Chloro Substituents Research Articles

Role of secondary interactions in a series of 2:1 halogen-bonded cocrystals formed between 4-(dimethylamino)pyridine and ditopic halogen-bond donors.

The structures of a series of 2:1 cocrystals formed between 4-(dimethylamino)pyridine and each of 1,2,4,5-tetrachloro-3,6-diiodobenzene, 2C7H10N2·C6Cl4I2, 1,2,4,5-tetrabromo-3,6-diiodobenzene, 2C7H10N2·C6Br4I2, 1-bromo-4-iodo-2,3,5,6-tetrafluorobenzene, 2C7H10N2·C6BrF4I, and 1,2-dibromo-4,5-difluoro-3,6-diiodobenzene, 2C7H10N2·C6Br2F2I2, are reported. In all five structures, the core halogen-bonded 2:1 trimolecular units have geometrically similar parameters, with the central halogen-bond donor flanked by two pyridine halogen-bond acceptors twisted with respect to the central halogen-bond donor at angles ranging from 76 to 86°. The I...N halogen-bond separations are all short, ranging from 73.3 to 76.7% of the sum of the van der Waals radii, while the C-I...N bond angles are essentially linear. The Br...N halogen-bond separation in the cocrystal formed with 1-bromo-4-iodo-2,3,5,6-tetrafluorobenzene is 80.4% of the sum of the van der Waals radii. Subtle differences in the crystal packings are attributed to the role of secondary C-H...π and weak π-type interactions with chloro and bromo substituents. The cocrystals 2C7H10N2·C6Cl4I2 and 2C7H10N2·C6Br4I2 are isomorphous.

3D-QSAR, Pharmacophore Modeling, ADMET, and DFT Studies of Halogenated Conjugated Dienones as Potent MAO-B Inhibitors.

It has been reported that the extension of conjugation in chalcone scaffolds considerably enhanced the potency, selectivity, reversibility, and competitive mode of MAO-B inhibition. In this study, using the experimental results of IC50 values of fifteen halogenated conjugated dienone derivatives (MK1-MK15) against MAO-B, we developed a 3DQSAR model. Further, we created a 3D pharmacophore model in active compounds in the series. The built model selected three variables (G2U, RDF115m, RDF155m) among the 653 AlvaDesc molecular descriptors, with a r2 value of 0.87 and a Q2 cv for cross-validation equal to 0.82. The three variables were mostly associated with the direction of symmetry and the likelihood of discovering massive atoms at great distances. The evaluated molecules exhibited a good correlation between experimental and predicted data, indicating that the IC50 value of the structure MK2 was related to the interatomic distances of 15.5 Å between bromine and chloro substituents. Furthermore, the molecules in the series with the highest activity were those with enhanced second component symmetry directional index from the 3D representation, which included the structures MK5 and MK6. Additionally, a pharmacophore hypothesis was developed and validated using the decoy Schrodinger dataset, with an ROC score of 0.87 and an HHRR 1 fitness score that ranged from 2.783 to 3.00. The MK series exhibited a significant blood-brain barrier (BBB) permeability, according to exploratory analyses and in silico projections, and almost all analogues were expected to have strong BBB permeability. Further DFT research revealed that electrostatics were important in the interactions with MAO-B.

D4-Symmetric Dirhodium Tetrakis(binaphthylphosphate) Catalysts for Enantioselective Functionalization of Unactivated C-H Bonds.

Dirhodium tetrakis(2,2'-binaphthylphosphate) catalysts were successfully developed for asymmetric C-H functionalization with trichloroethyl aryldiazoacetates as the carbene precursors. The 2,2'-binaphthylphosphate (BNP) ligands were modified by introduction of aryl and/or chloro functionality at the 4,4',6,6' positions. As the BNP ligands are C2-symmetric, the resulting dirhodium tetrakis(2,2'-binaphthylphosphate) complexes were expected to be D4-symmetric, but X-ray crystallographic and computational studies revealed this is not always the case because of internal T-shaped CH-π and aryl-aryl interactions between the ligands. The optimum catalyst is Rh2(S-megaBNP)4, with 3,5-di(tert-butyl)phenyl substituents at the 4,4' positions and chloro substituents at the 6,6' positions. This catalyst adopts a D4-symmetric arrangement and is ideally suited for site-selective C-H functionalization at unactivated tertiary sites with high levels of enantioselectivity, outperforming the best dirhodium tetracarboxylate catalyst developed for this reaction. The standard reactions were conducted with a catalyst loading of 1 mol % but lower catalyst loadings can be used if desired, as illustrated in the C-H functionalization of cyclohexane in 91% ee with 0.0025 mol % catalyst loading (29,400 turnover numbers). These studies further illustrate the effectiveness of donor/acceptor carbenes in site-selective intermolecular C-H functionalization and expand the toolbox of catalysts available for catalyst-controlled C-H functionalization.

Anion- and water-facilitated oxidative carbon–carbon bond cleavage and diketonate carboxylation in Cu(II) chlorodiketonate complexes

The O2-dependent carbon–carbon (CC) bond cleavage reactions of the mononuclear Cu(II) chlorodiketonate complexes [(6-Ph2TPA)Cu(PhC(O)CClC(O)Ph)]ClO4 (1-ClO4) and [(bpy)Cu(PhC(O)CClC(O)Ph)(ClO4)] (3-ClO4) have been further examined in terms of their anion and water dependence. The bpy-ligated Cu(II) chlorodiketonate complex 3-ClO4 is inherently more reactive with O2 than the 6-Ph2TPA-ligated analog 1-ClO4. Added chloride is needed to facilitate O2 reactivity for 1-ClO4 but not for 3-ClO4 at 25(1) °C. Evaluation of kobs for the reaction of 1-ClO4 with O2 under pseudo first-order conditions as a function of the amount of added chloride ion produced saturation type behavior. The bpy-ligated 3-ClO4 exhibits different behavior, with rate enhancement resulting from both the addition of chloride ion and water. Computational studies indicate that the presence of water lowers the barrier for O2 activation for 3-ClO4 by ∼12 kcal/mol whereas changing the anion from perchlorate to chloride has a smaller effect (lowering of the barrier by ∼3 kcal/mol). Notably, the effect of water for 3-ClO4 is of similar magnitude to the barrier-lowering chloride effect found in the O2 activation pathway for 1-ClO4. Thus, both systems involve lower energy O2 activation pathways available, albeit resulting from different ligand effects. Probing the effect of added benzoate anion, it was found that the chloro substituent in the diketonate moiety of 1-ClO4 and 3-ClO4 will undergo displacement upon treatment of each complex with tetrabutyl ammonium benzoate to give Cu(II) benzoyloxydiketonate complexes (4 and 5). Complexes 4 and 5 exhibit slow O2-dependent CC cleavage in the presence of added chloride ion. These results are discussed in the context of the chemistry identified for various divalent metal chlorodiketonate complexes, which have relevance to catalytic systems and metalloenzymes that mediate O2-dependent CC cleavage within diketonate substrates.

Electronic inductive and resonance effects of substituents on concerted two-proton-coupled electron transfer between electrogenerated superoxide and hydroquinone derivatives in N,N-dimethylformamide

Improving energy conversion technologies is pivotal for reducing the effects of global warming. The use of electron transfer catalysts based on electron carriers found in organisms, such as redox biomimetic quinone systems, is a promising route for truly efficient energy conversion. Herein, we report the density functional theory (DFT)-based analysis of the reaction between electrogenerated superoxide radical anion (O2•−) and methyl- or chloro-substituted benzene-1,4-diol (hydroquinone) derivatives in N,N-dimethylformamide. We investigate the electrochemical scavenging of O2•− by hydroquinone derivatives involving two proton transfers (PTs) and one electron transfer (ET). We show that chloro and methyl substituents promote a proton-coupled electron transfer (PCET) reaction with the effect increasing with the number of substituent groups. Our DFT results demonstrate that the substituent effect promotes either of the PT or ET processes, along a sequential PCET pathway. The electrochemical and DFT analyses of the substituent effect indicate that the concerted two-proton-coupled electron transfer (2PCET) promoted by an increasing number of the substituents is a plausible pathway for the reaction between electrogenerated O2•− and hydroquinone derivatives. In addition, our findings show that the resonance effect is the main driving force for the promotion of 2PCET.

Facile synthesis of pyrimidine substituted-1,3,4-oxadiazole, 1,3,4-thiadiazole and 1,2,4-triazole derivatives and their antimicrobial activity correlated with molecular docking studies

Organosilicon reagent-trimethylsilyl isothiocyanate, a common reagent for the development of 1,3,4-oxadiazoles, 1,3,4-thiadiazoles and 1,2,4-triazoles was reported by the reaction with heteroaromatic acid hydrazides under conventional and ultrasonication methodologies in a polar protic solvent, ethanol under appropriate conditions. Molecular docking studies were performed with the X-ray crystal structures of the target molecules (PDB ID: 2w9s and PDB ID: 6f0e). The docking results indicated that H-bond interactions and hydrophobic interactions were responsible for the inhibition of protein. All 15 synthesized molecules showed excellent binding energy than the standard drugs. The compounds 3a, 3b, 3e, 5a, 5b, 5e and 7a exhibited low MIC values against S. aureus whereas 3a, 3b, 5a, 5b and 7a against B. subtilis. The compounds 5a, and 5b also displayed low MIC values against P. aeruginosa. The MBC of these compounds is 2×MIC, and is equal to standard drug, Chloramphenicol. The compounds 3a, 3b, 3e, 5a, 5b, 5d and 5e showed low MIC values against A. niger whereas 3a, 5a, 5b, 7a, 7b and 7e against P. Chrysogenum. The MFC is 2×MIC and is equal to standard drug, Fluconazole. The structure-activity relationship of the compounds revealed that unsubstituted, methyl and nitro substituted compounds showed greater antimicrobial activity than those with chloro and bromo substituents. [Display omitted]

Synthesis, Characterization, Crystal Structures and Urease Inhibition of Some Thiosemicarbazones

Six new thiosemicarbazones were prepared and structurally characterized by elemental analysis, NMR and IR spectra and single-crystal X-ray diffraction. The compounds were evaluated for their Jack bean urease inhibitory activities. Among the compounds, those with hydroxyl and chloro substituent groups have effective activity with IC50 values of 1.8-12.7 μmol L–1. Docking simulations were performed to insert the molecules of the compounds into the active urease site determined by the crystal structure to determine their probable binding modes.

Design and Synthesis of Quinoline‐Pyrazine Based Carboxamides: Leukemic Cancer Active Ugi Adducts

AbstractThe design and synthesis of new chemical entities (NCEs) with suitable physicochemical properties are playing a key role in medicinal research areas. Hence, we have designed and synthesized the 10 diverse scaffolds by rightly selecting the quinoline and pyrazine to articulate carboxamide derivatives in a single‐step process with maximum conversation in a shorter time through diverse studies of Ugi multi‐component reaction. Molecular docking studies against FMS‐like tyrosine kinase‐3 (FLT3) provided well‐clustered solutions for the binding modes of these molecules and shed light on the key structural features governing the binding affinity. Two carboxamides derivatives with 3,4,5‐trimethoxy, and chloro substituents showed comparable potency in Leukemia cell lines and medium efficacy in Breast and Melanoma cancer. These results suggest that pyrazine and quinoline‐based carboxamides may be prominent as new anti‐cancer agents in chemotherapy. Additionally, in silico analysis was employed to predict the comprehensive physicochemical ADME profile (absorption, distribution, metabolism, and excretion) of the carboxamide derivatives which was proven drug‐like properties.

Pyrazole Scaffold: Potential PTP1B Inhibitors for Diabetes Treatment.

The overexpression of the Protein Tyrosine Phosphatase 1B (PTP1B), a key role in the development of insulin resistance, diabetes (T2DM) and obesity, seems to have a substantial impact as a negative regulator of the insulin and leptin signaling pathways. Therefore, inhibiting PTP1B is a prospective therapeutic approach for the treatment of diabetes and obesity. However, the pyrazole scaffold is expected to be of significant pharmaceutical interest due to its broad spectrum of pharmacological actions. This study aims to focus on the significance of pyrazole scaffold in medicinal chemistry, the impact of PTP1B in diabetes and the therapeutic approach of pyrazole scaffold to treat T2DM. A comprehensive analysis of the published literature in several pharmaceutical and medical databases, such as the Web of Science (WoS), PubMed, ResearchGate, ScienceDirect etc., were indeed successfully completed and classified accordingly. Results: As reviewed, the various derivatives of the pyrazole scaffold exhibited prominent PTP1B inhibitory activity. The result showed that derivatives of oxadiazole and dibenzyl amine, chloro substituents, 1, 3-diaryl pyrazole derivatives with rhodanine-3-alkanoic acid groups, naphthalene and also 1, 3, 5-triazine-1H-pyrazole-triazolothiadiazole derivatives, octyl and tetradecyl derivative, indole- and N-phenylpyrazole-glycyrrhetinic acid derivatives with trifluoromethyl group, 2,3-pyrazole ring-substituted-4,4-dimethyl lithocholic acid derivatives with 4- fluoro phenyl substituted and additional benzene ring in the pyrazole scaffold significantly inhibits PTP1B. In silico study observed that pyrazole scaffold interacted with amino acid residues like TYR46, ASP48, PHE182, TYR46, ALA217 and ILE219. Diabetes is a metabolic disorder that elevates the risk of mortality and severe complications. PTP1B is a crucial component in the management of diabetes and obesity. As a result, PTP1B is a promising therapeutic target for the treatment of T2DM and obesity in humans. We concluded that the pyrazole scaffold has prominent inhibitory potential against PTP1B.

Design, synthesis, and biological evaluation studies of novel thiophene substituted thiazolidinones scaffold as promising antimicrobial agents

AbstractGlobal public health is profoundly imperiled by antimicrobial resistance (AMR) and has made it extremely difficult to effectively control infectious diseases which are connected to it, so a new series of 5‐benzylidene‐2‐(thiophen‐2‐yl)‐3‐(4H‐1,2,4‐triazol‐4‐yl)thiazolidin‐4‐ones (5a–o) is synthesized. Spectral techniques have been utilized to characterize and confirm the structures of targeted molecules. The outcomes are to be compared with typical drugs given that compounds are examined against gram‐positive and gram‐negative strains of bacteria and fungus. Against bacterial strains, products with nitro, methyl, and bromo substituents in the p‐position of the benzene ring, as well as products with the nitro group at the m‐position, showed very excellent activities against bacterial strains, while compounds with chloro substituent at p‐position and m‐position demonstrated good activity against the fungal strains Aspergillus niger and Fusarium javanicum.

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.

Synthesis, molecular docking, analgesic, anti-inflammatory, and ulcerogenic evaluation of thiophene-pyrazole candidates as COX, 5-LOX, and TNF-α inhibitors.

The thiophene bearing pyrazole derivatives (7a-j) were synthesized and examined for their in vitro cyclooxygenase, 5-lipoxygenase, and tumour inducing factor-α inhibitory activities followed by the in vivo analgesic, anti-inflammatory, and ulcerogenic evaluations. The synthesized series (7a-j) were characterized using 1H NMR, 13C NMR, FT-IR, and mass spectral analysis. Initially, the compounds (7a-j) were evaluated for their in vitro cyclooxygenase, 5-lipoxygenase, and tumour inducing factor-α inhibitory activities and the compound (7f) with two phenyl substituents in the pyrazole ring and chloro substituent in the thiophene ring and the compound (7g) with two phenyl substituents in the pyrazole ring and bromo substituent in the thiophene ring were observed as potent compounds among the series. The compounds (7f and 7g) with effective in vitro potentials were further analyzed for analgesic, anti-inflammatory, and ulcerogenic evaluations. Also, to ascertain the binding affinities of compounds (7a-j), docking assessments were carried out and the ligand (7f) with the highest binding affinity was docked to know the interactions of the ligand with amino acids of target proteins.

Effect of para‐Substituents on meso‐Functionalized Oxidovanadium(IV) Porphyrins as Catalysts for Oxygen Atom Transfer Mediated Oxidation of Benzoin to Benzil under Mild Conditions

AbstractSystematic analysis of the effect of para‐substituents (H, Cl, Br and OMe) on the meso‐phenyl group in vanadyl meso‐tetraphenylporphyrins ([VIVO(TPP)] (R=H, 1), [VIVO(TCPP)] (R=Cl, 2), [VIVO(TBPP)] (R=Br, 3) and [VIVO(TMPP)] (R=OMe, 4)) on their properties and catalytic oxygen atom transfer (OAT) for oxidation of benzoin to benzil using DMSO as well as 30 % aqueous H2O2 as the sacrificial oxygen source have been studied. Electrochemical and theoretical (density functional theory) studies are in good agreement with the influence of these substituents on the catalytic property of these complexes. Complex [VIVO(TCPP)] (2) displayed the best catalytic activity for the conversion (92 %) of benzoin to benzil in 30 h with >99 % product selectivity when DMSO was used as an oxygen source, whereas excellent conversion (~100 %) of benzoin to benzil was noticed in 18 h with 95 % product selectivity when 30 % aqueous H2O2 was used as a source of oxygen. Furthermore, among these complexes, the electron‐withdrawing nature of the chloro substituent at the p‐position of meso‐phenyl group significantly influences the oxygen atom transfer. Experimental and simulated EPR studies confirmed the +4 oxidation of vanadium in these complexes. The structure of 2, 3 and 4, confirmed by single crystal X‐ray diffraction method, are domed in shape, and the displacement of V(IV) ion from the mean porphyrin plane follows the order: 2 (0.458 Å) <3 (0.459 Å) <4 (0.479 Å). We observed that the electron‐withdrawing nature of chloro substituent at the p‐position of meso‐phenyl group influence the oxygen atom transfer from vanadyl porphyrin to dimethyl sulfide much.

Synthesis of Isatin-based Chalcone Derivatives and Their Activity as Antioxidants

The body needs antioxidants to combat free radicals and guard against their damaging effects on healthy cells that might result in degenerative disorders. Several degenerative diseases include hypertension, heart disease, diabetes, stroke, and cancer. The human body can deal with free radical attacks caused by radiation, stress, cigarette smoke, and environmental pollution, so it requires additional external antioxidants to protect against free radical attacks. Chalcone is a compound that has an α,β-unsaturated carbonyl system, which makes chalcone compounds have biological activity. Chalcone compounds may be used in pharmacology as antioxidants, antifungals, antibacterial agents, anticancer agents, and for other biological activities. This study aims to synthesize a chalcone derivative, namely 3-(2-oxo-2-phenylethylidene)indolin-2-one and 5-chloro-3-(2-oxo-2-phenylethylidene)indolin-2-one containing a chloro substituent, as well as test the potential of these compounds as antioxidants. The reflux method of claisen-schmidt condensation of isatin and acetophenone was used to create chalcone derivatives. Spectroscopy was used to characterize the produced chemicals (UV-VIS, IR, and LCMS) and their antioxidant activity using the DPPH method. This study showed that the antioxidant activity of 3-(2-oxo-2-phenylethylidene)indolin-2-one and 5-chloro-3-(2-oxo-2-phenylethylidene)indolin-2-one compounds is very weak at low concentrations.

Structure-Activity Relationships of Triphenylethylene Derivatives and Their Evaluation as Anticancer and Antiviral Agents.

Tamoxifen (TAM) is a selective estrogen receptor modulator (SERM) that is used in the treatment of breast cancer, yet with the risk of developing uterine cancer. A perfect SERM would act as an estrogen activator on bones, the cardiovascular system, and the central nervous system while providing neutral or estrogen blocking effects on the breast and the uterus. Herein, we report on the design, synthesis, and evaluation of new rigid and flexible TAM analogues. Mainly, a chloro substituent is introduced at the para position of the TAM ring C blocking the CYP2D6 hydroxylation site. Most compounds showed estrogenic activity higher than TAM using the yeast estrogen screen assays, indicating the determinant role of the chloro substituent upon functional activity. Despite being estrogenic, compound 2B showed potent antiproliferative activity in the NCI 60 cell lines with mean GI50 = 3.67 μM, GI50 = 1.05 μM on MCF-7 cell lines, and GI50 = 1.30 μM on MDA-MB-231. The estrogenic activity of compound 2B was further confirmed by stimulating alkaline phosphatase in Ishikawa cells, and it showed no increase in relative uterine wet weight in ovariectomized rats. Compound 2F showed EC90 = 0.31 μg/mL and SI90 = 60 against Ebola virus; this is 200-fold more potent than the positive control favipiravir. This is the first time to report estrogenic triphenylethylenes as anti-EBOV agents. The anti-EBOV activity reported is a function of the substitution pattern of the scaffold rather than the functional activity. Moreover, compound 3D showed excellent PO pharmacokinetic properties in mice. In conclusion, for this class of TAM-like compounds, the blockage of the p-position of ring C is decisive for the functional activity; meanwhile, the triarylethylene substitution pattern is detrimental for the antiviral activity.

An Expedient Three-component Synthesis of Novel Pyrido-pyrimidine Derivatives: Antimicrobial Activity, Molecular Docking, and ADME Studies

A facile and efficient protocol for one-pot three-component synthesis of a series of novel 4-substituted-2-thioxo-3,4-dihydro-1H-pyrido[1,2-a]pyrimido[4,5-d]pyrimidin-5(2H)-one derivatives has been developed. Compounds were synthesized by the reaction of 2H-pyrido[1,2-a]pyrimidine-2,4(3H)-dione, various aromatic aldehydes, and thiourea using Iodine as catalyst in acidic medium. The synthesized compounds obtained in good to excellent yields (52–83%) with improved reaction time and chloro substituent at four-position yielded the product in excellent quantity (83%). The synthesized compounds have been characterized by 1H, and 13C NMR, IR, and mass spectral analysis, and screened for their in vitro antibacterial activity against Bacillus subtilis, Salmonella typhemurium, Escherichia. coli, and Staphylococcus aureus using disk diffusion method. Biological screening revealed that the newly synthesized compounds exhibit interesting activities against several bacterial strains. Among all the synthesized compounds, the in vitro antibacterial activity displayed by compound 6j was highest against S. typhemurium with ZOI 23.5. mm (MIC = 3.125 µg/mL). Docking studies further supported the findings, and provided for the basis of linkages in terms of conventional hydrogen bonds, and pi- bonding patterns. In nutshell, the present study thus paved the way for developing lead compounds which could be potentially used as an efficient antibacterial drug in humans after appropriate animal, and clinical trials.

8(meso)-Pyridyl-BODIPYs: Effects of 2,6-Substitution with Electron-Withdrawing Nitro, Chloro, and Methoxycarbonyl Groups.

The introduction of electron-withdrawing groups on 8(meso)-pyridyl-BODIPYs tends to increase the fluorescence quantum yields of this type of compound due to the decrease in electronic charge density on the BODIPY core. A new series of 8(meso)-pyridyl-BODIPYs bearing a 2-, 3-, or 4-pyridyl group was synthesized and functionalized with nitro and chlorine groups at the 2,6-positions. The 2,6-methoxycarbonyl-8-pyridyl-BODIPYs analogs were also synthesized by condensation of 2,4-dimethyl-3-methoxycarbonyl-pyrrole with 2-, 3-, or 4-formylpyridine followed by oxidation and boron complexation. The structures and spectroscopic properties of the new series of 8(meso)-pyridyl-BODIPYs were investigated both experimentally and computationally. The BODIPYs bearing 2,6-methoxycarbonyl groups showed enhanced relative fluorescence quantum yields in polar organic solvents due to their electron-withdrawing effect. However, the introduction of a single nitro group significantly quenched the fluorescence of the BODIPYs and caused hypsochromic shifts in the absorption and emission bands. The introduction of a chloro substituent partially restored the fluorescence of the mono-nitro-BODIPYs and induced significant bathochromic shifts.

Palladium‐Catalyzed C‐H Bond Functionalization of Benzo[1,2‐b : 4,5‐b′]dithiophene‐4,8‐dione: A One Step Access to 2‐Arylbenzo[1,2‐b : 4,5‐b′]dithiophene‐4,8‐diones

AbstractThe reactivity of benzo[1,2‐b : 4,5‐b′]dithiophene‐4,8‐dione in Pd‐catalyzed C−H arylation was investigated. Using aryl bromides as aryl source in the presence of carbonate bases in 1,4‐dioxane, the mono‐C2‐arylated benzo[1,2‐b : 4,5‐b′]dithiophene‐4,8‐diones were regioselectively obtained. This procedure allowed to introduce both electron‐rich and electron‐poor aryl substituents on the benzo[1,2‐b : 4,5‐b′]dithiophene‐4,8‐dione unit. These conditions were also effective for the coupling with 1‐bromonaphthalene, 9‐bromophenanthrene as well as aryl bromides bearing synthetically useful nitrile, chloro and methoxy substituents. The photophysical properties of representative arylated compounds have been performed by joint experimental and theoretical studies.

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.

"Magic Chloro": Profound Effects of the Chlorine Atom in Drug Discovery.

Chlorine is one of the most common atoms present in small-molecule drugs beyond carbon, hydrogen, nitrogen, and oxygen. There are currently more than 250 FDA-approved chlorine-containing drugs, yet the beneficial effect of the chloro substituent has not yet been reviewed. The seemingly simple substitution of a hydrogen atom (R = H) with a chlorine atom (R = Cl) can result in remarkable improvements in potency of up to 100,000-fold and can lead to profound effects on pharmacokinetic parameters including clearance, half-life, and drug exposure in vivo. Following the literature terminology of the "magic methyl effect" in drugs, the term "magic chloro effect" has been coined herein. Although reports of 500-fold or 1000-fold potency improvements are often serendipitous discoveries that can be considered "magical" rather than planned, hypotheses made to explain the magic chloro effect can lead to lessons that accelerate the cycle of drug discovery.