Fluoro Atom Research Articles

Synthesis, spectroscopy and biological investigation via DFT, ADMET and molecular docking of Thiadiazole/Oxadiazole based bis-Schiff bases: A potential towards diabetes and microbes

A novel series of varied substituted thiadiazole/oxadiazole based bis-Schiff base derivatives (1–10) was synthesized and characterized using NMR (13CNMR and 1HNMR) and HREI-mass spectrometry. To determine their anti-diabetic potential, these analogues were examined against α-amylase and α-glucosidase. These compounds demonstrated varied inhibitory range between IC50 = 1.10 ± 0.50 to 21.40 ± 0.20 µM (α-amylase) and 2.50 ± 0.05 to 21.40 ± 0.10 µM (α-glucosidase), when contrasted with Acarbose, a well-known marketed drug (IC50 = 3.16 ± 0.22 &4.8 ± 0.21 µM for α-amylase and α-glucosidase respectively). Analog-9 having tri-fluoromethyl group at para position of benzene ring emerged as lead candidate among these synthesized compounds. The effective activity of compound-9 may be due to involvement of fluoro atoms interacting via hydrogen-bonding with the selected sites of diabetic enzymes, α-amylase and α-glucosidase. Furthermore, for exploration of binding interactions of potent drugs and reactivity of potent analogues, molecular docking as well as DFT was performed. For investigation of drug likeness and toxicity, ADME analysis was also conducted.

Insights into the role of potent thiadiazole based Schiff base derivatives in targeting type-II diabetes: A combine in-vitro and in-silico approaches

A novel series of varied substituted thiadiazole based Schiff base analogues (1–21) were designed and characterized using NMR (13C, 1H) and HREI-mass spectrometry, and secerned against the enzymes responsible for hyperglycemia i-e α-amylase and α-glucosidase. Newly designed analogues demonstrated distinct inhibitory activities having IC50= 1.10 ± 0.50 to 21.40 ± 0.20 µM (for alpha-amylase) and 2.50 ± 0.05 to 21.40 ± 0.10 µM (for alpha-glucosidase) in contrast to acarbose a well-known marketed drug (IC50 = 3.16 ± 0.22 & 4.8 ± 0.21 µM for α-amylase and α-glucosidase, respectively). Compound (20) with tri-fluoromethyl at para position of aromatic ring revealed as lead candidate among the members of synthesized series, having effective inhibitory activity against enzymes α-amylase and α-glucosidase. The excellent activity of compound (20) might be due to involvement of fluoro atom interacting via H-bonding with the active sites of enzymes α-amylase and α-glucosidase being targeted. Furthermore, for exploration of binding interactions of potent drugs, molecular docking was performed. For investigation of drug likeness and toxicity, ADME analysis was also conducted.

A 3,3'-Difluoro-2,2'-Bithiophene Based Donor Polymer Realizing High Efficiency (>17%) Single Junction Binary Organic Solar Cells.

In this study, two novel donor-acceptor (D-A) copolymers are designed and synthesized, DTBT-2T and DTBT-2T2F with 2,2'-bithiophene or 3,3'-difluoro-2,2'-bithiophene as the donor unit and dithienobenzothiadiazole as the acceptor unit, and used them as donor materials in non-fullerene organic solar cells (OSCs). Due to enhanced planarity of polymer chains resulted by the intramolecular F···S noncovalent interactions, the incorporation of 3,3'-difluoro-2,2'-bithiophene unit instead of 2,2'-bithiophene into the polymers can enhance their molecular packing, crystallinity and hole mobility. The DTBT-2T:L8-BO based binary OSCs deliver a power conversion efficiency (PCE) of only 9.71% with a Voc of 0.78V, a Jsc of 20.69mAcm-2 , and an FF of 59.67%. Moreover, the introduction of fluoro atoms can lower the highest occupied molecular orbital levels. As a result, DTBT-2T2F:L8-BO based single-junction binary OSCs exhibited less recombination loss, more balanced charge mobility, and more favorable morphology, resulting in an impressive PCE of 17.03% with a higher Voc of 0.89V, a Jsc of 25.40mAcm-2, and an FF of 75.74%. These results indicate that 3,3'-difluoro-2,2'-bithiophene unit can be used as an effective building block to synthesize high performance polymer donor materials. This work greatly expands the selection range of donor units for constructing high-performance polymers.

Identification of CH2-linked quinolone-aminopyrimidine hybrids as potent anti-MRSA agents: Low resistance potential and lack of cross-resistance with fluoroquinolone antibiotics

The structural optimization of B14, an antibacterial agent we previously obtained, has led to the discovery of a new class of CH2-linked quinolone-aminopyrimidine hybrids with potent anti-MRSA activities. Surprisingly, the hybrids lacking a C-6 fluoro atom at the quinolone nucleus showed equal or even stronger anti-MRSA activities than their corresponding 6-fluoro counterparts, despite the well-established structure-activity relationships (SARs) indicating that the 6-fluoro substituent enhances the antibacterial activity in conventional fluoroquinolone antibiotics. Moreover, these new hybrids, albeit structurally related to conventional fluoroquinolones, showed no cross-resistance with fluoroquinolone drugs. The most active compound, 15m, exhibited excellent activities with a MIC value of 0.39 μg/mL against both fluoroquinolone-sensitive strain USA500 and -resistant MRSA isolate Mu50. Further resistance development studies indicated MRSA is unlikely to acquire resistance against 15m. Moreover, 15m displayed favorable in vivo half-life and safety profiles. These findings suggest a rationale for further evolution of quinolone antibiotics with a high barrier to resistance.

Development of Novel Fluorinated Polyphenols as Selective Inhibitors of DYRK1A/B Kinase for Treatment of Neuroinflammatory Diseases including Parkinson’s Disease

Natural polyphenol derivatives such as those found in green tea have been known for a long time for their useful therapeutic activity. Starting from EGCG, we have discovered a new fluorinated polyphenol derivative (1c) characterized by improved inhibitory activity against DYRK1A/B enzymes and by considerably improved bioavailability and selectivity. DYRK1A is an enzyme that has been implicated as an important drug target in various therapeutic areas, including neurological disorders (Down syndrome and Alzheimer's disease), oncology, and type 2 diabetes (pancreatic β-cell expansion). Systematic structure-activity relationship (SAR) on trans-GCG led to the discovery that the introduction of a fluoro atom in the D ring and methylation of the hydroxy group from para to the fluoro atom provide a molecule (1c) with more desirable drug-like properties. Owing to its good ADMET properties, compound 1c showed excellent activity in two in vivo models, namely the lipopolysaccharide (LPS)-induced inflammation model and the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) animal model for Parkinson's disease.

Piperazine ring toxicity in three novel anti-breast cancer drugs: an in silico and in vitro metabolic bioactivation approach using olaparib as a case study.

The metabolic activation of small-molecule drugs into electrophilic reactive metabolites is widely recognized as an indicator of idiosyncratic adverse drug reactions (IADRs). Three novel anti-breast cancer drugs containing piperazine rings, ribociclib (Kisqali®, RCB), abemaciclib (Verzenio®, ABC), and olaparib (Lynparza®, OLP), were selected to study the effect of different chemical environment on the piperazine ring activation using in silico and in vitro metabolic experiments. ABC and RCB were previously studied and we noticed the piperazine ring in ABC could be strongly bioactivated generating more reactive intermediates than piperazine ring in RCB. OLP was further used as a case study to show the power of in silico software to predict the piperazine ring activation that was approved using in vitro experiments. Initially, predictions of susceptible sites in the metabolism and reactivity pathways were performed using the StarDrop P450 model and XenoSite reactivity tool, respectively. Later, in vitro OLP metabolites were characterized based on rat liver microsomes (RLMs) using KCN (trapping agent) using LC-MS/MS. The main goal of the current study was to answer the question of whether the presence of a piperazine ring in the chemical structure should be always considered a structural alert. Piperazine ring in RBC and ABC was bioactivated through a metabolic sequence that involves the hydroxylation of α-carbon to the tertiary nitrogen atoms of the piperazine ring. In the case of OLP, no cyano adduct was formed due to the presence of two carbonyl groups attached to the two nitrogen atoms of the piperazine ring (neutral amide groups). From the results, piperazine ring in certain cases should not be considered as a structural alert as in the case of OLP due to the presence of two electron withdrawing group that stops the proposed toxicity. Also blocking the bioactive center (α-carbon) using steric hindrances such as methyl group, also the isosteric replacement of α-carbon hydrogen with fluoro atom can aid in reducing the toxic side effects of ABC and RCB. These experiments were done in vitro through incubation with RLMs in the presence of KCN. Also, the results are supported by data generated from in silico software. In the future, drug discovery studies using this concept could be undertaken, allowing for the development of new drugs with reasonable safety profiles. Overall, in vitro RLMs incubations and in silico experiments were able to predict successfully that the piperazine ring should not always be considered a structural alert.

2-Alkyl substituted benzimidazoles as a new class of selective AT2 receptor ligands

Ligands comprising a benzimidazole rather than the imidazole ring that is common in AT2R ligands e.g. in the AT2R agonist C21, can provide both high affinity and receptor selectivity. In particular, compounds encompassing benzimidazoles, substituted in the 2-position with small bulky groups such as an isopropyl (Ki = 4.0 nM) or a tert-butyl (Ki = 5.3 nM) or alternatively a thiazole heterocycle (Ki = 5.1 nM) demonstrate high affinity and AT2R selectivity. An n-butyl chain, as found in the AT1R selective sartans, makes the ligand less receptor selective. The isobutyl group on the biaryl scaffold present in most AT2R selective ligands reported so far was originally derived from the nonselective potent AT1R/AT2R ligand L-162,313. Notably, in all ligands discussed herein, the isobutyl group was substituted by an n-propyl group and ligands with high affinity to AT2R were provided and in addition the majority of them demonstrate a favorable AT2R/AT1R selectivity. The introduction of fluoro atoms in various positions had no pronounced effect on the affinity data. Ligands with a thiazole or a tert-butyl group attached to the 2-position and with a terminal trifluoromethyl butoxycarbonyl sidechain exhibited a similar stability as C21 in human liver microsomes, while other ligands examined were less stable in the microsome assay.

Antimicrobial Activity Evaluation of Newly Synthesized N,N-Disubstituted Taurinamidobenzenesulfonamide Derivatives

Herein we synthesized 6 new N,N-disubstituted taurinamidobenzensulfonamide derivatives and characterized their structures by means of 1H and 13C NMR, HR-MS analysis. In addition, their in vitro antibacterial and antifungal activities were tested against two gram-positive, two gram-negative bacteria, and two fungal strains by using broth microdilution method. Compounds 1 (methoxy substitution) and 2 (methyl substitution) displayed the best antibacterial activity against Escherichia coli and Staphylococcus aureus, respectively. E. faecalis was affected by compounds 1, 2, 4, and 6, becoming the most susceptible pathogen compared to other tested bacterial and fungal strains. Interestingly, changing fluoro atom in compound 6 with the chloro atom, as in compound 5, deteriorated the antibacterial activity against all bacterial strains. As a result, these results provide us to investigate the relationship between structural changes and antibacterial/antifungal activity, which can be further used to develop more effective taurine derivatives.

Design, synthesis and antiproliferative activity evaluation of fluorine-containing chalcone derivatives

A series of new chalcones containing fluoro atom at B ring have been designed, synthesized, and evaluated to be antiproliferative activity against a panel of human tumor cell lines. Some of the analogs (8, 9, 12, 45, 46 and 48) displayed powerful antiproliferative effects to certain human tumor cells, but all of them were devoid of any cytotoxicity towards the normal HEK 293. Acridine orange staining data supported that the cytotoxic and antiproliferative effects of the synthesized analogs on tumor cells are mediated through apoptosis. The compounds 12 and 46 manifested concentration-dependent antiproliferative activity in human hepatocellular carcinoma cell lines using an xCELLigence assay. The structures and antiproliferative activity relationship were further supported by in silico molecular docking study of the compounds against tubulin protein which suggests our compounds interference to cell division. Communicated by Ramaswamy H. Sarma

Design, synthesis, molecular modeling, and biological evaluation of acrylamide derivatives as potent inhibitors of human dihydroorotate dehydrogenase for the treatment of rheumatoid arthritis

Human dihydroorotate dehydrogenase (DHODH) is a viable target for the development of therapeutics to treat cancer and immunological diseases, such as rheumatoid arthritis (RA), psoriasis and multiple sclerosis (MS). Herein, a series of acrylamide-based novel DHODH inhibitors as potential RA treatment agents were designed and synthesized. 2-Acrylamidobenzoic acid analog 11 was identified as the lead compound for structure–activity relationship (SAR) studies. The replacement of the phenyl group with naphthyl moieties improved inhibitory activity significantly to double-digit nanomolar range. Further structure optimization revealed that an acrylamide with small hydrophobic groups (Me, Cl or Br) at the 2-position was preferred. Moreover, adding a fluoro atom at the 5-position of the benzoic acid enhanced the potency. The optimization efforts led to potent compounds 42 and 53‒55 with IC50 values of 41, 44, 32, and 42 nmol/L, respectively. The most potent compound 54 also displayed favorable pharmacokinetic (PK) profiles and encouraging in vivo anti-arthritic effects in a dose-dependent manner.

Effect of the Fluoro-Substituent Position on the Crystal Structure and Photoluminescence of Microcrystals of Platinum β-Diketonate Complexes.

Molecular packing has an important effect on the photophysical properties of crystalline materials. We demonstrate in this work the modulation of molecular packing and emission properties of microcrystals by minor molecular structural variations. Four platinum β-diketonate complexes, with two fluoro substituents (1) or one fluoro atom substituted on different positions of the auxiliary phenylpyridine ligand (2-4) have been synthesized. These complexes were used to prepare one-dimensional microcrystals with well-defined shapes and uniform sizes. Although 1-4 display similar emission spectra in the solution state, the corresponding microcrystals display different emission colors from green to yellow and orange. In addition, different temperature-responsive (80-298 K) emission spectral changes have been observed from these microcrystals, including the intensity variation of the locally excited (LE) emission without obvious wavelength shifts, competition between the LE and metal-metal-to-ligand charge-transfer emissions, and the sole wavelength shift of the π-π excimer emissions. These differences in emission properties are rationalized by different molecular packings of these materials, as revealed by single-crystal X-ray analyses.

Improved mesomorphic behaviour and large birefringence of fluorinated liquid crystals containing ethynyl and 1-methyl-1H-benzimidazole moieties

ABSTRACT With altering molecular dipole moments via lateral fluoro atom and π-conjugation through carbon–carbon triple bond, improved mesomorphic behaviour is achieved for new kind of fluorinated mesogenic compounds containing ethynyl and 1-methyl-1H-benzimidazole moieties, namely, 2-[4-[2-[4-(alkoxy) phenyl]ethynyl]-3-fluorophenyl]-1-methyl-1H-benzimidazole derivatives (nPEF(3)PMx). The compounds nPEF(3)PMx mainly display enantiotropic nematic mesophases with mesophase ranges of 27.1–59.1 °C and 62.7–96.7°C on heating and cooling for nPEF(3)PMH, 59.499.1°C and 96.2–144.6°C for nPEF(3)PMM, and 101.6–109.4°C and 104.9–157.2°C for nPEF(3)PMN (n < 8), respectively. Compared with nonfluorinated reference analogues I, nPEF(3)PMx give obviously lower melting points and much wider or comparable nematic mesophase ranges, meanwhile, they show much lower melting points and higher nematic mesophase stability than reference analogues II because of their reduced molecular dipole moments and enhanced π-conjugation. In addition, the compounds nPEF(3)PMx are composed of benzene ring, ethynyl bridge and benzimidazole mesogenic unit, therefore, they have high birefringence of 0.48–0.62 resulted from their large π-conjugated molecule. The result indicates that nPEF(3)PMx has a potential application in liquid crystal mixture.

Molecular docking, design, synthesis and biological evaluation of novel 2,3-aryl-thiazolidin-4-ones as potent NNRTIs

ABSTRACTNonnucleoside reverse transcriptase inhibitors (NNRTIs) remain the most promising anti-AIDS agents that target the HIV-1 reverse transcriptase enzyme (RT). However, the efficiency of approved NNRTI drugs has decreased by the appearance of drug-resistant viruses and side effects upon long-term usage. Thus, there is an urgent need for developing new, potent NNRTIs with broad spectrum against HIV-1 virus and with improved properties. In this study, a series of thiazolidinone derivatives was designed based on a butterfly mimicking scaffold consisting of a substituted benzothiazolyl moiety connected with a substituted phenyl ring via a thiazolidinone moiety. The most promising derivatives were selected using molecular docking analysis and PASS prediction program, synthesized and evaluated for HIV-1 RT inhibition. Five out of fifteen tested compounds exhibited good inhibitory action. It was observed that the presence of Cl or CN substituents at the position 6 of the benzothiazole ring in combination with two fluoro atoms at the ortho-positions or a hydrogen acceptor substituent at the 4-position of the phenyl ring are favourable for the HIV RT inhibitory activity.

Structure analysis and antiviral activity of CW-33 analogues against Japanese encephalitis virus

Japanese encephalitis virus (JEV) is a member of neurotropic flaviviruses transmitted by mosquito bites, causing severe central nervous system disorders. Current JEV genotype III vaccines have a low protection against genotype I isolates in the risk zone. The lead compound CW-33, ethyl 2-(3′,5′-dimethylanilino)-4-oxo-4,5-dihydrofuran-3-carboxylate, demonstrates the antiviral activity against JEV with an IC50 values of 38.5 μM for virus yield reduction (Int J Mol Sci 2016,17: E1386). This study synthesized fourteen CW-33 analogues containing a fluoro atom or one methoxy group at the C-2, C-3, or C-4 of anilino ring, and then evaluated for their antiviral activity and mechanism. Among 6 amalogues, CW-33A (ethyl 2-(2-fluoroanilino)-4-oxo- 4,5-dihydrofuran-3-carboxylate), and CW-33D (ethyl 2-(3-methoxyanilino)-4-oxo- 4,5-dihydrofuran-3-carboxylate exhibited antiviral potentials in viral cytopathic effect (CPE) inhibition. CW-33A significantly suppressed the viral protein expression, genome synthesis and intracellular JEV particle production, showing a higher inhibitory effect on JEV yield than CW-33 and CW-33D. The study demonstrated that a mono-fluoro substitution on at the C-2 anilino ring of CW-33 improved the antiviral activity JEV, revealing the structure-activity relationship for developing novel agents against JEV infection.

Targeted Fluoro Positioning for the Discovery of a Potent and Highly Selective Matrix Metalloproteinase Inhibitor.

Invited for this month's cover picture is the group of Professor Rainer Riedl from the Institute of Chemistry and Biotechnology at the Zurich University of Applied Sciences (ZHAW), Switzerland. The cover picture depicts the structure‐based design of a drug‐like small molecule inhibitor of matrix metalloproteinase‐13 (MMP‐13) with a combined dual binding motif. The targeted introduction of a single fluoro atom was of vital importance for the optimization of the inhibitor. For more details, read the full text of the Communication at 10.1002/open.201600158.

Synthesis, activity and docking studies of phenylpyrimidine–carboxamide Sorafenib derivatives

Two series of Sorafenib derivatives bearing phenylpyrimidine–carboxamide moiety (16a–g and 17a–p) were designed, synthesized and evaluated for the IC50 values against three cancer cell lines (A549, MCF-7 and PC-3). Two selected compounds (17f and 17n) were further evaluated for the activity against VEGFR2/KDR kinase. More than half of the synthesized compounds showed moderate to excellent activity against three cancer cell lines. Compound 17f showed equal activity to Sorafenib against MCF-7 cell line, with the IC50 values of 6.35±0.43μM. Meanwhile, compound 17n revealed more active than Sorafenib against A549 cell line, with the IC50 values of 3.39±0.37μM. Structure–activity relationships (SARs) and docking studies indicated that the second series (17a–p) showed more active than the first series (16a–g). What’s more, the introduction of fluoro atom to the phenoxy part played no significant impact on activity. In addition, the presence of electron-donating on aryl group was benefit for the activity.

Synthesis and evaluation of halogenated 12N-sulfonyl matrinic butanes as potential anti-coxsackievirus agents

Twenty-eight new 12N-benzenesulfonyl matrinic butane and halogenated 12N-sulfonyl matrinic butane/ethane derivatives were designed, synthesized and evaluated for their anti-coxsakievirus activities against CVB3 taking compound 1 as the lead. SAR analysis indicated the introduction of a fluoro atom on the 1'-position might be helpful for keeping potency. Among them, compound 8a exhibited potential activities against all CVBs with IC50 ranging from 0.69 to 5.14 μM, suggesting a broad-spectrum anti-coxsackievirus B feature. In addition, it also displayed an excellent PK and a good safety profile, indicating a highly druggable nature. Thus, we consider compound 8a to be a promising drug candidate in the treatment of not only viral myocarditis caused by CVB3 but also various diseases infected with coxsackieviruses B.

Structural Characterization of [Zn(O2CAr4F‐Ph)2(TAD)] and Determination of Its Stable Conformation by DFT Calculations

In the titled complex, [Zn(C19H11O2F2)2(C8H22N4)]∙0.5CH2Cl2, the Zn2+ cation, with two axial carboxylate ligands, is located in a hexacoordinate ZnO2N4 environment. Two strong intra‐molecular hydrogen‐bonding interactions (CO⋯ H—N) between the carboxylate ligand and amine are observed, in addition to two weak intra‐molecular interactions among the aromatic C—H moieties and oxygen atoms of the carboxylate ligand. An inter‐molecular interaction is also detected between the aromatic C—H of the carboxylate ligand and the fluoro atom of the other carboxylate ligand. According to B3LYP/LANL2DZ calculations, the energy minimum of the title complex is achieved when the planes of the OCO moieties of the axial carboxylates are perpendicular, as observed in the crystal structure.

Synthesis and Anti-HIV-1 Evaluation of Some Novel MC-1220 Analogs as Non-Nucleoside Reverse Transcriptase Inhibitors.

Some novel MC-1220 analogs were synthesized by condensation of 4,6-dichloro-N-methylpyrimidin-2-amine derivatives (1a,b and 15) and/or 4-chloro-6-methoxy-N,N,5-trimethylpyrimidin-2-amine (2a) with the sodium salt of 2,6-difluorophenylacetonitrile followed by treatment with aqueous sodium hydroxide in methanol, alkylation, reduction, halogenation, and/or acidic hydrolysis. All synthesized compounds were evaluated for their activity against HIV-1. The most active compound in this study was compound 7, which showed activity against HIV-1 comparable to that of MC-1220. The only difference in structure between compound 7 and MC-1220 is a fluoro atom instead of a CH3 group.

Synthesis, and docking studies of phenylpyrimidine-carboxamide derivatives bearing 1H-pyrrolo[2,3-b]pyridine moiety as c-Met inhibitors

Four series of phenylpyrimidine-carboxamide derivatives bearing 1H-pyrrolo[2,3-b]pyridine moiety (14a–e, 15a–g, 16a–e and 17a–g) were designed, synthesized and evaluated for the IC50 values against three cancer cell lines (A549, PC-3 and MCF-7). Four selected compounds (15e, 16a–b and 17a) were further evaluated for the activity against c-Met kinase, HepG2 and Hela cell lines. Most of the compounds showed excellent cytotoxicity activity and selectivity with the IC50 valuables in single-digit μM to nanomole range. Eleven of them are equal to more active than positive control Foretinib against one or more cell lines. The most promising compound 15e showed superior activity to Foretinib against A549, PC-3 and MCF-7 cell lines, with the IC50 values of 0.14±0.08μM, 0.24±0.07μM and 0.02±0.01μM, which were 4.6, 1.6 and 473.5 times more active than Foretinib (0.64±0.26μM, 0.39±0.11μM, 9.47±0.22μM), respectively. Structure–activity relationships (SARs) and docking studies indicated that the replacement of phenylpicolinamide scaffold with phenylpyrimidine fragment of the target compounds was benefit for the activity. What’s more, the introduction of fluoro atom to the aminophenoxy part played no significant impact on the activity and any substituent group on aryl group is unfavourable for the activity.