Influence of N(1) protonation on the orientation of the N(6) substituent in hypermodified nucleic acid base N6-(N-glycylcarbonyl) adenine

The influence of protonation at N(1) on the conformational preferences of the N(6) substituent in the modified nucleic acid base N⁶-(N-glycylcarbonyl) adenine, gc⁶Ade, was investigated by the quantum chemical perturbative configuration interaction using localized orbitals (PCILO) method. The preferred orientation of the glycylcarbonyl substituent changes on the protonation of N(1). In the preferred conformation, the carbonyl oxygen O(10) is placed on the same side as N(1)H and provides stabilization through intramolecular hydrogen bonding of O(10) with HN(1). The amino acid component is so oriented that the carboxyl oxygen O(13b) is aligned closely with the N(6)H direction. Thus, the preferred molecular orientation is further stabilized by intramolecular hydrogen bonding involving HN(6) with O(13b). The alternative conformation has 0.5 kcal/mol higher energy than has the preferred conformation. The preferred conformation is about 1 kcal/mol more stable than is the conformation obtained by the flipping of torsion angle β alone, from the favored orientation for the unprotonated gc⁶Ade. © 1997 John Wiley & Sons, Inc. Int J Quant Chem 62: 551–556, 1997     

Conformational flipping of the N(6) substituent in diprotonated N6‐(N‐glycylcarbonyl)adenines: The role of N(6)H in purine‐ring‐protonated ureido adenines

Conformational transitions of the N(6) substituent, in hypermodified nucleic acid base N⁶‐(N‐glycylcarbonyl)adenine, gc⁶Ade, on diprotonation of the adenine ring at any two of N(1), N(3), and N(7) sites, are studied using the quantum chemical perturbative configuration interaction with localized orbitals (PCILO) method. The N(6) substituent retains the usual “distal” orientation (α=0°) in (N(1),N(3)) diprotonated gc⁶Ade, but the “proximal” orientation (α=180°) is preferred instead, for (N(3),N(7)) and (N(7),N(1)) diprotonated gc⁶Ade. The proximal orientation may alter the reading frame during translation. Intramolecular N(6)HO(13b) hydrogen bonding is the key common feature, present in the preferred structure, for each of these variously diprotonated gc⁶Ade. © 2000 John Wiley & Sons, Inc. Int J Quant Chem 78: 398–405, 2000     

Theoretical studies on conformational preferences of model modified nucleic acid base N6-(N-alanylcarbonyl) adenine

Conformational preferences of model modified nucleic acid base N⁶-(N-alanylcarbonyl) adenine, ac⁶Ade, have been investigated using the quantum chemical PCILO (perturbative configuration interaction using localized orbitals) method. The multidimensional conformational space has been searched using selected grid points formed by combining the various torsion angles that take favored values derived from energy variation with respect to each torsion angle individually. The preferred molecular structure is stabilized by an intramolecular hydrogen bond from N(11)H of the amino acid to N(1) of the adenine. The observed crystal structure conformations for the naturally occurring, anticodon adjacent, threonyl analogs, tc⁶Ade, correspond to the predicted most stable conformation for the model modified base ac⁶Ade. Three stable, low energy conformations differing in the orientations of the carboxyl group and the amino acid side chain are predicted within 1 kcal/mol of the most stable structure. The possible bifurcated hydrogen bonding of N(11)H with N(1) and either of the carboxyl oxygens is of minor significance. The indicated orientational flexibility for the carboxyl group and the amino acid side chain may enable convenient probing of the molecular environment, in the vicinity of the anticodon in tRNA, by the amino acid substituent, with only modest changes in energy stabilization.     

Supramolecular architectures in the salt trimethoprimium ferrocene‐1‐carboxylate and the cocrystal 4‐amino‐5‐chloro‐2,6‐dimethylpyrimidine–ferrocene‐1‐carboxylic acid (1/1)

In the salt trimethoprimium ferrocenecarboxylate [systematic name: 2,4‐diamino‐5‐(3,4,5‐trimethoxybenzyl)pyrimidin‐1‐ium ferrocene‐1‐carboxylate], (C₁₄H₁₉N₄O₃)[Fe(C₅H₅)(C₆H₄O₂)], (I), of the antibacterial compound trimethoprim, the carboxylate group interacts with the protonated aminopyrimidine group of trimethoprim via two N—H…O hydrogen bonds, generating a robust R ₂²(8) ring motif (heterosynthon). However, in the cocrystal 4‐amino‐5‐chloro‐2,6‐dimethylpyrimidine–ferrocene‐1‐carboxylic acid (1/1), [Fe(C₅H₅)(C₆H₅O₂)]·C₆H₈ClN₃, (II), the carboxyl–aminopyrimidine interaction [R ₂²(8) motif] is absent. The carboxyl group interacts with the pyrimidine ring via a single O—H…N hydrogen bond. The pyrimidine rings, however, form base pairs via a pair of N—H…N hydrogen bonds, generating an R ₂²(8) supramolecular homosynthon. In salt (I), the unsubstituted cyclopentadienyl ring is disordered over two positions, with a refined site‐occupation ratio of 0.573 (10):0.427 (10). In this study, the two five‐membered cyclopentadienyl (Cp) rings of ferrocene are in a staggered conformation, as is evident from the C…Cg …Cg …C pseudo‐torsion angles, which are in the range 36.13–37.53° for (I) and 22.58–23.46° for (II). Regarding the Cp ring of the minor component in salt (I), the geometry of the ferrocene ring is in an eclipsed conformation, as is evident from the C…Cg …Cg …C pseudo‐torsion angles, which are in the range 79.26–80.94°. Both crystal structures are further stabilized by weak π–π interactions.     

Design of two series of 1:1 cocrystals involving 4‐amino‐5‐chloro‐2,6‐dimethylpyrimidine and carboxylic acids

Two series of a total of ten cocrystals involving 4‐amino‐5‐chloro‐2,6‐dimethylpyrimidine with various carboxylic acids have been prepared and characterized by single‐crystal X‐ray diffraction. The pyrimidine unit used for the cocrystals offers two ring N atoms (positions N1 and N3) as proton‐accepting sites. Depending upon the site of protonation, two types of cations are possible [Rajam et al. (2017). Acta Cryst. C 73 , 862–868]. In a parallel arrangement, two series of cocrystals are possible depending upon the hydrogen bonding of the carboxyl group with position N1 or N3. In one series of cocrystals, i.e. 4‐amino‐5‐chloro‐2,6‐dimethylpyrimidine–3‐bromothiophene‐2‐carboxylic acid (1/1), 1 , 4‐amino‐5‐chloro‐2,6‐dimethylpyrimidine–5‐chlorothiophene‐2‐carboxylic acid (1/1), 2 , 4‐amino‐5‐chloro‐2,6‐dimethylpyrimidine–2,4‐dichlorobenzoic acid (1/1), 3 , and 4‐amino‐5‐chloro‐2,6‐dimethylpyrimidine–2‐aminobenzoic acid (1/1), 4 , the carboxyl hydroxy group (–OH) is hydrogen bonded to position N1 (O—H…N1) of the corresponding pyrimidine unit (single point supramolecular synthon). The inversion‐related stacked pyrimidines are doubly bridged by the carboxyl groups via N—H…O and O—H…N hydrogen bonds to form a large cage‐like tetrameric unit with an R₄²(20) graph‐set ring motif. These tetrameric units are further connected via base pairing through a pair of N—H…N hydrogen bonds, generating R₂²(8) motifs (supramolecular homosynthon). In the other series of cocrystals, i.e. 4‐amino‐5‐chloro‐2,6‐dimethylpyrimidine–5‐methylthiophene‐2‐carboxylic acid (1/1), 5 , 4‐amino‐5‐chloro‐2,6‐dimethylpyrimidine–benzoic acid (1/1), 6 , 4‐amino‐5‐chloro‐2,6‐dimethylpyrimidine–2‐methylbenzoic acid (1/1), 7 , 4‐amino‐5‐chloro‐2,6‐dimethylpyrimidine–3‐methylbenzoic acid (1/1), 8 , 4‐amino‐5‐chloro‐2,6‐dimethylpyrimidine–4‐methylbenzoic acid (1/1), 9 , and 4‐amino‐5‐chloro‐2,6‐dimethylpyrimidine–4‐aminobenzoic acid (1/1), 10 , the carboxyl group interacts with position N3 and the adjacent 4‐amino group of the corresponding pyrimidine ring via O—H…N and N—H…O hydrogen bonds to generate the robust R₂²(8) supramolecular heterosynthon. These heterosynthons are further connected by N—H…N hydrogen‐bond interactions in a linear fashion to form a chain‐like arrangement. In cocrystal 1 , a Br…Br halogen bond is present, in cocrystals 2 and 3 , Cl…Cl halogen bonds are present, and in cocrystals 5 , 6 and 7 , Cl…O halogen bonds are present. In all of the ten cocrystals, π–π stacking interactions are observed.     

Conformational preferences of modified nucleic acid bases N6-(Δ2-isopentenyl) adenine and 2-methylthio-N6-(Δ2-isopentenyl) adenine by the quantum chemical PCILO calculations

Conformational preferences of the hypermodified nucleic acid bases N⁶-(Δ²-isopentenyl) adenine, (i⁶Ade) and its 2-methylthio derivative (ms²i⁶Ade) have been investigated theoretically by the quantum chemical perturbative configuration interaction using localized orbitals (PCILO ) method. The predicted most stable conformation of i⁶Ade and ms²i⁶Ade are such that the isopentenyl substituent is oriented away from the imidazole moiety of the adenine ring. The atoms N(6), C(10), and C(11) remain coplanar with the adenine ring for both molecules. However, in contrast to the predicted cis orientation of the C(10)? C(11) bond with respect to the C(6)? N(6) bond in i⁶Ade, the trans orientation is favored for ms²i⁶Ade. The plane of the isopentenyl group is rotated by 120° from that of the purine base in i⁶Ade, whereas rotation by 60° is favored in ms²i⁶Ade. The favored orientation of the methylthio group with respect to the C(2)? N(3) bond is trans; however, the alternative cis arrangement is also quite probable. The conformational implications of the methylthiolation of the isopentenyladenine are brought out in the context of the considerably large range of accessible (β,γ) and χ orientations. The compatible roles of i⁶Ade and ms²i⁶Ade in tRNA are thus understood, besides their distinguishing features.     

Synthesis,characterization, X-ray diffraction studies and biological evaluation of tert-butyl 4-(2-ethoxy-2-oxoethyl)-piperazine-1-carboxylate and tert-butyl 4-(2-hydrazino-2-oxoethyl)piperazine-1-carboxylate

Two derivatives of N-Boc piperazine, an ester derivative, i.e., tert-butyl 4-(2-ethoxy-2-oxoethyl)-piperazine-1-carboxylate (1), and, a hydrazide derivative tert-butyl 4-(2-hydrazino-2-oxoethyl)piperazine-1-carboxylate (2) were synthesized and were characterized by FT-IR, ¹H & ¹³C NMR and LCMS spectroscopic studies. The structures of both 1 and 2 were further confirmed by single crystal X-ray diffraction analysis. The molecule of 1 is linear in shape with the ethyl acetate moiety adopting fully extended conformation, while the molecule of 2 is L-shaped with the molecule being twisted at the C10 atom. The crystal structure of 1 adopts a two-dimensional zig-zag architecture featuring C–H…O intermolecular interactions, while that of 2 features strong N–H…O hydrogen bonds and intermolecular interactions of the type N–H…N and C–H…N, resulting in a two-dimensional structure. Furthermore, a detailed analysis of the intermolecular interactions and crystal packing of 1 and 2 via Hirshfeld surface analysis and fingerprint plots was performed. The antibacterial and antifungal activities of both the compounds have been studied against several microorganisms, and were found to be moderately active.     

N6‐Furfuryladenine (kinetin) hydrochloride

In the title compound, N⁶‐furfuryl­adenin‐3‐ium chloride, C₁₀H₁₀N₅O⁺·Cl⁻, the adenine moiety exists as the N3‐protonated N7–H tautomer. The orientation of the N6 substituent (furfuryl moiety) is distal to the imidazole ring of the adenine base. The dihedral angle between the adenine plane and the furfuryl ring plane is 76.1 (2)°. Three N—H⋯Cl hydrogen bonds are responsible for the formation of a supramolecular chain‐like pattern. These supramolecular chains are interconnected by C—H⋯Cl hydrogen bonds to form a hydrogen‐bonded sheet and a three‐dimensional hydrogen‐bonded network.     

Crystal structure and Hirshfeld surface analysis of a salt of antineoplastic kinase inhibitor vandetanib

A salt of vandetanib, namely, 4-({4-[(4-bromo-2-fluorophenyl)amino]-6-methoxyquinazolin-7-yl}methoxy)-1-methylpiperazin-1-ium 2-(butylamino)-4-phenoxy-6-sulfamoylbenzoate acetonitrile monosolvate, C₂₂H₂₅BrFN₄O₂⁺·C₁₇H₁₉N₂O₅S⁻·C₂H₃N, composed of kinase inhibitor vandetanib and sulfamyl diuretic bumetanide in a 1:1 molar ratio, is reported. There is proton transfer between the piperidine ring of vandetanib and the carboxyl group of bumetanide to form the salt. In the vandetanib cation, the arene and pyrimidine rings are not coplanar, their planes subtending a dihedral angle of 60.47 (14)°. The roles of the intermolecular interactions in the crystal packing were clarified using Hirshfeld surface analysis, and two-dimensional fingerprint plots indicate that the most important contributions to the crystal packing are from H…H (40.5%), O…H/H…C (20.7%), C…H/ H…C (18.8%) and N…C/C…N (9.0%) contacts.     

7‐Iodo‐5‐aza‐7‐deazaguanine ribonucleoside: crystal structure,physical properties,base‐pair stability and functionalization

The positional change of nitrogen‐7 of the RNA constituent guanosine to the bridgehead position‐5 leads to the base‐modified nucleoside 5‐aza‐7‐deazaguanosine. Contrary to guanosine, this molecule cannot form Hoogsteen base pairs and the Watson–Crick proton donor site N3—H becomes a proton‐acceptor site. This causes changes in nucleobase recognition in nucleic acids and has been used to construct stable `all‐purine' DNA and DNA with silver‐mediated base pairs. The present work reports the single‐crystal X‐ray structure of 7‐iodo‐5‐aza‐7‐deazaguanosine, C<sub>10</sub>H<sub>12</sub>IN<sub>5</sub>O<sub>5</sub> ( 1 ). The iodinated nucleoside shows an anti conformation at the glycosylic bond and an N conformation (O4′‐endo) for the ribose moiety, with an antiperiplanar orientation of the 5′‐hydroxy group. Crystal packing is controlled by interactions between nucleobase and sugar moieties. The 7‐iodo substituent forms a contact to oxygen‐2′ of the ribose moiety. Self‐pairing of the nucleobases does not take place. A Hirshfeld surface analysis of 1 highlights the contacts of the nucleobase and sugar moiety (O—H…O and N—H…O). The concept of pK‐value differences to evaluate base‐pair stability was applied to purine–purine base pairing and stable base pairs were predicted for the construction of `all‐purine' RNA. Furthermore, the 7‐iodo substituent of 1 was functionalized with benzofuran to detect motional constraints by fluorescence spectroscopy.     

Synthesis of Artificial Glycoconjugate Polymers Carrying 6-O-Phosphocholine α-D-Glucopyranoside,Biologically Active Segment of Main Cell Membrane Glycolipids of Mycoplasma Fermentas

ABSTRACT

The conformation of two mannose-based amidines, the N-benzylmannoamidine and a pseudo (1→6) dimannoside, has been evaluated using semi-empirical AMI calculations and ¹H NMR studies. The most stable conformations of the mannoamidine ring correspond to the half-chair forms ³H₄ and ⁴H₃. The conformations (Z) or (E) about the exocyclic C-N bond depend on the substituents and it was shown that, in solution, the N-benzylmannoamidine was (E)-configured whilst the pseudo (1→6) dimannoside was (Z)-configured. Using the grid-search approach, the potential energy maps of both mannoamidines were calculated as a function of the torsion angles which define the orientation of the amidine substituent. Three stable conformers were identified for the N-benzylmannoamidine and seven for the pseudo (1→6) dimannoside. Inter-glycosidic NOE have provided evidence for a preferred conformation of the pseudo (1→6) dimannoside in solution. The transition state structure of the α-phenylmannose hydrolysis was optimized using the AMI method and compared to the N-benzylmannoamidine. The developing oxocarbenium ion is well matched by the mannoamidine ring but the orientation of the phenyl group in the inhibitor differs significantly from the position of the leaving group in the transition state. The use of sugar type amidines as haptens to obtain catalytic antibodies is then discussed.

     

Interplay of noncovalent interactions in antiseptic quaternary ammonium surfactant Miramistin

The molecular and crystal structure of the widely used antiseptic benzyldimethyl{3‐[(1‐oxotetradecyl)amino]propyl}ammonium chloride monohydrate (Miramistin, MR ), C₂₆H₄₇N₂O⁺·Cl^?·H₂O, was determined by a single‐crystal X‐ray diffraction study and analyzed in the framework of the QTAIM (quantum theory of atoms in molecules) approach using both periodic and molecular DFT (density functional theory) calculations. The various noncovalent intermolecular interactions of different strengths were found to be realized in the hydrophilic parts of the crystal packing (i.e. O—H…Cl, N—H…Cl, C—H…Cl, C—H…O and C—H…π). The hydrophobic parts are built up exclusively by van der Waals H…H contacts. Quantification of the interaction energies using calculated electron‐density distribution revealed that the total energy of the contacts within the hydrophilic and hydrophobic regions are comparable in value. The organic MR cation adopts the bent conformation with the head group tilted back to the long‐chain alkyl tail in both the crystalline and the isolated state due to stabilization of this geometry by several intramolecular C—H…π, C—H…N and H…H interactions. This conformation preference is hypothesized to play an important role in the interaction of MR with biomembranes.     

Effect of the position of a methoxy substituent on the antimicrobial activity and crystal structures of 4‐methyl‐1,6‐diphenylpyrimidine‐2(1H)‐selenone derivatives

Derivatives of pyrimidine‐2(1H)‐selenone are a group of compounds with very strong antimicrobial activity. In order to study the effect of the position of the methoxy substituent on biological activity, molecular geometry and intermolecular interactions in the crystal, three derivatives were prepared and evaluated with respect to their antimicrobial activities, and their crystal structures were determined by X‐ray diffraction. The investigated compounds, namely, 1‐(X‐methoxyphenyl)‐4‐methyl‐6‐phenylpyrimidine‐2(1H)‐selenones (X = 2, 3 and 4 for 1 , 2 and 3 , respectively), C₁₈H₁₆N₂OSe, showed very strong activity against selected strains of Gram‐positive bacteria and fungi. Two compounds, 1 and 2 , crystallize in the monoclinic space group P2₁/c, while 3 crystallizes in the space group P2₁/n; 1 has two molecules in the asymmetric unit and the other two ( 2 and 3 ) have one molecule. The geometries of the investigated compounds differ slightly in the mutual orientations of the aromatic and pyrimidineselenone rings. The O atom in 1 stabilizes the conformation of the molecules via intramolecular C—H…O hydrogen bonding. The packing of molecules is determined by weak C—H…N and C—H…Se intermolecular interactions and additionally in 1 and 2 by C—H…O intermolecular interactions. The introduction of the methoxy substituent results in greater selectivity of the investigated compounds.     

N‐Tosyl‐l‐proline benzene hemisolvate: a rare example of a hydrogen‐bonded carboxylic acid dimer with symmetrically disordered H atoms

The carboxylic acid group is an example of a functional group which possess a good hydrogen‐bond donor (–OH) and acceptor (C=O). For this reason, carboxylic acids have a tendency to self‐assembly by the formation of hydrogen bonds between the donor and acceptor sites. We present here the crystal structure of N‐tosyl‐l ‐proline (TPOH) benzene hemisolvate {systematic name: (2S)‐1‐[(4‐methylbenzene)sulfonyl]pyrrolidine‐2‐carboxylic acid benzene hemisolvate}, C₁₂H₁₅NO₄S·0.5C₆H₆, (I), in which a cyclic R₂²(8) hydrogen‐bonded carboxylic acid dimer with a strong O—(H)…(H)—O hydrogen bond is observed. The compound was characterized by single‐crystal X‐ray diffraction and NMR spectroscopy, and crystallizes in the space group I2 with half a benzene molecule and one TPOH molecule in the asymmetric unit. The H atom of the carboxyl OH group is disordered over a twofold axis. An analysis of the intermolecular interactions using the noncovalent interaction (NCI) index showed that the TPOH molecules form dimers due to the strong O—(H)…(H)—O hydrogen bond, while the packing of the benzene solvent molecules is governed by weak dispersive interactions. A search of the Cambridge Structural Database revealed that the disordered dimeric motif observed in (I) was found previously only in six crystal structures.     

Structure and Conformational Analysis of 5,5-Bis(bromomethyl)-2-(4-methoxyphenyl)-1,3-dioxane

The structure of 5,5-bis(bromomethyl)-2-(4-methoxyphenyl)-1,3-dioxane has been studied by ¹H and ¹³C NMR and X-ray diffraction. Molecules of the title compound exist in the chair conformation with equatorial orientation of the methoxyphenyl substituent. The dioxane ring inversion path, free conformational energy, and optimal conformation of the aryl group have been determined by computer simulation in terms of the DFT PBE/3ζ method. The calculation results are consistent with the X-ray diffraction data.     

L-(-)-α-苯乙胺类立方烷结构2-萘甲酸二聚体盐的晶体结构

L-(-)-α-苯乙胺与消旋的类立方烷结构2-萘甲酸二聚体相互作用形成铵盐,其晶体结构表明,L-(-)-α-苯乙胺与类立方烷结构2-萘甲酸二聚体作用形成的铵离子通过氢键N_2A-HN_2B…O_5A和N_1A-HN_1A…O_3A与类立方烷结构2-萘甲酸二聚体结合在一起.同时类立方烷结构2-萘甲酸二聚体的两个对映异构体之间也存在分子间氢键O_1A-H_1AA…O_6A和O_1B-H_1AB…O_6B.这些氢键将类立方烷结构2-萘甲酸二聚体的两个对映异构体连在同一个晶胞中,呈现两条分子链状堆积.     

Conformational dimorphism in o‐nitrobenzoic acid: alternative ways to avoid the O…O clash

Polymorphism is a challenging phenomenon and the competitive packing alternatives which are characteristic for polymorphs may be encountered for essentially rigid molecules. A second crystal form of the well known compound o‐nitrobenzoic acid, C₇H₅NO₄, an important intermediate in the production of dyes, pharmaceuticals and agrochemicals, is described. Although obtained serendipitously, its intra‐ and intermolecular features match expectations from database searches and theoretical calculations. O—H…O hydrogen‐bonded carboxylic acid dimers represent the building blocks in both polymorphs. For steric reasons and in agreement with a calculated potential energy surface, the carboxylic acid and nitro groups cannot simultaneously be coplanar with the benzene ring but have to tilt. In the well established crystal form, this out‐of‐plane torsion is more pronounced for the nitro substituent. In contrast, the new polymorph is characterized by a major tilt of the carboxylic acid group. The molecules in both alternative crystal forms achieve a similar compromise with respect to acceptable intramolecular O…O contacts.     

Ab initio- and density-functional studies of conformational behaviour of N-formylmethionine in gaseous phase

The current work is a study of the conformational space of the non-ionic N-formylmethionine molecule around its seven structurally significant internal backbone torsional angles at B3LYP/6-31++G(d,p) levels of theory in the gaseous phase. The potential energy surface exploration reveals that a total of 432 different conformers would result if all the possible combinations of the internal rotations were to be considered. A set of twelve conformers of the N-formylmethionine molecule are then further analysed in terms of their relative stabilities, theoretically predicted harmonic vibrational frequencies, HOMO-LUMO energy gaps, ESP charges, rotational constants and dipole moments calculated using MP2/6-31++G(d,p) and B3LYP/6-311++G(d,p) levels. The calculated relative energy-range of the conformers at the MP2 level is 11.08 kcal mol^?1 (1 kcal = 4.1868 kJ), whereas the same obtained at the B3LYP level is 10.02 kcal mol^?1. The results of this study provide a good account of the role of four types of intramolecular H-bonds, namely O…H—O, O…H—N, O…H—C and N…H—C, in influencing the energies of the conformers as well as their conformational and vibrational spectroscopic aspects. The relative stability order of the conformers appears to depend on the level of theory used while the vibrational frequencies calculated at the B3LYP level are in better agreement with the experimental values.     

<Superscript>1</Superscript>H and <Superscript>13</Superscript>C NMR Study of Bifurcated Intramolecular Hydrogen Bonds in 2,6-Bis(2-pyrrolyl)pyridine and 2,6-Bis(1-vinyl-2-pyrrolyl)pyridine

According to the ¹H and ¹³C NMR data, bifurcated intramolecular hydrogen bond NH?N?HN in 2,6-bis(2-pyrrolyl)pyridine fixes its molecule in a conformation with syn orientation of the pyrrole rings. An analogous bifurcated hydrogen bond CH?N?HC is formed in 2,6-bis(1-vinyl-2-pyrrolyl)pyridine. 2-(1-Vinyl-2-pyrrolyl)-6-(2-pyrrolyl)pyridine is characterized by unsymmetrical bifurcated hydrogen bond NH? N?HC.     

Solid‐State Form Screen of Cardiosulfa and Its Analogues

Cardiosulfa is a biologically active sulfonamide molecule that was recently shown to induce abnormal heart development in zebrafish embryos through activation of the aryl hydrocarbon receptor (AhR). The present report is a systematic study of solid‐state forms of cardiosulfa and its biologically active analogues that belong to the N‐(9‐ethyl‐9H‐carbazol‐3‐yl)benzene sulfonamide skeleton. Cardiosulfa (molecule 1 ; R¹=NO₂, R²=H, R³=CF₃), molecule 2 (H, H, CF₃), molecule 3 (CF₃, H, H), molecule 4 (NO₂, H, H), molecule 5 (H, CF₃, H), and molecule 6 (H, H, H) were synthesized and subjected to a polymorph search and solid‐state form characterization by X‐ray diffraction, differential scanning calorimetry (DSC), variable‐temperature powder X‐ray diffraction (VT‐PXRD), FTIR, and solid‐state (ss) NMR spectroscopy. Molecule 1 was obtained in a single‐crystalline modification that is sustained by N? H???π and C? H???O interactions but devoid of strong intermolecular N? H???O hydrogen bonds. Molecule 2 displayed a N? H???O catemer C(4) chain in form I, whereas a second polymorph was characterized by PXRD. The dimorphs of molecule 3 contain N? H???π and C? H???O interactions but no N? H???O bonds. Molecule 4 is trimorphic with N? H???O catemer in form I, and N? H???π and C? H???O interactions in form II, and a third polymorph was characterized by PXRD. Both polymorphs of molecule 5 contain the N? H???O catemer C(4) chain, whereas the sulfonamide N? H???O dimer synthon R₂²(8) was observed in polymorphs of 6 . Differences in the strong and weak hydrogen‐bond motifs were correlated with the substituent groups, and the solubility and dissolution rates were correlated with the conformation in the crystal structure of 1 , 2 , 3 , 4 , 5 , 6 . Higher solubility compounds, such as 2 (10.5 mg mL^?1) and 5 (4.4 mg mL^?1), adopt a twisted confirmation, whereas less‐soluble 1 (0.9 mg mL^?1) is nearly planar. This study provides practical guides for functional‐group modification of drug lead compounds for solubility optimization.