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1.
Bioorg Chem ; 139: 106704, 2023 10.
Article in English | MEDLINE | ID: mdl-37453239

ABSTRACT

An efficient [4 + 2] cyclization protocol to synthesize a series of twelve examples of 1,2,3-triazolo[4,5-b]aminoquinolines (5) as novel structurally modified tacrines was obtained by reacting readily accessible precursors (i.e., 3-alky(aryl)-5-amino-1,2,3-triazole-4-carbonitriles (3)) and selected cycloalkanones (4) of five-, six-, and seven-membered rings. We evaluated the AChE and BChE inhibitory activity of the novel modified tacrines 5, and the compound derivatives from cyclohexanone (4b) showed the best AChE and BChE inhibitory activities. Specifically, 1,2,3-triazolo[4,5-b]aminoquinolines 5bb obtained from 3-methyl-carbonitrile (3b) showed the highest AChE (IC50 = 12.01 µM), while 5ib from 3-sulfonamido-carbonitrile (3i) was the most significant inhibitor for BChE (IC50 = 1.78 µM). In general, the inhibitory potency of compound 5 was weaker than the pure tacrine reference, and our findings may help to design and develop novel anticholinesterase drugs based on modified tacrines.


Subject(s)
Acetylcholinesterase , Butyrylcholinesterase , Acetylcholinesterase/metabolism , Butyrylcholinesterase/metabolism , Tacrine/pharmacology , Molecular Docking Simulation , Structure-Activity Relationship , Cholinesterase Inhibitors/chemistry , Molecular Structure
2.
ACS Omega ; 8(19): 17274-17287, 2023 May 16.
Article in English | MEDLINE | ID: mdl-37214703

ABSTRACT

In this work, we present a regiocontrolled methodology to prepare 1-substituted-3(5)-carboxyalkyl-1H-pyrazoles using trichloromethyl enones as starting materials. It was found that the selectivity of the reaction depends on the nature of the hydrazine: when using arylhydrazine hydrochlorides, synthesis of the 1,3-regioisomer was achieved (22 examples, 37-97% yields), while the corresponding free hydrazine led exclusively to the 1,5-regioisomer (12 examples, 52-83% yields). The trichloromethyl group was used as a precursor for the carboxyalkyl moiety, furnishing a one-pot three-component regioselective protocol suitable for preparing both isomers at moderate to excellent yields. The selectivity of the reaction was investigated through NMR analyses and the structures of the products were unambiguously determined by SCXR analyses.

3.
ACS Omega ; 7(22): 18930-18939, 2022 Jun 07.
Article in English | MEDLINE | ID: mdl-35694463

ABSTRACT

This study reports two strategies for preparing O-alkyl derivatives of 6-substituted-4-(trifluoromethyl)pyrimidin-(1H)-ones: a linear protocol of alkylation, using a CCC-building block followed by [3 + 3]-type cyclocondensation with 2-methylisothiourea sulfate and a convergent protocol based on direct alkylation, using 4-(iodomethyl)-2-(methylthio)-6-(trihalomethyl)pyrimidines. It was found that the cyclocondensation strategy is not feasible; thus, the direct chemoselective O-alkylation was performed, and 18 derivatives of the targeted pyrimidines were obtained in 70-98% yields. The structure of the products was unambiguously determined via single crystal X-ray analyses and two-dimensional nuclear magnetic resonance experiments.

4.
Chembiochem ; 23(14): e202200248, 2022 07 19.
Article in English | MEDLINE | ID: mdl-35570195

ABSTRACT

A convenient synthesis of a broad series of thirteen examples of alkyne-spacer derivatives 2 from the well-known Sonogashira cross-coupling reaction on diazenyl-pyrazolo[1,5-a]pyrimidin-2-amine compounds 1 is reported. The reactivity of heterocycles 1 due the presence of selected electron-donor (EDG) and electron-withdrawing (EWG) groups attached to different alkynes was evaluated. Also, the reactional versatility due the position variation of the bromo atom at the scaffolds 1 was also investigated. In general, derivatives presented strong absorption bands at the 250-500 nm optical window and UV to cyan emission properties. Also, the redox analysis was recorded by electrochemical cyclic voltammetry technique. For HSA biomacromolecule assays, spectroscopic studies by UV-Vis, steady-state and time-resolved emission fluorescence, and molecular docking calculations evidenced the ability of each compound to establish interactions with human serum albumin (HSA). Finally, the behavior presented for this new class of heterocycles makes them a promising tool as optical sensors for albumins.


Subject(s)
Amines , Serum Albumin, Human , Alkynes/chemistry , Humans , Molecular Docking Simulation , Spectrometry, Fluorescence
5.
J Org Chem ; 87(7): 4590-4602, 2022 04 01.
Article in English | MEDLINE | ID: mdl-35285227

ABSTRACT

The selective N- or O-alkylation of 4-(trihalomethyl)pyrimidin-2(1H)-ones, using 5-bromo enones/enaminones as alkylating agents, is reported. It was found that the selectivity toward the N- or O-regioisomer is driven by the substituent present at the 6-position of the pyrimidine ring, thus enabling the preparation of each isomer as the sole product, in 60-95% yields. Subsequent cyclocondensation of the enaminone moiety with nitrogen dinucleophiles led to pyrimidine-azole conjugates in 55-83% yields.


Subject(s)
Alkylation , Isomerism
6.
Chembiochem ; 23(4): e202100649, 2022 02 16.
Article in English | MEDLINE | ID: mdl-34878702

ABSTRACT

The synthesis, structural analysis, and evaluation of the photophysical properties of twelve novel 2-aryl(heteroaryl)-6-(4-alkyl(aryl)-1H-1,2,3-triazol-1-yl)-4-(trifluoromethyl)quinolines (6-8), where aryl(heteroaryl)=Ph, 4-Me-C6 H4 , 4-F-C6 H4 and 2- furyl; 4-alkyl(aryl)=-CH2 OH, -(CH2 )5 CH3 and Ph, are reported. Hybrid scaffolds 6-8 were synthesized at 77-95 % yields by regioselective copper-catalysed azide-alkyne cycloaddition (CuAAC) reaction of unpublished 6-azido-4-(trifluoromethyl)quinolines (2) with selected terminal alkynes (3-5). Azido intermediates 2 were obtained from the reaction of 6-amino-4-(trifluoromethyl)quinolines (1) and sodium azide at good yields (78-87 %). Compounds 6-8 were structurally fully characterized by 1 H-, 13 C- and 19 F- and 1 H-13 C 2D-NMR (HSQC, HMBC) spectroscopy, X-ray diffraction (SC-XRD) and HRMS analysis. Moreover, the photophysical properties, DNA- and HSA-binding experiments (bio-interactions), and molecular docking studies for compounds 6-8 were performed. These are discussed and compared with similar compounds from recent research.


Subject(s)
DNA/chemistry , Molecular Docking Simulation , Serum Albumin, Human/chemistry , Animals , Cattle , Humans , Photochemical Processes
7.
Spectrochim Acta A Mol Biomol Spectrosc ; 269: 120768, 2022 Mar 15.
Article in English | MEDLINE | ID: mdl-34952444

ABSTRACT

This paper describes the synthesis, structural study, and evaluation of electrochemical and photophysical properties by UV-Vis absorption and fluorescence emission analysis (solution and solid-state) of a series of eight 3,5-aryl-substituted 1-phenyl-2-pyrazolines (5), where 3-aryl = 2-OH-C6H4 (5a-g) or Ph (5h), and 5-aryl = Ph (a, h), 1-naphthyl (b), 4-Br-C6H4 (c), 4-F-C6H4 (d), 4-OCH3-C6H4(e), 4-NO2-C6H4 (f), 4-(N(CH3)2)-C6H4(g). The UV-Vis absorption properties of 2-pyrazolines were evaluated in DCM, MeCN, AcOEt, EtOH, and DMSO as the solvent and showed a fluorescence shift for the polar aprotic solvents. The steady-state fluorescence emission exhibited a band in the blue region when excited at the least energetic transition of each compound, although the excited-state intramolecular proton (ESIPT) effect was not detected. In the solid state, compounds presented similar behavior regarding absorption and emission properties compared to the solution assays. With the electrochemical analyses performed for the synthesized 2-pyrazolines, it was possible to conclude that the redox potentials were influenced by the electronic and steric effects of the substituents on the aryl rings and, according to the electronic nature of the substituents, which electron-donating groups were favored. Finally, the TD-DFT analyses revealed that all compounds had delocalized electron density throughout the 2-pyrazolines unit and were not influenced by the substituent bonded at C-5. Nonetheless, LUMO orbital analysis showed that only derivatives 5b and 5f have this localized density over the substituents.


Subject(s)
Electrons , Protons , Coloring Agents , Solvents , Spectrometry, Fluorescence
8.
Beilstein J Org Chem ; 17: 2799-2811, 2021.
Article in English | MEDLINE | ID: mdl-34925619

ABSTRACT

A new series of ten examples of Schiff bases, namely (E)-2-(((2-alkyl(aryl/heteroaryl)-4-(trifluoromethyl)quinolin-6-yl)imino)methyl)phenols 3, was easily synthesized with yields of up to 91% from the reactions involving a series of 2-(R-substituted) 6-amino-4-(trifluoromethyl)quinolines 1 and 4(5)-R1-substituted salicylaldehydes 2 - in which alkyl/aryl/heteroaryl for 2-R-substituents are Me, Ph, 4-MeC6H4, 4-FC6H4, 4-NO2C6H4, and 2-furyl, and R1-substituents are 5-NEt2, 5-OCH3, 4-Br, and 4-NO2. Complementarily, the Schiff bases showed low to good quantum fluorescence yield values in CHCl3 (Φf = 0.12-0.80), DMSO (Φf = 0.20-0.75) and MeOH (Φf = 0.13-0.85). Higher values of Stokes shifts (SS) were observed in more polar solvents (DMSO; 65-150 nm and MeOH; 65-130 nm) than in CHCl3 (59-85 nm). Compounds 3 presented good stability under white-LED irradiation conditions and moderate ROS generation properties were observed.

9.
Ultrason Sonochem ; 79: 105683, 2021 Nov.
Article in English | MEDLINE | ID: mdl-34562732

ABSTRACT

The pyrimidine scaffold is present in many bioactive drugs; therefore, efficient synthetic routes that provide shorter reaction times, higher yields, and site-selective reactions are constantly being sought. Ultrasound (US) irradiation has emerged as an alternative energy source in the synthesis of these heterocyclic scaffolds, and over the last ten years there has been a significant increase in the number of publications mentioning US in either the construction or derivatization of the pyrimidine core. This review presents a detailed summary (with 140 references) of the effects of US (synergic or not) on the construction and derivatization of the pyrimidine core through classical reactions (e.g., multicomponent, cyclocondensation, cycloaddition, and alkylation reactions). The main points that were taken into consideration are as follows: chemo- and regioselectivity issues, and the results of conventional heating methods compared to US and mechanistic insights that are also presented and discussed for key reactions.

10.
Bioorg Chem ; 108: 104649, 2021 03.
Article in English | MEDLINE | ID: mdl-33517001

ABSTRACT

Five new examples of 9,10-chloro(bromo)-7-amine-spiro[chromeno[4,3-b]quinoline-6,1'-cycloalkanes] - in which cycloalkanes = cyclopentane, cyclohexane, and cycloheptane - were synthesized at yields of 42-56%, using a sequential one-pot two-step cyclocondensation reaction of three different scaffolds of 2-aminobenzonitriles and the respective spiro[chroman-2,1'-cycloalkan]-4-ones, and using AlCl3 as the catalyst in a solvent-free method. Subsequently, the five new spirochromeno-quinolines and nine quinolines previously published by us (14 modified tacrine scaffolds) were subjected to AChE and BChE inhibitory activity evaluation. The molecule containing a spirocyclopentane derivative had the highest AChE and BChE inhibitory activity (IC50 = 3.60 and 4.40 µM, respectively), and in general, the non-halogenated compounds were better inhibitors of AChE and BChE than the halogenated molecules. However, the inhibitory potency of compounds 3a-n was weaker than that of tacrine. By molecular docking simulations, it was found that the size of the spirocarbocyclic moieties is inversely proportional to the inhibitory activity of the cholinesterases, probably because an increase in the size of the spirocyclic component sterically hindered the interaction of tacrine derivatives with the active site of tested cholinesterases. The findings obtained here may help in the design and development of new anticholinesterase drugs.


Subject(s)
Cholinesterase Inhibitors/pharmacology , Cholinesterases/metabolism , Cycloparaffins/pharmacology , Quinolines/pharmacology , Animals , Cholinesterase Inhibitors/chemical synthesis , Cholinesterase Inhibitors/chemistry , Cycloparaffins/chemical synthesis , Cycloparaffins/chemistry , Dose-Response Relationship, Drug , Electrophorus , Horses , Molecular Docking Simulation , Molecular Structure , Quinolines/chemical synthesis , Quinolines/chemistry , Structure-Activity Relationship
11.
Front Pharmacol ; 11: 1328, 2020.
Article in English | MEDLINE | ID: mdl-33013370

ABSTRACT

The synthesis, antimicrobial activity evaluations, biomolecule-binding properties (DNA), and absorption and emission properties of a new series of (Z)-1,1,1-trichloro-4-alkyl(aryl)amino-4-arylbut-3-en-2-ones (4, 5) and 2,2-difluoro-3-alkyl(aryl)amino-4-aryl-6-(trichloromethyl)-2H-1,3,2-oxazaborinin-3-ium-2-uides (6, 7) in which 3(4)-alkyl(aryl) = H, Me, iso-propyl, n-butyl, C6H5, 4-CH3C6H4, 4-CH3OC6H4, 4-NO2C6H4, 4-FC6H4, 4-BrC6H4, 2-naphthyl, is reported. A series of ß-enaminoketones (4, 5) is synthesized from the O,N-exchange reaction of some amines (3) with (Z)-1,1,1-trichloro-4-methoxy-4-aryl-but-3-en-2-ones (1, 2) at 61-90% yields. Subsequently, reactions of the resulting ß-enaminoketones with an appropriate source of boron (BF3.OEt2) gave the corresponding oxazaborinine derivatives (6, 7) at 50-91% yields. UV-Vis and emission properties of biomolecule-binding properties for the DNA of these new BF2-ß-enamino containing CCl3 units were also evaluated. Some compounds from the present series also exhibited potent antimicrobial effects on various pathogenic microorganisms at concentrations below those that showed cytotoxic effects. Compounds 4d, 4e, 6e, and 6f showed the best results and are very significant against P. zopfii, which causes diseases in humans and animals.

12.
Int J Biol Macromol ; 160: 1114-1129, 2020 Oct 01.
Article in English | MEDLINE | ID: mdl-32450323

ABSTRACT

The present work reports the biological assays between synthetic BF2-naphtyridine complexes and four proteins: human serum albumin (HSA), calf-thymus DNA (CT-DNA), tyrosinase and acetylcholinesterase enzymes via spectroscopic analysis at physiological conditions, combined with molecular docking simulations. The BF2-complexes presented spontaneous and moderate binding ability to HSA through the ground-state association (static fluorescence quenching mechanism). The main binding site is Sudlow's site I (subdomain IIA) and the binding does not perturb significantly both secondary and surface structure of HSA. Despite BF2-complexes showed good binding ability with HSA, these compounds presented weak intercalative ability with CT-DNA (the most conventional and simple model to preliminary studies), except in the case of 1 h, which suggested that the presence of electronic donor groups in both aromatic ring moieties of BF2-complex structure can increase the intercalative ability for DNA strands. Competitive binding displacement assays in the presence of methyl green and molecular docking calculations indicated that the studied compounds interact preferentially in the major groove of DNA. In addition, the assayed compounds presented the ability to activate or inhibit both tyrosinase (the decontrolled activity can induce melanoma carcinoma) or AChE (involved in reactions related to the function of neurotransmitters) enzymes.


Subject(s)
Acetylcholinesterase/chemistry , Boron Compounds/chemistry , Cholinesterase Inhibitors/chemical synthesis , Monophenol Monooxygenase/chemistry , Naphthyridines/chemistry , Acetylcholinesterase/metabolism , Binding Sites , Cholinesterase Inhibitors/pharmacology , DNA/chemistry , DNA/metabolism , Humans , Molecular Docking Simulation , Monophenol Monooxygenase/antagonists & inhibitors , Monophenol Monooxygenase/metabolism , Protein Binding , Serum Albumin/chemistry , Serum Albumin/metabolism
13.
ACS Omega ; 4(6): 9697-9709, 2019 Jun 30.
Article in English | MEDLINE | ID: mdl-31460060

ABSTRACT

A systematic investigation to assess the degree of similarity between polymorphs was carried out. A similarity indices (IX) approach was applied in ten series of polymorphs with different characteristics and number of molecules in the asymmetric unit. Geometric (ID), contact area (IC), and stabilization energy (IG) parameters were used. It was possible to situate each comparison in different regions of similarity within the polymorphism phenomenon and determine the boundaries between quasi-isostructural polymorphs and polymorphs of low similarity. The multiparameter IDCG index was used as a robust tool to determine the total similarity within the polymorphism phenomenon. The highest contribution of the stabilization energy parameter (45%) toward the final value of similarity (IDCG) was observed, followed by the contact area index (32%). The geometric index contributed approximately 23% to the final value of IDCG. This information reinforces the importance of the contact area and stabilization energy in assessing the degree of similarity between crystalline structures. A new descriptor (IQ) based on the comparison of the energetic contribution of intermolecular interaction types present in each crystal structure is presented. IQ can be a versatile tool and applicable even for systems that do not share any similarity.

14.
J Org Chem ; 84(14): 8976-8983, 2019 07 19.
Article in English | MEDLINE | ID: mdl-31259554

ABSTRACT

The synthetic potential of 5-bromo-1,1,1-trifluoro-4-methoxypent-3-en-2-one toward the catalyst-free synthesis of N-pyrrolyl(furanyl)-piperazines, 1,4-diazepanes, and 1,4-diazocanes through a telescoped protocol is reported. This three-component one-pot method provided 23 examples with high chemo- and regioselectivity at yields up to 96%.

15.
Phys Chem Chem Phys ; 21(12): 6662-6671, 2019 Mar 28.
Article in English | MEDLINE | ID: mdl-30855605

ABSTRACT

Boron dipyrromethene type molecules (BODIPYs) are versatile molecules which have been used for applications ranging from photodynamic therapy to solar cells (DSSC). However, these molecules usually do not present high two-photon absorption cross-sections, limiting their use in nonlinear optical applications. Herein, we study a series of BF2-naphthyridine based boron-complexes with electron-donating and withdrawing groups to increase their two-photon absorption. We have found two-photon absorption cross-sections up to approximately 270 GM, which corresponds to an increase of approximately five times in comparison to the average cross-section value reported for molecules with similar conjugation length, indicating such compounds as potential materials for nonlinear applications in both the visible and infrared spectral regions.

16.
Org Biomol Chem ; 17(9): 2384-2392, 2019 02 27.
Article in English | MEDLINE | ID: mdl-30724957

ABSTRACT

Reaction of 5-bromo enones with pyrazoles provided a series of unexpected N,O-aminal derivatives, through a 1,4-conjugated addition at the ß-carbon of the 5-bromo enones instead of the expected nucleophilic substitution of the bromine. This reaction also furnished the 1,3-regioisomer of the pyrazole. A similar reaction of pyrazoles using 5-bromo enaminones furnished only N-alkylated pyrazoles-with high regioselectivity and at good yields-through nucleophilic substitution of the bromine.

17.
Soft Matter ; 14(32): 6716-6727, 2018 Aug 15.
Article in English | MEDLINE | ID: mdl-30062361

ABSTRACT

Supramolecular gels present several applications in which the gelator properties are closely dependent on their structure and solvent. Despite this, there are few studies on the effect of the gelation ability of gelators with slight molecular changes. Therefore, N-arylestearamides (in which aryl = phenyl (1), 4-tolyl (2) and 4-acetylphenyl (3)) were evaluated in different solvents. The critical gelefication concentration (CGC) values indicated that the substituents can significantly affect the concentration at which the supramolecular gels are formed, mainly in non-aromatic solvents (e.g. cyclohexane, acetonitrile and DMSO). From UV-Vis and DSC data, we verified that the gel-sol and sol-gel transitions (Tgel-sol and Tsol-gel) increase in the order of 1 < 2 < 3. Organogel strength was evaluated for 1-3 as a function of concentration and solvent type using rheology data. Gel strength is concentration-dependent and a strength order was found in acetonitrile, cyclohexane and DMSO, in which: 1 ∼ 2 > 3. Dynamic viscoelastic measurements as a function of temperature sweeps indicate a predominantly enthalpic contribution to the elasticity of the organogels formed from 1-3. Temperature-dependent 1H NMR indicates that NHO interactions may be responsible for the molecular association of molecules into 1D fibers, while 3D fibers were formed from van der Waals interactions.

18.
ACS Omega ; 3(10): 13850-13861, 2018 Oct 31.
Article in English | MEDLINE | ID: mdl-31458083

ABSTRACT

A series of seven N-phenylamides [R-C(O)NHPh, in which R: CH3, C(CH3)3, Ph, CF3, CCl3, CBr3, and H] were used as models in this study. Molecular packing and intermolecular interactions were evaluated by theoretical calculations, solution NMR, and quantum theory of atoms in molecules analyses. Crystallization mechanisms were proposed based on the energetic and topological parameters using the supramolecular cluster as demarcation. Concentration-dependent 1H NMR experiments corroborated the proposed interactions between molecules. For all compounds (except for R: H, which initially formed tetramers), layers (two-dimensional) or chains (one-dimensional) were formed in the first stage of the proposed crystallization mechanisms. The presence of strong intermolecular NH···O=C interactions promoted the first stages. The study in solution provided different values of association constant (K ass) governed by the hydrogen bond NH···O=C, showing that the stronger interactions are directly influenced by the substituent steric hindrance. A correlation between K ass(NH···O=C) from the solution and the NH···O=C interaction energy in the crystal showed a good trend.

19.
ACS Omega ; 3(3): 2569-2578, 2018 Mar 31.
Article in English | MEDLINE | ID: mdl-31458545

ABSTRACT

The quest for concepts of isostructurality in organic crystals has been long and mostly based on geometric data, even with the development of modern software. This field of study is of great interest to the pharmaceutical industry and for the prediction of crystal structures. Despite this, there is still no methodology that provides broad quantitative and comparable similarity data between two complete crystalline structures. The present study demonstrated that the similarity between two crystalline structures could be estimated from the similarity between the two "supramolecular clusters". Quantitative indexes for similarity comparisons of crystal structures were shown using nine 5-aryl-1-(1,1-dimethylethyl)-1H-pyrazoles as a model. This proposal includes the quantitative data of a geometric parameter (I D), a contact area parameter (I C), and an energetic parameter (I G). The proposed indexes exhibited good perspective regarding the similarity data and distinct regions of similarity. The range of similarity was set at I X ≥ 0.80, 0.80 > I X > 0.60, and I X ≤ 0.60 (X = D, C, or G). Indexes with a value near 1.0 indicate systems with isostructural, isocontact, and isoenergetic behavior. The results indicated that supramolecular structures with high similarity must have high values for all three indexes (I D, I C, and I G).

20.
Molecules ; 23(1)2017 Dec 22.
Article in English | MEDLINE | ID: mdl-29271950

ABSTRACT

Understanding the supramolecular environment of crystal structures is necessary to facilitate designing molecules with desirable properties. A series of 12 novel 1,3,5-tris(1-phenyl-1H-pyrazol-5-yl)benzenes was used to assess the existence of planar stacking columns in supramolecular structures of pyrazoles. This class of molecules with different substituents may assist in understanding how small structural changes affect the supramolecular environment. The obtained compounds did not present the formation of planar stacking interactions between benzenes in solid or liquid states. This supposition was indicated by single crystal diffraction, Density Functional Theory (DFT) and quantum theory of atoms in molecules (QTAIM) calculations, and concentration-dependent liquid-state ¹H nuclear magnetic resonance (NMR). NMR showed that chemical shifts of benzene and pyrazole hydrogens confirm that planar stacking interactions are not formed in solution. The crystalline structures presented different molecular conformations. The molecular structures of 5 and 9b are in a twisted conformation, while compound 7 showed a conformation analogous to a calyx form.


Subject(s)
Benzene Derivatives/chemistry , Pyrazoles/chemistry , Crystallography, X-Ray , Hydrogen Bonding , Models, Molecular , Molecular Conformation , Static Electricity , Thermodynamics
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