UT-A1 selective (IC50 1.3 vs. 10mM), and others such as thioisonicotinamide were UT-B selective (IC50>15 vs. 2.8mM).

Aza-BODIPY dyes with enhanced hydrophilicity.

Attempts to make a diamino disulfonic acid derivative of an aza-BODIPY showed it was difficult to add BF2 to a disulfonated azadipyrromethene, and sulfonation of an aza-BODIPY resulted in loss of the BF2 fragment. We conclude the electron-deficient character of aza-BODIPY dyes destabilizes them relative to BODIPY dyes. Consequently, sulfonation of the aza-BODIPY core is not a viable strategy to increase water solubility. This assertion was indirectly supported via stability studies of a BODIPY and an aza-BODIPY in aqueous media. To afford the desired compound type, an aza-BODIPY with two amino and two sulfonic acid groups was prepared via modification of the aryl substituents with cysteic acid.

Lessons from chlorophylls: modifications of porphyrinoids towards optimized solar energy conversion.

Practical applications of photosynthesis-inspired processes depend on a thorough understanding of the structures and physiochemical features of pigment molecules such as chlorophylls and bacteriochlorophylls. Consequently, the major structural features of these pigments have been systematically examined as to how they influence the S1 state energy, lifetimes, quantum yields, and pigment photostability. In particular, the effects of the macrocyclic π-electron system, central metal ion (CMI), peripheral substituents, and pigment aggregation, on these critical parameters are discussed. The results obtained confirm that the π-electron system of the chromophore has the greatest influence on the light energy conversion capacity of porphyrinoids. Its modifications lead to changes in molecular symmetry, which determine the energy levels of frontier orbitals and hence affect the S1 state properties. In the case of bacteriochlorophylls aggregation can also strongly decrease the S1 energy. The CMI may be considered as another influential structural feature which only moderately influences the ground-state properties of bacteriochlorophylls but strongly affects the singlet excited-state. An introduction of CMIs heavier than Mg2+ significantly improves pigments' photostabilities, however, at the expense of S1 state lifetime. Modifications of the peripheral substituents may also influence the S1 energy, and pigments’ redox potentials, which in turn influence their photostability.

DFT analysis of substituent effects on electron-donating efficacy of pyridine

Studies on pyridine, C5H5N, and pyridine derivatives (simulations) of the type C5(X) n H5−n N (X = −C≡CH; –C≡CF; –C≡N; –CH(=O)) are carried out using the DFT method employing B3LYP/LanL2DZ level of theory. The effects of substituent modification (type and position) on electron density enrichment of pyridyl nitrogen atoms and thus its effectiveness as a donor atom for incoming metal ions have been investigated. Computational results showed that first, substituents exert interesting effects on both the accumulated charge density on nitrogen and the geometrical parameters (C2=N bond length and C2···N···C6 bond angle) of the examined pyridine simulations. Second, depending on the type of the substituent, substituents showed variable trends in effect. For example, –C≡CH and –C≡CF show a similar trend, which is overall noticed to be different from that observed for –C≡N –CH(=O). Third, the influence of substituent modification on electronic localization/delocalization is further viewed by calculating the charge density distribution surfaces and the occupancy of the frontier HOMO molecular orbitals. Gathered images of charge density surfaces and HOMO orbitals for all simulates clearly showed how charge density is distributed over the pyridine system and truly found to be very helpful in providing deep insight into how charge density is accumulated over nitrogen specifically. In result, –C≡CF among all, was found to enrich the charge density on pyridyl nitrogen the most. This was attributed to the existence of fluorine atoms in the structure of the attached substituent. Fluorine atom, was able of extending the electron density delocalization—pathway more than the other substituents do. Actually, this investigation is a pursuing to our research work which basically aims to put under control various variables that would promote the inorganic complex to be a good chromophore in low energy regions and to be further employed in chemosensation. In this report, we attempt to move one extra step ahead and expand our knowledge to wisely engineer and design a feasible chemosensor that is capable of responding in the visible region.

Stereochemical modification of geminal dialkyl substituents on pantothenamides alters antimicrobial activity

Pantothenamides are N-substituted pantothenate derivatives which are known to exert antimicrobial activity through interference with coenzyme A (CoA) biosynthesis or downstream CoA-utilizing proteins. A previous report has shown that replacement of the ProR methyl group of the benchmark N-pentylpantothenamide with an allyl group (R-anti configuration) yielded one of the most potent antibacterial pantothenamides reported so far (MIC of 3.2μM for both sensitive and resistant Staphylococcus aureus). We describe herein a synthetic route for accessing the corresponding R-syn diastereomer using a key diastereoselective reduction with Baker’s yeast, and report on the scope of this reaction for modified systems. Interestingly, whilst the R-anti diastereomer is the only one to show antibacterial activity, the R-syn isomer proved to be significantly more potent against the malaria parasite (IC50 of 2.4±0.2μM). Our research underlines the striking influence that stereochemistry has on the biological activity of pantothenamides, and may find utility in the study of various CoA-utilizing systems.

Investigations into Asymmetric Post-Metallocene Group 4 Complexes for the Synthesis of Highly Regioirregular Polypropylene

A series of asymmetric post-metallocene group 4 complexes based on a modular anilide(pyridine)phenoxide framework have been synthesized and tested for propylene polymerization activity. These complexes, upon activation with methylaluminoxane (MAO), produce highly regioirregular and stereoirregular polypropylene with moderate to good activities. Surprisingly, modification of the anilide R-group substituent from 1-phenethyl to benzyl or adamantyl did not significantly change the polymer microstructure as determined by ^(13)C NMR spectroscopy. Although polymer molecular weights and polydispersities vary with propylene pressure, temperature, and activator, regio- and stereoirregularity were also found to be relatively insensitive to these variables. When the polymerization is conducted at 70 °C under dihydrogen, partial decomposition to a highly active catalyst that produces an isotactic microstructure occurs; the undecomposed catalyst continues to produce highly regioirregular and stereoirregular polypropylene under these conditions.

Synthesis and anti-proliferative activity evaluation of N3-acyl-N5-aryl-3,5-diaminoindazole analogues as anti-head and neck cancer agent

BackgroundHead and neck squamous cell carcinoma (HNSCC) is the 11th leading cancer by incidence worldwide. Surgery and radiotherapy have been the major treatment for patients with HNSCC while chemotherapy has become an important treatment option for locally advanced HNSCC. Understanding of the molecular mechanisms underlying HNSCC impelled the development of targeted therapeutic agents. The development and combinations of targeted therapies in different cellular pathways may be needed to fulfill the unmet needs of current HNSCC chemotherapy.ResultsA series of N3-acyl-N5-aryl-3,5-diaminoindazoles were synthesized and their anti-proliferative activities were evaluated against human cancer cell lines, Caki, A549, AMC-HN1, AMC-HN3, AMC-HN4, AMC-HN6, and SNU449. The cellular selectivity of compound was obtained by the modification of substituent at N5-aryl group of 3,5-diaminoindazole. Compound 9a and 9b showed more than 7-fold selectivity for AMC-HN4 and AMC-HN3, respectively.ConclusionsN3-acyl-N5-aryl-3,5-diaminoindazole analogues can be used as hits in the development of anticancer drug for HNSCC.

Substituent-controlled preference of carbonyl group–metal coordination in d8metal complexes with non-symmetric pentadentate ligands. Structural and stereochemical aspects

Chirally switchable Ni(II) and Pd(II) complexes were synthesized and fully characterized by X-ray crystallography and additionally by spectroscopic means (NMR and MS). The syntheses and characterization of their ligands are also reported. It was found that control of the stereochemical preference between (S*,S*) and (S*,R*) diastereomers by substituent modification of the ligand sidearms was possible in the solid state with the preferred atomic coordinations of the sidearms consistent with expectations based on the electron-withdrawing properties of the substituent -o-CF3 group. The dilemma arising in terms of assigning the absolute configuration descriptors resulting from selecting between strictly following only the covalent bonds of the ligand and disregarding the nature of the bonds altogether and thus bringing the coordinate bonds into consideration to determine the stereochemical priority sequence is hereby resolved by declaring that the latter option is to be preferred. The results obtained here provide a clear indication that sidearm substitution of the Ni(II) and Pd(II) complexes need not disturb macromolecular stereochemical arrangements leading to quasidiastereomeric relationships. This permits the design of molecular systems sensitive to external stimuli with predictable macromolecular structure.

Substituent effect on fluorophores instead of ionophores: its implication in highly selective fluorescent probes for Zn2+ over Cd2+

Three fluorescent molecules with different substituent modification on 5-position showing different extents of fluorescent response to Zn2+ and distinct discriminating effect of RZn/RCd have been readily synthesized. The addition of a dithiol group induces the discriminating effect of RZn/RCd to be obviously improved from twice to 32 times.

Synthesis of P-Triazole Dithienophospholes and a Cyclodextrin-Based Sensor via Click Chemistry

The synthesis of a series of highly luminescent, functional dithienophospholes via a click reaction is reported. Slight modification of the lateral aromatic substituents leads to a significant difference in their solid-state organization. In addition, a novel water-soluble β-cyclodextrin hybrid is demonstrated to be an effective sensor for picric acid.

Improved Cav2.2 Channel Inhibitors through a gem-Dimethylsulfone Bioisostere Replacement of a Labile Sulfonamide.

We report the investigation of sulfonamide-derived Cav2.2 inhibitors to address drug-metabolism liabilities with this lead class of analgesics. Modification of the benzamide substituent provided improvements in both potency and selectivity. However, we discovered that formation of the persistent 3-(trifluoromethyl)benzenesulfonamide metabolite was an endemic problem in the sulfonamide series and that the replacement of the center aminopiperidine scaffold failed to prevent this metabolic pathway. This issue was eventually addressed by application of a bioisostere strategy. The new gem-dimethyl sulfone series retained Cav2.2 potency without the liability of the circulating sulfonamide metabolite.

Stereoselective synthesis and anti-proliferative effects on prostate cancer evaluation of 5-substituted-3,4-diphenylfuran-2-ones

Series of 5-substituted-3,4-diphenylfuran-2-ones were stereoselectively prepared. Their potential anti-proliferative effects on prostate cancer and some of their cyclooxygenases (COXs) inhibitory activities were evaluated. Structure–activity relationship (SAR) data, acquired by substituent modification at the para-position and ortho-position of the C-3 phenyl ring and 5-substituted modification of the central furanone, showed that 3-(2-chloro-phenyl)-4-(4-methanesulfonyl-phenyl)-5-(1-methoxy-ethyl)-5H-furan-2-one (13p) was the most potent compound and could effectively reduce the proliferation of prostate cancer cells (PC3 cell IC50 = 20 μM; PC3 PCDNA cell IC50 = 5 μM; PC3 SKP2 cell IC50 = 5 μM; DU145 cell IC50 = 25 μM). The cell cycle analysis for 13p in DU145 indicated that 13p may induce G1 phase arrest.

Intramolecular Cyclization of Arylalkynes with C‐O Bond Formation on Ruthenium Complexes

AbstractCyclization of terminal arylalkynes containing aldehyde (1a), ketone (1b‐c) or hydroxyl (6a‐c) functionality on the aryl ring induced by ruthenium complex is investigated. For the reaction of Cp(PPh3)2RuCl with o‐ethynyl benzaldehyde 1a, a vinylidene intermediate was formed which is followed by a carbonyl attack to give 2a. However, for 1b‐c, with a ketone replacing the aldehyde group, isobenzofuryl carbene complexes (4b‐c) were formed as the major products along with the isochromene carbene complexes (2b‐c) as the minor products. For three o‐enynyl phenol compounds 6a‐c with different substituents on the aryl ring, the reactions take place at the triple bond first giving vinylidene intermediates which undergo facile intramolecular cyclization to yield the cyclic oxocarbene complexes 7a‐c in excellent yields. Modification of various substituents at Cβ of the carbene ligand of 7 by the use of different alkyl halides can be readily achieved under mild condition. For the chromane ring derivatives 11, the two allyl groups underwent ring closing metathesis reaction in the presence of Grubb's catalyst and yielded the tricyclic product 12. These chemical reactions and their mechanisms are corroborated by structure determinations of two ruthenium complexes using single crystal X‐ray diffraction analysis.

Thioureas as Reporting Elements for Metal-Responsive Fluorescent Chemosensors

Proof that sulfur is a viable reporting element for the development of fluorescent chemosensors for metal ions is presented. To date, the majority of metal-responsive fluorescent chemosensors have relied on metal-nitrogen coordination to provide a fluorescence response, most commonly by suppressing photoinduced electron transfer (PET) quenching. While chemosensors with direct application to biology, medicine, and analytical chemistry have been so developed, reliance on the coordination chemistry of nitrogen remains a practical and conceptual limitation. Building on the fact that thioureas can quench fluorescence emission by PET, it is shown that the quenched emission of thiourea-appended naphthalimides can be restored by metal binding and that metal affinity and selectivity can be controlled through structural modification of the thiourea substituents. Further, such chemosensors can function in aqueous media and, unlike nitrogen-based chemosensors, are unresponsive to increases in [H(+)]. Given that the coordination properties of sulfur are distinct from those of nitrogen, this work lays the foundation for the development of a new class of interesting and useful metal-responsive fluorescent probes.

Synthesis of New BINAP-Based Aminophosphines and Their 31P-NMR Spectroscopy

BINAP aminophosphines are prevalent N,P-bidentate, chiral ligands for asymmetric catalysis. While modification via the BINAP-nitrogen linkage is well explored and has provided a diverse body of derivatives, modification of the other substituents of the phosphorous center is another avenue in generating new congeners of this important class of chiral ligands. Herein reported are new BINAP aryl aminophosphines with electron rich or deficient substituents on the aryl rings. This scalable synthesis converted readily available starting material, (S)-BINOL, to a key intermediate (S)-NOBIN, from which the final chiral aminophosphines were prepared via a palladium-catalyzed, phosphonylation reaction. The aryl substituents are able to modify the electronic properties of the phosphorous center as indicated by the range of 31P-NMR shifts of these new ligands. A computational analysis was performed to linearly quantitate contributions to the 31P-NMR shifts from both resonance and field effects of the substituents. This correlation may be useful for designing and preparing other related aminophosphines with varying ligand properties.

Exploring DNA binding properties and biological activities of dihydropyrimidinones derivatives

The effects of substituent modifications for three dihydropyrimidinones derivatives on DNA binding properties were investigated using viscometry in combination with spectroscopy and isothermal titration calorimetry (ITC). The results indicated that substitution in 4 rd position of benzene ring has significant effects on DNA binding mode, affinity and energetics. Electron-donating substitution was favorable for intercalating into DNA bases and had higher DNA binding affinity. However, electron-withdrawing substitution was preferable to bind to DNA in partial intercalation mode with relatively weak DNA binding affinity. Simultaneously, electron-donating substitution could result in more favorable binding enthalpy relative to electron-donating substitution and the parent compound. Antitumor activities of these analogs over BEL-7402 and PC-12 cells were studied to explore the structure activity relationships (SARs), which suggested that electron-donating substitution in 4 rd position of benzene ring could greatly enhance the antitumor activities. However, electron-withdrawing substitution has little effect on the antitumor activity. The present results favor the development of potential drugs related with dihydropyrimidinones derivatives in the treatment of some diseases.

Small organic single-crystalline one-dimensional micro- and nanostructures for miniaturized devices

1D π-conjugated organic micro- or nanostructures keep all the advantages found in organic single crystals, e.g. high crystallinity, but without the tricky growth associated with large-sized crystals. They also present low-cost processing, solution processable materials, and large-area fabrication, and are compatible with flexible substrates. Electronic and optical properties of 1D π-conjugated organic micro- and nanomaterials can be tuned by changing their size at the central core or chemical modification of the aromatic substituents, among other alternatives. Current challenges are to find and develop an accurate control of the morphology, size, degree of uniformity, and alignment of the micro- and nanometer-sized organic single crystals, for future applications in miniaturized devices.

Impact of functionalized linkers on the energy landscape of ZIFs

Zeolitic imidazolate frameworks (ZIFs) are well-known for their thermal and chemical stability, as well as for their structural diversity reminiscent of those found in the realm of zeolites. Linker–linker interactions were recognized as essential in the discovery of new topologies through the choice of substituted imidazolates. However, the impact of the linker through modification of the imidazolate's substituents on the energy landscape of ZIFs remains to be rationalized. In this work, LiB-based ZIFs serve as model crystal structures to explore the impact of linker–linker interactions, varying the number and position of methyl groups. The study focuses on the characteristics of experimental and hypothetical structures studied by first principle DFT-D calculations, and further interpreted through QSPR and Non covalent interaction (NCI) analysis. We provide an empirical QSPR model accounting for linker and topology effects on the stability of the frameworks. Both the position and number of substituents on the imidazolate linkers have a profound impact on the energy landscape of ZIFs, reshuffling the ranking of stabilized versus less stable topologies that were otherwise almost isoenergetic with unsubstituted imidazolate. NCI analysis revealed that methyl substituents induce repulsive interactions within the boron-centred cluster that are compensated by attractive non-bonded interactions at the larger scale of the solid. Besides the kinetic factors at play in ZIF synthesis which are difficult to consider from a modelling perspective, our calculations show that thermodynamic considerations are at work, explaining the intractability of certain topologies with certain linkers. Our calculations provide insight into the magnitude of the thermodynamic penalties that must be overcome in order to form particular topologies and the energy scale that needs to be overcome to generate lower density materials – a target for many experimental groups. The identified dominant linker–linker interactions could be exploited to overcome the limitations of current synthesis techniques.

Density-functional analysis of substituent effects on photochemistry of Ru(II)-polypyridyl complexes

Studies on complexes of the type: [Ru(en)2L2]2+, en = ethylenediamine, L = pyridine (Py), 2-, 3-, or 4-methylpyridine (PyCH3), 2-, 3-, or 4-acetylpyridine (PyCOCH3) and 2-, 3-, or 4-cyanopyridine (PyCN) are carried out using the DFT method and B3LYP/LanL2DZ level of theory. The trends in substituent modifications (type and position) caused by electron-releasing group (methyl) and electron-withdrawing groups (acetyl and cyano) on the electronic structure and related properties have been investigated. Computational results show: first, substituents exert interesting effects on both ground and excited states of the examined complexes. Second, electron-releasing group (methyl), for example, causes a blue shift in the electronic MLCT ground band. However, electron-withdrawing groups (acetyl and cyano) cause a red shift in the electronic MLCT ground band. Third, substituent modification (by influencing the geometrical parameters, like bond length and angle, and thus the dependent optical properties of the involved complexes) helps in designing and engineering effective and selective colorimetric chemosensors to be employed in chemosensation.