Fluoro Substituents Research Articles

Isomer‐Dependent Melting Behavior of Low Molar Mass Azobenzene Derivatives: Observation of a Higher Melting Z‐Isomer

AbstractAzobenzene compounds are putative solar thermal fuels (STF) due to the excellent photostability and structural control of isomerization rates. Azobenzenes, in which both Z‐ and E‐isomers are liquid at room temperature, are promising candidates for STF flow technology. A literature survey of melting points led to the synthesis and isomer separation of ortho‐ and meta‐monosubstituted azobenzenes with fluoro, methyl, ethyl, trifluoromethyl and methoxy substituents and several dimethyl substituted azobenzenes. Four of the compounds are liquid azobenzenes with higher specific energy than literature work with higher molar mass, liquid compounds. Eight of the compounds unexpectedly displayed a higher melting point for the Z‐isomer which is rarely observed. Intermolecular close contacts in the crystal lattice of the Z‐isomer are the main factor responsible for the higher melting temperatures.

Synthesis and in vitro Metabolic Stability of Sterically Shielded Antimycobacterial Phenylalanine Amides.

Nα-aroyl-N-aryl-phenylalanine amides (AAPs) are RNA polymerase inhibitors with activity against Mycobacterium tuberculosis and non-tuberculous mycobacteria. We observed that AAPs rapidly degrade in microsomal suspensions, suggesting that avoiding hepatic metabolism is critical for their effectiveness in vivo. As both amide bonds are potential metabolic weak points of the molecule, we synthesized 16 novel AAP analogs in which the amide bonds are shielded by methyl or fluoro substituents in close proximity. Some derivatives show improved microsomal stability, while being plasma-stable and non-cytotoxic. In parallel with the metabolic stability studies, the antimycobacterial activity of the AAPs against Mycobacterium tuberculosis, Mycobacterium abscessus, Mycobacterium avium and Mycobacterium intracellulare was determined. The stability data are discussed in relation to the antimycobacterial activity of the panel of compounds and reveal that the concept of steric shielding of the anilide groups by a fluoro substituent has the potential to improve the stability and bioavailability of AAPs.

Effects of mono- or di-fluoro-substitution on spin crossover behavior in a pair of Schiff base-like FeII-coordination polymers.

Spin crossover (SCO) has long been a hot topic in the field of molecular magnetism owing to its unique bistability character. Rational control of thermal hysteresis and transition temperature (T1/2) is crucial for their practical applications, which rely on precise manipulation of the substituents of SCO coordinating ligands and molecular packing interactions. In this study, we designed two different bridging ligands (2-FDPB: 4,4'-(2-fluoro-1,4-phenylene)dipyridine; 2,3-FDPB: 4,4'-(2,3-difluoro-1,4-phenylene)dipyridine) featuring one and two fluoro substitution on the central benzene ring and applied a Schiff base-like equatorial tetradentate ligand {diethyl(E,E)-2,2'-[4,5-difluoro-1,2-phenyl-bis(iminomethylidyne)]bis(3-oxobutanoate)-(2-)-N,N',O3,O3'} (H2L) to coordinate with the FeII ion. Two FeII-coordination chain polymers [FeII(L)(2,3-FDPB)]·0.25CH2Cl2 (1) and [FeII(L)(2-FDPB)]·0.5CH3OH (2) were obtained. 1 crystallizes in the monoclinic P21/n space group with only one FeII center, while 2 crystallizes in the triclinic P1̄ space group with two independent FeII centers. Unlike the identical 2D layer stacking in 1, 2 exhibited alternating stacking of the extending 2D layers and meshed chains. Magnetic measurements revealed the typical thermally induced spin crossover behavior (SCO): 1 exhibited a 41 K-wide thermal hysteresis with transition temperatures of T1/2↑ = 245 K and T1/2↓ = 204 K, while 2 showed a higher transition temperature (T1/2 = 330 K) with no thermal hysteresis. Magneto-structural correlation studies suggest that the electron-withdrawing effect present in the fluoro substituents does not have a significant impact on the SCO behaviors. Despite the fluoro substituents having a similar atomic radius of hydrogen atoms, variations in the number of these substituents can alter the crystallization behavior of these complexes, which in turn affects the solvents, molecular stacking patterns, and intermolecular interactions, ultimately influencing the SCO behaviors.

Analyzing the impact of the size of fluoro and chloro substituents on induced mesomorphism in hydrogen bonded liquid crystals.

Synthesis of new supramolecules with specific properties and realistic applications requires a sound knowledge of the structure-property relationships of the synthesized molecules. Non-covalent interaction like hydrogen bonding is conducive in realizing mesomorphism. The induction of the liquid crystalline character is associated with the strength of hydrogen bonds formed between the interacting components, which are affected by the change of polarity and polarizability of both components upon change in their terminal polar substituents. When the polar substituents are similar in their reactivity, how does the size of the polar substituent influence the mesomorphism? New hydrogen bonded liquid crystals are synthesized with fluorine and chlorine as substituents, and the mesomorphic behaviour is studied with the size of the substituent as a critical parameter. The chemical characterization is carried out by FTIR measurements, the phase characterization by polarizing optical microscopy and the thermal characterization by differential scanning calorimetry. The DFT method utilizing wb97x-D theory along with the cc-pVTZ basis set were used for the calculations. The hybrid functional B3LYP-D3 and Gaussian type basis set 6-31G(d,p) were used for studying the orientation of the molecules. It is observed that the ortho substituents reduce the co-planarity, meta substituents lead to the molecular broadening while para substituents exhibited highest mesomorphism by enhancing longitudinal dipole moment. Fluoro substituted compounds are exhibiting higher mesomorphism while the bulky chloro substituents are helping to better stack the molecules possessing longer chain lengths.

Regiocontrol Using Fluoro Substituent on 3,6-Disubstituted Arynes.

The effect of fluoro substituent on the regioselectivity of several reactions of 3,6-disubstituted arynes was studied. These arynes contained another inductively electron-withdrawing substituent other than fluorine. A reasonable degree of regiocontrol was achieved in the (3 + 2) cycloaddition reaction of 3,6-disubstituted aryne containing both fluorine and bromine atoms with benzyl azide. Furthermore, the insertion reaction of aryne into Sn-F σ-bonds and the three-component coupling reaction involving the insertion of aryne into C=O π-bonds also led to the high degree of regiocontrol.

Catalyst-Free Synthesis of Novel 4-(Benzofuran-2-yl)-N-phenylthiazol-2(3H)-imines, Crystal Structure Elucidation, and the Effect of Phenyl Substitution on Crystal Packing

A one-pot reaction of an equimolar mixture of 4-methoxyaniline, phenyl isothiocyanate, and 2-bromoacetylbenzofuran in absolute ethanol in the absence of any catalysts afforded 4-(benzofuran-2-yl)-3-(4-methoxyphenyl)-N-phenylthiazol-2(3H)-imine with an 83% yield. Under similar conditions, 4-flouroaniline provided a mixture of the expected 4-(benzofuran-2-yl)-3-(4-fluorophenyl)-N-phenylthiazol-2(3H)-imine and unexpected 4-(benzofuran-2-yl)-N-(4-fluorophenyl)-3-phenylthiazol-2(3H)-imine at an overall 73% yield. The structures of the synthesized heterocycles were confirmed using NMR spectroscopy. The products were recrystallized from dimethylformamide to afford samples suitable for structural determination via single-crystal diffraction. The molecules of the products share a common backbone and have similar conformations. They also display some common intermolecular interactions, including C–H···X (X = N, O, π) and π···π contacts. The molecules differ due to the methoxy and fluoro substituents on their phenyl rings, resulting in variations in the extended network in the crystals. Electron density maps and Hirshfeld surfaces have been used to rationalize the intermolecular contacts.

3-Methoxy-2-phenylimidazo[1,2-b]pyridazines highly active against Mycobacterium tuberculosis and Mycobacterium marinum

A series of 3-methoxy-2-phenylimidazo[1,2-b]pyridazine derivatives which were highly active against autoluminescent Mycobacterium tuberculosis (Mtb) and Mycobacterium marinum (Mm) in an in vitro assay were identified. SAR analysis showed that the most active compounds, which included a phenyl group bearing fluoro substituent(s) at C2, a methoxy function at C3, and a benzyl-heteroatom moiety at C6, exhibited in vitro MIC90 values generally around 0.63–1.26 μM against Mtb and Mm. However, these compounds were inactive against Mtb in vivo (mice), and investigations revealed very short metabolic half-lives (<10 min) when incubated with mouse liver microsomes. Multiple observations of side products produced from oxidative cleavage of the imidazole moiety during the chemical synthesis work suggested that this is a likely metabolic pathway leading to the lack of observed activity in vivo.

Synthesis, biological evaluation and in silico studies of novel thiadiazole-hydrazone derivatives for carbonic anhydrase inhibitory and anticancer activities

ABSTRACT Thiadiazole and hydrazone derivatives (5a–5i) were synthesized and their chemical structures were verified and described by 1H NMR, 13C NMR, and HRMS spectra. Three cancer cell lines (MCF-7, MDA, and HT-29) and one healthy cell line (L929) were used to test the cytotoxicity activity of synthesized compounds as well as their inhibitory activity against carbonic anhydrase I, II and IX isoenzymes. Compound 5d (29.74 µM) had a high inhibitory effect on hCA I and compound 5b (23.18 µM) had a high inhibitory effect on hCA II. Furthermore, compound 5i was found to be the most potent against CA IX. Compounds 5a-5i, 5b and 5i showed the highest anticancer effect against MCF-7 cell line with an IC50 value of 9.19 and 23.50 µM, and compound 5d showed the highest anticancer effect against MDA cell line with an IC50 value of 10.43 µM. The presence of fluoro substituent in the o-position of the phenyl ring increases the effect on hCA II, while the methoxy group in the o-position of the phenyl ring increases the activity on hCA I as well as increase the anticancer activity. Cell death induction was evaluated by Annexin V assay and it was determined that these compounds cause cell death by apoptosis. Molecular docking was performed for compounds 5b and 5d to understand their biological interactions. The physical and ADME properties of compounds 5b and 5d were evaluated using SwissADME.

Synthesis and Structural Analysis of N3‐Methyluridine and 2’‐Alkoxy/Fluoro‐N3‐Methyluridine Nucleosides by Using NMR Spectroscopy, X‐Ray Crystallography, and Computational Methods

AbstractDual modifications (base and sugar) in siRNA have the potential to overcome off‐target effects and impart nuclease resistance. Here we present the synthesis and detailed structural analysis of N3‐methyluridine and 2’‐alkoxy/fluoro‐N3‐methyluridine modifications, the rationally designed modifications for oligonucleotide therapeutics. Using X‐ray crystallography and 1H NMR spectral data, it is clear that the C2’‐endo conformation of N3‐methyluridine switches to the C3’‐endo pucker state preferentially due to the introduction of electron‐withdrawing 2’‐alkoxy or fluoro substituents. DFT study confirms that the modifications preferentially acquire the C3’‐endo conformation. NBO analysis indicates that in the presence of the 2’‐alkoxy/fluoro substituents, the C3’‐endo conformation is stabilized due to nO4’→σ*C1’‐N1 anomeric as well as σC3’‐H→σ*C2’‐R and σC1’‐C2’→σ*C3’‐OH hyperconjugation effects. The W−C hydrogen bond energies of the modified nucleosides were calculated using the DFT and SAPT methods at the modified base pair regions, and it was observed that one of the hydrogen bonds gets disrupted due to the presence of the N3‐methyl group, causing significant decline in hydrogen bond energy. These detailed structural studies will help to expand the scope of these destabilizing modifications in the rational design of RNAi‐based therapeutics.

Design, Synthesis and Antimicrobial Activity of 1,3-Diazine Derivatives

Background: Pyrimidines have been shown to possess numerous biological activities, such as antimicrobial, anticancer, anticonvulsant, antiviral, and anti-inflammatory. Objective: Encouraged by these data, the synthesis of 2-((1H-benzo[d]imidazol-2-yl)methylthio)-4- amino-6-phenylpyrimidine-5-carbonitrile (3a-g) was performed. Methods: 4-amino-2-mercapto-6-phenylpyrimidine-5-carbonitrile was dissolved in an aqueous sodium hydroxide solution, and to this clear solution, 2-chloromethyl-1H-benzimidazole in methanol was added, and the reaction mixture was stirred under reflux to get the desired product. The structures of the newly synthesized compounds were confirmed by their physical, chemical, and spectral data. The synthesized derivatives were screened for their in vitro antibacterial activity against Gram-positive bacteria, Staphylococcus aureus and Bacillus subtilis, and Gram-negative bacteria, Escherichia coli and Pseudomonas aeruginosa, by using ciprofloxacin as a reference standard. While, their antifungal activity was evaluated against Aspergillus niger and Candida albicans using fluconazole as a reference drug. The docking study was performed to check the interactions of target compounds (3a-g) with homo sapiens DHFR (PDB: 1S3V), bacterial (S. aureus) DHFR (PDB: 2W9T), and DHPS (PDB: 1AD4) protein. The dock score and binding interactions were recorded. Result: The antimicrobial activity study indicated compounds with chloro (3b), fluoro (3f), and bromo (3g) substituents to show good antibacterial as well as antifungal activity. The docking study revealed that the same compounds, i.e., 3b, 3f, and 3g, showed good dock score and comparable interactions compared to the reference ligand (trimethoprim/sulfadiazine), which confirmed their selectivity. Conclusion: It can be presumed that the synthesized compounds have the capability for further promotion as novel antimicrobial agents.

Synthesis and Cytotoxic Evaluation of New Fluoro and Trifluoromethyl Substituents Containing Chromeno[2,3‐d]pyrimidines

AbstractIn this research, microwave‐assisted “one‐pot” multicomponent reactions have been employed for the synthesis of new chromeno[2,3‐d]pyrimidines containing fluorine atoms. The biological significance of the obtained compounds was highlighted by evaluating in vitro for cytotoxic activity against four human cancer cell lines (HepG2, hepatoma carcinoma; MCF7, breast cancer; A549, non‐small lung cancer; KB, epidermoid carcinoma). Interestingly, two compounds revealed significant inhibitory activity against A549 cell line, and showed low toxicity to human embryonic kidney (Hek‐293) cell line. The synthetic efficacy and cytotoxic potency have offered an opportunity to further development of chromeno[2,3‐d]pyrimidines containing fluorine atoms as potential anticancer agents.

Rh(I)-Catalyzed Enantioselective Arylation of Cyclic N-Sulfonyl Diketimines Using Planar-Chiral Phosphine-Olefin Ligands Based on a (Cyclopentadienyl)manganese(I) Scaffold with a Highly Fluorinated Aryl Phosphino Group.

Catalytic enantioselective 1,2-addition reactions of arylboronic acids with 1,2,5-thiadiazoline 1,1-dioxide derivatives were achieved using planar-chiral phosphine-olefin ligand L5 with a bis[(2,3,4,5,6-pentafluoro)phenyl]phosphino group, showing ≤98% ee. The enantioselectivities of the addition products were improved by increasing the number of fluoro substituents on the aromatic ring of the ligand. X-ray crystallographic studies of 3aa and [RhCl/L5]2 revealed the absolute configuration of the enantioenriched addition product 3 and the mode of phosphine-olefin bidentate coordination of L5 to a rhodium(I) cation.

Vibrational frequency Analysis, DFT and in Vitro Fungicidal Activity Studies of Biphenyl-4-Carboxylic Acid, 2,4-Difluorobiphenyl and 4-Acetylbiphenyl- A Comparative Study

Comparative spectroscopic investigation of Biphenyl-4-carboxylic acid (BCA), 4-Acetylbiphenyl (ACB) and 2,4-difluorobiphenyl (DFB) are obtained by using Density Functional Theory (DFT) with B3LYP functional at 6-311++G(d, p) basis set. The vibrational assignments have been proposed with aid of the results of Normal Coordinate Analysis (NCA). The effects of carboxyl, acetyl and fluoro substituents on the vibrational frequencies of biphenyl have been investigated and compared. The molecular stability and bond strength was investigated by applying the Natural Bond Orbital (NBO) analysis. The other molecular properties like Mulliken charge analysis, HOMO-LUMO analysis and Molecular Electrostatic Potential (MESP) of the title compounds have been reported. In vitro analysis have been performed with two fungal pathogens Aspergillus niger and Candida albicans using well diffusion method. BCA compound exhibited excellent activity against the Aspergillus niger with zone of inhibition values in the range of 22 and 25 mm in 40 and 80 µl with 10 mg/ml. Molecular docking studies of the most active compound are carried out, and results showed reasonable binding modes in the fungicide active site of phytase protein Fophys and Succinate dehydrogenase (SDH) proteins. A preliminary Structure-Activity Relationship study of the biphenyl derivatives has led to the recognition of some important structural requirements for antifungal activity. Furthermore the fungicide-likeness analysis of BCA, DFB and ACB compounds have been developed to predict its fungicide activity by using fungiPAD webtool.

Fluoro, Trifluoromethyl, and Trifluoroacetyl Substituent Effects on Cycloaddition Reactivities: Computations and Analysis.

The importance of fluoro and trifluoromethyl substituents in drug effectiveness prompted the computational exploration of fluorine-containing substituents in valuable synthetic cycloadditions. Diels-Alder or 1,3-dipolar cycloaddition reactions of typical reactants, cyclopentadiene, N-phenyldiazoacetamide, tetrazine, and N-phenylsydnone involving fluorine-containing substituents (F, CF3, and COCF3) were studied with M06-2X density functional theory. Inductive and conjugative effects influence normal and inverse electron-demand reactions differently. These results provide a guide to the design and use of cycloadditions for the introduction of fluoro and trifluoromethyl substituents in synthetic processes.

Synthesis, biological assessment, and computational investigations of nifedipine and monastrol analogues as anti-leishmanial major and anti-microbial agents.

Leishmaniasis includes a range of parasitic diseases caused by numerous types of the protozoan kinetoplastid parasite. Fungal and bacterial pathogens have led to infectious illnesses causing some main public health problem in current years. A series of dihydropyridine and tetrahydropyrimidine derivatives having fluoro, bromo, and nitro substituents at para-phenyl ring on C4 of dihydropyridine and tetrahydropyrimidine rings were synthesized. Then, anti-leishmanial and antimicrobial potencies of compounds were assessed. All compounds were synthesized via Hantzsch and Biginelli reactions. All derivatives were evaluated for their anti-leishmanial and antimicrobial activities. Moreover, docking and molecular dynamics simulation calculations of the compounds in PRT1 binding site were performed to report the results of anti-leishmanial and antimicrobial activities. Compounds 4a and 4b showed the highest anti-amastigote and anti-promastigote activities. Compound 4a revealed the highest antimicrobial activity against E. coli, P. aeruginosa, and C. albicans strains. In addition, compound 4c showed the highest activity against S. aureus. The fluoro, bromo, and nitro substituents in para-position of phenyl group at C4 of dihydropyridine and tetrahydropyrimidine moieties as well as the bulk and length of the chain linking to the ester moieties are essential for anti-leishmanial and anti-microbial activities of these derivatives. Low cytotoxicity was shown by most of derivatives against macrophages. The molecular docking studies were in agreement with in vitro assay. Moreover, hydrogen binds, RMSF, RMSD, and Rg, strongly showed the steady binding of 4a and 4b compounds in PRT1 active site.

Designing High-Performance Wide Bandgap Polymer Donors by the Synergistic Effect of Introducing Carboxylate and Fluoro Substituents

Designing High-Performance Wide Bandgap Polymer Donors by the Synergistic Effect of Introducing Carboxylate and Fluoro Substituents

Synthesis and Cytotoxic Evaluation of Fluoro and Trifluoromethyl Substituents Containing Novel Naphthoquinone-Fused Podophyllotoxins

A series of novel naphthoquinone-fused podophyllotoxins containing fluoro and trifluoromethyl substituents were synthesized in a medium with good yields using two different synthetic approaches: microwave-assisted four-component reactions of 2-hydroxy-1,4-naphthoquinone, tetronic acid, fluorinated arylaldehydes, and ammonium acetate, and microwave-assisted three-component reactions of 2-amino-1,4-naphthoquinone, tetronic acid, and fluorinated arylaldehydes. The structures of all products were confirmed by spectral analysis. Together, cytotoxicity assessment of the products against four human cancer cell lines (human carcinoma [KB], human hepatocellular carcinoma [HepG2], lung cancer [A549], breast carcinoma [MCF7], and human embryonic kidney [Hek-293]) was performed by MTT assay. Among the obtained compounds, compound 7f turned out to be the most potent anticancer agent with significant cytotoxic activity against KB, HepG2, and MCF cancer cell lines.

Synthesis and Biological Evaluation of Aurachin D Analogues as Inhibitors of Mycobacterium tuberculosis Cytochrome bd Oxidase.

A revised total synthesis of aurachin D (1a), an isoprenoid quinolone alkaloid that targets Mycobacterium tuberculosis (Mtb) cytochrome bd (cyt-bd) oxidase, was accomplished using an oxazoline ring-opening reaction. The ring opening enabled access to a range of electron-poor analogues, while electron-rich analogues could be prepared using the Conrad-Limpach reaction. The aryl-substituted and side-chain-modified aurachin D analogues were screened for inhibition of Mtb cyt-bd oxidase and growth inhibition of Mtb. Nanomolar inhibition of Mtb cyt-bd oxidase was observed for the shorter-chain analogue 1d (citronellyl side chain) and the aryl-substituted analogues 1g/1k (fluoro substituent at C6/C7), 1t/1v (hydroxy substituent at C5/C6) and 1u/1w/1x (methoxy substituent at C5/C6/C7). Aurachin D and the analogues did not inhibit growth of nonpathogenic Mycobacterium smegmatis, but the citronellyl (1d) and 6-fluoro-substituted (1g) inhibitors from the Mtb cyt-bd oxidase assay displayed moderate growth inhibition against pathogenic Mtb (MIC = 4-8 μM).

One pot, three component synthesis of fluoro and trifluoromethyl substituted unsymmetrical dihydropyrazine fused acridine-3-carboxamide using renewable 2-MeTHF solvent and their DFT studies

Six novel unsymmetrical trisubstituted urea derivatives were synthesized, characterised and their DFT studies were reported in this present work. 1,1′-carbonyldiimidazole (CDI) was used to generate carbonyl functional group of unsymmetrical urea by employing non-hazardous, renewable 2-MeTHF solvent. Excellent yields of unsymmetrical urea (90-95%) and higher purities of the products (>97%) were achieved under slow addition of a solution of 1.5 equivalent of CDI in 2-MeTHF to a pre-dissolved solution of 1.0 equivalent of fluoro or trifluoromethyl substituents containing aniline and 1.0 equivalent of dihydropyrazine fused acridine in 2-MeTHF at room temperature. Column chromatographic purification is not required in this methodology. DFT studies were carried for all six novel products.

Synthesis of fluoro and trifluoromethyl substituents containing novel tetracyclic N-benzylated benzopiperazine fused acridone regioisomers using a greener solvent 2-MeTHF and their DFT studies

The current work reports the synthesis of novel tetracyclic N-benzylated benzopiperazine fused acridone regioisomers tagged with three trifluoromethyl and three fluoride substituents. The novelty of this work is based on the execution of green chemical principles, 2-MeTHF (2-Methyl Tetrahydrofuran) was employed as renewable solvent during this benzylation reaction (carried out at room temperature) resulting higher yields (87-94%) under halogenated solvent free methodology. The optimized reaction consists of 1.0 equivalent of compound benzopiperazine fused acridone, 1.5 equivalents of compound appropriate benzyl bromide, 2.0 equivalents of KH, 2-MeTHF solvent (5ml with respect to 1mmol of compound 1).