ABSTRACT
The development of novel pharmaceutical tools to efficiently tackle tuberculosis is the order of the day due to the rapid development of resistant strains of Mycobacterium tuberculosis. Herein, we report novel potential formulations of a repurposed drug, the antimalarial mefloquine (MFL), which was combined with organic anions as chemical adjuvants. Eight mefloquine organic salts were obtained by ion metathesis reaction between mefloquine hydrochloride ([MFLH][Cl]) and several organic acid sodium salts in high yields. One of the salts, mefloquine mesylate ([MFLH][MsO]), presented increased water solubility in comparison with [MFLH][Cl]. Moreover, all salts with the exception of mefloquine docusate ([MFLH][AOT]) showed improved permeability and diffusion through synthetic membranes. Finally, in vitro activity studies against Mycobacterium tuberculosis revealed that these ionic formulations exhibited up to 1.5-times lower MIC values when compared with [MFLH][Cl], particularly mefloquine camphorsulfonates ([MFLH][(1R)-CSA], [MFLH][(1S)-CSA]) and mefloquine HEPES ([MFLH][HEPES]).
Subject(s)
Antimalarials , Mycobacterium tuberculosis , Antimalarials/pharmacology , HEPES , Mefloquine/pharmacology , Permeability , Salts , SolubilityABSTRACT
Studies displaying the combination of mefloquine (MFL) with anti-tuberculosis (TB) substances are limited in the literature. In this work, the effect of MFL-association with two first-line anti-TB drugs and six fluoroquinolones was evaluated against Mycobacterium tuberculosis drug resistant strains. MFL showed synergistic interaction with isoniazid, pyrazinamide, and several fluoroquinolones, reaching fractional inhibitory concentration indexes (FICIs) ranging from 0.03 to 0.5. In order to better understand the observed results, two approaches have been explored: (i) spectroscopic responses attributed to the effect of MFL on physicochemical properties related to a liposomal membrane model composed by soybean asolectin; (ii) molecular dynamics (MD) simulation data regarding MFL interaction with a membrane model based on PIM2, a lipid constituent of the mycobacterial cell wall. FTIR and NMR data showed that MFL affects expressively the region between the phosphate and the first methylene groups of soybean asolectin membranes, disordering these regions. MD simulations results detected high MFL density in the glycolipid interface and showed that the drug increases the membrane lateral diffusion, enhancing its permeability. The obtained results suggest that synergistic activities related to MFL are attributed to its effect of lipid disorder and membrane permeability enhancement.
Subject(s)
Antitubercular Agents/pharmacology , Mefloquine/pharmacology , Molecular Dynamics Simulation , Mycobacterium tuberculosis/drug effects , Antitubercular Agents/chemical synthesis , Antitubercular Agents/chemistry , Dose-Response Relationship, Drug , Magnetic Resonance Spectroscopy , Mefloquine/chemical synthesis , Mefloquine/chemistry , Microbial Sensitivity Tests , Molecular Structure , Phosphorus Isotopes , Spectroscopy, Fourier Transform Infrared , Structure-Activity RelationshipABSTRACT
BACKGROUND: Onychine is a 4-azafluorenone alkaloid isolated from the Annonaceae family, in low concentrations. Onychine and its analogs exhibit a wide range of pharmacological activities such as antifungal, antibacterial, anticancer, and antimalarial. Because of the high bioactivity of some 4-azafluorenone derivatives, several synthetic methods have been developed for their procurement. OBJECTIVE: Considering the importance of these alkaloids, we aim to present the main synthetic approaches to onychines and its derivatives and the biological activity of some 4-azafluorenones. METHODS: The most prominent methodologies for the synthesis of onychines were reviewed. RESULTS: In this work, we cover many synthetic approaches for the synthesis of onychine and 4-azafluorenone derivatives including intramolecular cyclizations, multicomponent reactions, microwave-assisted multicomponent reactions, Diels-alder reactions, among others. Moreover, we also review the biological activity of 4-azafluorenones. CONCLUSION: 4-azafluorenones have risen as prominent structures in medicinal chemistry; however, most of the time, access to new derivatives involves toxic catalysts, harsh reaction conditions, and long-step procedures. Therefore, the development of new synthetic routes with more operational simplicity, simple purification procedure, good yields, and low environmental impact, is desirable.
Subject(s)
Anti-Infective Agents/pharmacology , Antineoplastic Agents/pharmacology , Flavanones/pharmacology , Pyridones/pharmacology , Anti-Infective Agents/chemical synthesis , Antineoplastic Agents/chemical synthesis , Bacteria/drug effects , Cell Line, Tumor , Cyclization , Cycloaddition Reaction , Flavanones/chemical synthesis , Fungi/drug effects , Humans , Oxidation-Reduction , Plasmodium/drug effects , Pyridones/chemical synthesisABSTRACT
The syntheses and crystal structures of five 2-benzyl-idene-1-benzosuberone [1-benzosuberone is 6,7,8,9-tetra-hydro-5H-benzo[7]annulen-5-one] derivatives, viz. 2-(4-meth-oxy-benzyl-idene)-1-benzosuberone, C19H18O2, (I), 2-(4-eth-oxy-benzyl-idene)-1-benzosuberone, C20H20O2, (II), 2-(4-benzyl-benzyl-idene)-1-benzosuberone, C25H22O2, (III), 2-(4-chloro-benzyl-idene)-1-benzosuberone, C18H15ClO, (IV) and 2-(4-cyano-benzyl-idene)-1-benzosuberone, C19H15NO, (V), are described. The conformations of the benzosuberone fused six- plus seven-membered ring fragments are very similar in each case, but the dihedral angles between the fused benzene ring and the pendant benzene ring differ somewhat, with values of 23.79â (3) for (I), 24.60â (4) for (II), 33.72â (4) for (III), 29.93â (8) for (IV) and 21.81â (7)° for (V). Key features of the packing include pairwise C-Hâ¯O hydrogen bonds for (II) and (IV), and pairwise C-Hâ¯N hydrogen bonds for (V), which generate inversion dimers in each case. The packing for (I) and (III) feature C-Hâ¯O hydrogen bonds, which lead to [010] and [100] chains, respectively. Weak C-Hâ¯π inter-actions consolidate the structures and weak aromatic π-π stacking is seen in (II) [centroid-centroid separation = 3.8414â (7)â Å] and (III) [3.9475â (7)â Å]. A polymorph of (I) crystallized from a different solvent has been reported previously [Dimmock et al. (1999 â¸) J. Med. Chem. 42, 1358-1366] in the same space group but with a packing motif based on inversion dimers resembling that seen in (IV) in the present study. The Hirshfeld surfaces and fingerprint plots for (I) and its polymorph are com-pared and structural features of the 2-benzyl-idene-1-benzosuberone family of phases are surveyed.
ABSTRACT
A 1:1 epimeric mixture of 3-[(4-nitro-benzyl-idene)amino]-2(R,S)-(4-nitro-phen-yl)-5(S)-(propan-2-yl)imidazolidin-4-one, C19H19N5O5, was isolated from a reaction mixture of 2(S)-amino-3-methyl-1-oxo-butane-hydrazine and 4-nitro-benz-alde-hyde in ethanol. The product was derived from an initial reaction of 2(S)-amino-3-methyl-1-oxo-butane-hydrazine at its hydrazine group to provide a 4-nitro-benzyl-idene derivative, followed by a cyclization reaction with another mol-ecule of 4-nitro-benzaldehyde to form the chiral five-membered imidazolidin-4-one ring. The formation of the five-membered imidazolidin-4-one ring occurred with retention of the configuration at the 5-position, but with racemization at the 2-position. In the crystal, N-Hâ¯O(nitro) hydrogen bonds, weak C-Hâ¯O(carbon-yl) and C-Hâ¯O(nitro) hydrogen bonds, as well as C-Hâ¯π, N-Hâ¯π and π-π inter-actions, are present. These combine to generate a three-dimensional array. Hirshfeld surface analysis and PIXEL calculations are also reported.
ABSTRACT
The asymmetric unit of the title compound, C13H11N3O2S2, comprises two independent mol-ecules (A and B); the crystal structure was determined by employing synchrotron radiation. The mol-ecules exhibit essentially the same features with an almost planar benzo-thia-zole ring (r.m.s. deviation = 0.026 and 0.009â Å for A and B, respectively), which forms an inclined dihedral angle with the phenyl ring [28.3â (3) and 29.1â (3)°, respectively]. A difference between the mol-ecules is noted in a twist about the N-S bonds [the C-S-N-N torsion angles = -56.2â (5) and -68.8â (5)°, respectively], which leads to a minor difference in orientation of the phenyl rings. In the mol-ecular packing, A and B are linked into a supra-molecular dimer via pairwise hydrazinyl-N-Hâ¯N(thiazol-yl) hydrogen bonds. Hydrazinyl-N-Hâ¯O(sulfon-yl) hydrogen bonds between A mol-ecules assemble the dimers into chains along the a-axis direction, while links between centrosymmetrically related B mol-ecules, leading to eight-membered {â¯HNSO}2 synthons, link the mol-ecules along [001]. The result is an undulating supra-molecular layer. Layers stack along the b-axis direction with benzo-thia-zole-C-Hâ¯O(sulfon-yl) points of contact being evident. The analyses of the calculated Hirshfeld surfaces confirm the relevance of the above inter-molecular inter-actions, but also serve to further differentiate the weaker inter-molecular inter-actions formed by the independent mol-ecules, such as π-π inter-actions. This is also highlighted in distinctive energy frameworks calculated for the individual mol-ecules.
ABSTRACT
Background and Introduction: Mefloquine, a drug used to prevent and treat malaria is described possessing activity against the Mycobacterium tuberculosis (Mtb) as well as against multidrugresistant tuberculosis (MDR) and other types of bacteria. Despite their importance, few compounds based on the Mefloquine nucleus have been synthesized and evaluated against TB. MATERIALS AND METHODS: For the synthesis of all the compounds based on the Mefloquine nucleus we used a synthetic route which utilized the key derivative 4-methoxy-2,8-bis(trifluoromethyl)quinoline 2 as starting material. The compounds 3 (a-c), 4 (a-b) were synthesized after one step by reaction of 2 with appropriate amines substituted. The chloro derivatives 5 and 6 were obtained from compounds 4b and 4a by treatment with SOCl2 in CH2Cl2 at reflux in 75 and 80% yield, respectively. The analogue 6 was converted to 7 after treatment with ethanolamine under heating at 90oC in 64% yield and to the azido derivative 8 in 56% after reaction with sodium azide in MeOH at reflux for 2 h. The analogue 9 was obtained after reaction of 5 with ethanolamine at 90oC for 1 h in 90% yield. All the new compounds were identified by detailed spectral data, including 1H NMR, 13C NMR and high resolution mass spectra. All the compound were evaluated for their in vitro antibacterial activity against sensitive Mycobacterium tuberculosis ATCC 27294, using the microplate Alamar Blue assay (MABA). The more active compounds 3c, 7, and 9 were also evaluated against resistant strain SR 2571/0215 (resistant to Rifampicin and Isoniazid) by above method. All compounds were tested against three cancer cell lines: SF-295 (glioblastoma), HCT-116 (colon) and PC-3 (prostate) using the MTT assay. RESULTS: All the planned ten compounds were synthetically obtained in good global yield, displaying activity against sensitive Mycobacterium tuberculosis in vitro, with exception of one, with MIC values between 37.2 and 154.8 µM. The compounds 3c (37.2 µM), 7 (68.1 µM) and 9 (65.6 µM) showed the highest activity in this series with MIC values similar when compare to the standard Mefloquine (30 - 60 µM), being 3c the most potent. The more active compounds 3c, 7, and 9 were also evaluated against resistant strain, displaying MIC of 37.2, 136.2 and 65.6 µM, respectively. All compounds were tested against three cancer cell lines and showed low cytotoxicity. CONCLUSION: All synthesized compounds, with the exception of 5, exhibited activity against the Mtb. Compound 3c was the most potent against resistant and sensitive Mtb in this series, with MIC value of 37.2 µM. All compounds showed low cytotoxicity. These findings could be considered a good model to develop possible lead compounds in the fight against TB based on Mefloquine nucleus.
Subject(s)
Antitubercular Agents/pharmacology , Drug Resistance, Bacterial/drug effects , Mefloquine/pharmacology , Mycobacterium tuberculosis/drug effects , Antitubercular Agents/chemical synthesis , Antitubercular Agents/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Humans , Mefloquine/chemical synthesis , Mefloquine/chemistry , Microbial Sensitivity Tests , Molecular StructureABSTRACT
The crystal structures of four (E)-meth-oxy-benzaldehyde oxime derivatives, namely (2-meth-oxy-benzaldehyde oxime, 1, 2,3-di-meth-oxy-benzaldehyde oxime, 2, 4-di-meth-oxy-benzaldehyde oxime, 3, and 2,5-di-meth-oxy-benzaldehyde oxime, 4, are discussed. The arrangements of the 2-meth-oxy group and the H atom of the oxime unit are s-cis in compounds 1-3, but in both independent mol-ecules of compound 4, the arrangements are s-trans. There is also a difference in the conformation of the two mol-ecules in 4, involving the orientations of the 2- and 5-meth-oxy groups. The primary inter-molecular O-H(oxime)â¯O(hy-droxy) hydrogen bonds generate C(3) chains in 1 and 2. In contrast, in compound 3, the O-H(oxime)â¯O(hy-droxy) hydrogen bonds generate symmetric R 2 2(6) dimers. A more complex dimer is generated in 4 from the O-H(oxime)â¯O(hy-droxy) and C-H(2-meth-oxy)â¯O(hy-droxy) hydrogen bonds. In all cases, further inter-actions, C-Hâ¯O and C-Hâ¯π or π-π, generate three-dimensional arrays. Hirshfeld surface and fingerprint analyses are discussed.
ABSTRACT
The crystal structures of three salicyaldoxime compounds, namely 2-hy-droxy-4-methyl-benzaldehyde oxime, C8H9NO2, 1, 2,4-di-hydroxy-benzaldehyde oxime, C7H7NO3, 2, and 2-hy-droxy-4-meth-oxy-benzaldehyde oxime, C8H9NO3, 3, are discussed. In each compound, the hydroxyl groups are essentially coplanar with their attached phenyl group. The inter-planar angles between the C=N-O moieties of the oxime unit and their attached phenyl rings are 0.08â (9), 1.08â (15) and 6.65â (15)° in 1, 2 and 3, respectively. In all three mol-ecules, the 2-hy-droxy group forms an intra-molecular O-Hâ¯N(oxime) hydrogen bond. In compound (1), inter-molecular O-H(oxime)â¯O(hydrox-yl) hydrogen bonds generate R 2 2(14) dimers, related by inversion centres. In compound 2, inter-molecular O-H(oxime)â¯O(4-hy-droxy) hydrogen bonds generate C9 chains along the b-axis direction, while O-H(4-hydrox-yl)â¯O(2-hydrox-yl) inter-actions form zigzag C6 spiral chains along the c-axis direction, generated by a screw axis at 1, y, 1/4: the combination of the two chains provides a bimolecular sheet running parallel to the b axis, which lies between 0-1/2 c and 1/2-1 c. In compound 3, similar C9 chains, along the b-axis direction are generated by O-H(oxime)â¯O(4-meth-oxy) hydrogen bonds. Further weaker, C-Hâ¯π (in 1), π-π (in 2) and both C-Hâ¯π and π-π inter-actions (in 3) further cement the three-dimensional structures. Hirshfeld surface and fingerprint analyses are discussed.
ABSTRACT
The syntheses and crystal structures of 2-[2-(propan-2-yl-idene)hydrazin-yl]-1,3-benzo-thia-zol-3-ium 3-nitro-benzene-sulfonate (C10H12N2S+·C6H4NO5S-), (I), 2-[2-(3-nitro-benzene-sulfon-yl)hydrazin-yl]-1,3-benzo-thia-zole (C13H10N4O4S2), (II) and 2-[2-(3-nitro-benzene-sulfon-yl)hydrazin-yl]-1,3-benzo-thia-zol-3-ium 3-nitro-benzene-sulfonate (C13H11N4O4S2+·C6H4NO5S-), (III) are reported. Salt (I) arose from an unexpected reaction of 2-hydrazinylbenzo-thia-zole with the acetone solvent in the presence of 3-nitro-benzene-sulfonyl chloride, whereas (II) and (III) were recovered from the equivalent reaction carried out in methanol. The crystal of (I) features ion pairs linked by pairs of N-Hâ¯Os (s = sulfonate) hydrogen bonds; adjacent cations inter-act by way of short π-π stacking inter-actions between the thia-zole rings [centroid-centroid separation = 3.4274â (18)â Å]. In (II), which crystallizes with two neutral mol-ecules in the asymmetric unit, the mol-ecules are linked by N-Hâ¯N and N-Hâ¯On (n = nitro) hydrogen bonds to generate [[Formula: see text]1[Formula: see text]] chains, which are cross-linked by C-Hâ¯O and π-π stacking inter-actions. The crystal of (III) features centrosymmetric tetra-mers (two cations and two anions) linked by cooperative N-Hâ¯O hydrogen bonds; C-Hâ¯O and π-π inter-actions occur between tetra-mers.
ABSTRACT
The crystal structures of three isomeric (E)-N'-(chloro-phenyl-methyl-idene)-N-methyl-2-(thio-phen-2-yl)acetohydrazides (C14H13ClN2OS) are described, with the Cl atom in ortho (I), meta (III) and para (IV) positions in the benzene ring. The ortho-bromo derivative (II) (C14H13BrN2OS), which is isostructural with its chloro congener (I), is also reported. Mol-ecules (I)-(III) have similar conformations, which approximate to l-shapes, as indicated by their N-C-C-Ct (t = thio-phene) torsion angles of -90.1â (3), -91.44â (18) and -90.7â (9)°, respectively. The conformation of (IV) is different, with an equivalent torsion angle of -170.75â (11)° corresponding to a more extended shape for the mol-ecule. The thio-phene ring in each structure features 'flip' rotational disorder. The packing for (I) and (II) features inversion dimers, linked by pairs of C-Hâ¯O inter-actions, which generate R22(14) loops. In the crystal of (III), [010] C(8) chains arise, with adjacent mol-ecules linked by pairs of C-Hâ¯O hydrogen bonds. The packing for (IV) features unusually short C-Hâ¯O inter-actions arising from an H atom attached to the benzene ring (Hâ¯O = 2.18â Å), which lead to C(9) [301] chains. Hirshfeld fingerprint percentage contact contributions are similar for the four title compounds.
ABSTRACT
In this work, we report the antileishmanial activity of 23 compounds based on 2-pyrazyl and 2-pyridylhydrazone derivatives. The compounds were tested against the promastigotes of Leishmania amazonensis and L.â braziliensis, murine macrophages, and intracellular L.â amazonensis amastigotes. The most potent antileishmanial compound was selected for investigation into its mechanism of action. Among the evaluated compounds, five derivatives [(E)-3-((2-(pyridin-2-yl)hydrazono)methyl)benzene-1,2-diol (2 b), (E)-4-((2-(pyridin-2-yl)hydrazono)methyl)benzene-1,3-diol (2 c), (E)-4-nitro-2-((2-(pyrazin-2-yl)hydrazono)methyl)phenol (2 s), (E)-2-(2-(pyridin-2-ylmethylene)hydrazinyl)pyrazine (2 u), and (E)-2-(2-((5-nitrofuran-2-yl)methylene)hydrazinyl)pyrazine (2 v)] exhibited significant activity against L.â amazonensis amastigote forms, with IC50 values below 20â µm. The majority of the compounds did not show any toxic effect on murine macrophages. Preliminary studies on the mode of action of members of this hydrazine-derived series indicate that the accumulation of reactive oxygen species (ROS) and disruption of parasite mitochondrial function are important for the pharmacological effect on L.â amazonensis promastigotes.
Subject(s)
Hydrazones/chemistry , Hydrazones/pharmacology , Leishmania/drug effects , Trypanocidal Agents/chemistry , Trypanocidal Agents/pharmacology , Animals , Cells, Cultured , Female , Hydrazones/chemical synthesis , Leishmania braziliensis/drug effects , Leishmaniasis/drug therapy , Macrophages/parasitology , Mice , Mice, Inbred BALB C , Trypanocidal Agents/chemical synthesisABSTRACT
This work describes the synthesis, characterization and biological evaluation of three platinum complexes of the type [Pt(DMSO)(L)Cl]Cl, in which L represents a fluoroquinolone, namely, ciprofloxacin (cpl), ofloxacin (ofl), or sparfloxacin (spf). The new complexes were characterized by elemental analysis, high-resolution mass spectrometry (HRESIMS) and 1H, 13C and 195Pt NMR (nuclear magnetic resonance). The spectral data suggest that the fluoroquinolones act as bidentate ligands coordinated to Pt(II) through the nitrogen atoms of the piperazine ring. Microbiological assays against wild type Mycobacterium tuberculosis (ATCC 27294) showed that all complexes have been very potent, exhibiting antitubercular potency at concentrations <2⯵M, although none of the complexes presented higher potency than established anti-TB drugs. As to the resistant strains, the complex with sparfloxacin, [Pt(DMSO)(spf)Cl]Cl exhibited the best potential against most Mycobacterium tuberculosis clinical isolates. The cytotoxicity of these compounds was also evaluated in three breast cell lines: MCF-10 (a healthy cell), MCF-7 (a hormone responsive cancer cell) and MDA-MB-231 (triple negative breast cancer cell). In both tumor cell lines, [Pt(DMSO)(spf)Cl]Cl was more active and more selective than cisplatin. Flow cytometry analysis revealed that [Pt(DMSO)(spf)Cl]Cl induced late apoptotic cell death in MDA-MB-231 cells.
Subject(s)
Fluoroquinolones/pharmacology , Mycobacterium tuberculosis/drug effects , Cell Line, Tumor , Cell Survival/drug effects , Ciprofloxacin/pharmacology , Dimethyl Sulfoxide/pharmacology , Drug Screening Assays, Antitumor , Humans , MCF-7 Cells , Ofloxacin/pharmacology , Tuberculosis, Multidrug-Resistant/microbiologyABSTRACT
BACKGROUND: Over the last few years, fungal infections have emerged as a worrisome global public health problem. Candidiasis is a disease caused by Candida species and has been a problem worldwide mainly for immunosuppressed patients. Lately, the resistant strains and side effects have been reported as important issues for treating Candidiasis, which have to be solved by identifying new drugs. OBJECTIVE: The goal of this work was to synthesize a series of 1,3-benzoxathiol-2-one derivatives, XYbenzo[ d][1,3]oxathiol-2-ones, and evaluate their antifungal activity against five Candida species. METHODS: In vitro antifungal screening test and minimum inhibitory concentration determination were performed according to CLSI protocols using ketoconazole as the reference drug. The cytotoxicity of the most active compounds was evaluated by hemolysis and MTT (Vero cells) assays. RESULTS: Compounds 2 (XY = 6-hydroxy-5-nitro, MIC = 4-32 µg/mL) and 7 (XY = 6-acetoxy-5-nitro, MIC =16-64 µg/mL) showed good results when compared with current antifungals in CLSI values (MIC = 0.04-250 µg/mL). These compounds exhibited a safer cytotoxicity as well as a lower hemolytic profile than ketoconazole. CONCLUSION: Overall, the in vitro results pointed to the potential of compounds 2 and 7 as new antifungal prototypes to be further explored.
Subject(s)
Antifungal Agents/pharmacology , Heterocyclic Compounds, 2-Ring/pharmacology , Lactones/pharmacology , Antifungal Agents/chemical synthesis , Antifungal Agents/chemistry , Antifungal Agents/toxicity , Candida/drug effects , Crystallography, X-Ray , Heterocyclic Compounds, 2-Ring/chemical synthesis , Heterocyclic Compounds, 2-Ring/chemistry , Heterocyclic Compounds, 2-Ring/toxicity , Lactones/chemical synthesis , Lactones/chemistry , Lactones/toxicity , Microbial Sensitivity Tests , Molecular StructureABSTRACT
The syntheses and crystal structures of (E)-N'-(3-cyano-benzyl-idene)-N-methyl-2-(thio-phen-2-yl)acetohydrazide, C15H13N3OS, (I), and (E)-N'-(4-meth-oxy-benzyl-idene)-N-methyl-2-(thio-phen-2-yl)acetohydrazide, C15H16N2O2S, (II), with different substituents in the meta and para position of the benzene ring are described. Compounds (I) and (II) both crystallize with two mol-ecules in the asymmetric unit, with generally similar conformations [r.m.s. overlay fits for (I) and (II) of 0.334 and 0.280â Å, respectively] that approximate to L-shapes. The thio-phene rings in (I) are well ordered, whereas those in (II) exhibit 'flip' rotational disorder [occupancies 0.662â (2) and 0.338â (2) for mol-ecule 1, and 0.549â (3) and 0.451â (3) for mol-ecule 2]. The packing for (I) features short C-Hâ¯O inter-actions arising from the C-H grouping adjacent to the cyanide group and C-Hâ¯Nc (c = cyanide) links arising from the methine groups to generate [110] double chains. Weak C-Hâ¯π inter-actions inter-link the chains into a three-dimensional network. The packing for (II) features numerous C-Hâ¯O and C-Hâ¯π inter-actions arising from different donor groups to generate a three-dimensional network. Hirshfeld fingerprint plots indicate significant differences in the percentage contact surfaces for (I) and (II).
ABSTRACT
Zika virus (ZIKV), an arthropod-born Flavivirus, has been associated with a wide range of neurological diseases in adults, foetuses and neonates. Since no vaccine is available, repurposing of antiviral drugs currently in medical use is necessary. Mefloquine has confirmed anti-ZIKV activity. We used medicinal chemistry-driven approaches to synthesize and evaluate the ability of a series of new 2,8-bis(trifluoromethyl)quinoline derivatives to inhibit ZIKV replication in vitro, in order to improve the potency of mefloquine. We found that quinoline derivatives 3a and 4 were the most potent compounds within this series, both with mean EC50 values of 0.8 µM, which represents a potency 5 times that of mefloquine. These results indicate that new 2,8-bis(trifluoromethyl)quinoline chemical structures may be promising for the development of novel anti-ZIKV drugs.
Subject(s)
Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Mefloquine/pharmacology , Quinolines/chemistry , Quinolines/pharmacology , Zika Virus/drug effects , Animals , Antiviral Agents/chemical synthesis , Antiviral Agents/toxicity , Chlorocebus aethiops , Drug Design , Quinolines/chemical synthesis , Quinolines/toxicity , Structure-Activity Relationship , Vero Cells , Virus Replication/drug effects , Zika Virus/physiologyABSTRACT
Zika virus (ZIKV), an emerging Flavivirus, was recently associated with severe neurological complications and congenital diseases. Therefore, development of antiviral agents capable of inhibiting ZIKV replication is urgent. Chloroquine is a molecule with a confirmed safety history for use with pregnant women, and has been found to exhibit anti-ZIKV activity at concentrations around 10 µM. This suggests that modifications to the chloroquine structure could be promising for obtaining more effective anti-ZIKV agents. Here, we report the ability of a series of N-(2-(arylmethylimino)ethyl)-7-chloroquinolin-4-amine derivatives to inhibit ZIKV replication in vitro. We have found that the quinoline derivative, N-(2-((5-nitrofuran-2-yl)methylimino)ethyl)-7-chloroquinolin-4-amine, 40, was the most potent compound within this series, reducing ZIKV replication by 72% at 10 µM. Compound 40 exhibits an EC50 value of 0.8 ± 0.07 µM, compared to that of chloroquine of 12 ± 3.2 µM. Good activities were also obtained for other compounds, including those with aryl groups = phenyl, 4-fluorophenyl, 4-nitrophenyl, 2,6-dimethoxyphenyl, 3-pyridinyl and 5-nitrothien-2-yl. Syntheses of these quinoline derivatives have been obtained both by thermal and ultrasonic means. The ultrasonic method produced comparable yields to the thermal (reflux) method in very much shorter times 30-180 s compared to 30-180 min reactions times. These results indicate that this group of compounds is a good follow-up point for the potential discovery of new drugs against the Zika disease.
Subject(s)
Antiviral Agents/chemical synthesis , Antiviral Agents/pharmacology , Chloroquine/chemical synthesis , Chloroquine/pharmacology , Temperature , Ultrasonic Waves , Zika Virus/drug effects , Animals , Antiviral Agents/chemistry , Chlorocebus aethiops , Chloroquine/chemistry , Chloroquine/toxicity , Vero Cells , Virus Replication/drug effects , Zika Virus/physiologyABSTRACT
The crystal structures of three isomeric (E)-N-methyl-N'-(nitro-benzyl-idene)-2-(thio-phen-2-yl)acetohydrazides (formula C14H13N3O3S) are described, with the nitro group in ortho, meta and para positions in the benzene ring. In each crystal structure, mol-ecules are linked by various weak inter-actions (C-Hâ¯O and C-Hâ¯π bonds, and π-π stacking), leading to three-dimensional networks in each case, but with little similarity between them.
ABSTRACT
BACKGROUND: Schiff bases have been greatly studied in biological field due to their wide range of pharmacological activities, such as antitubercular and antitumour. In the search of novel antitubercular agents, several compounds containing pharmacophoric group of ethambutol have been synthesized and evaluated against mycobacteria species causing tuberculosis. In this work, we investigate whether ethylenediamine, Schiff base as well as nitro group together could contribute to the formation of novel molecules with dual biological activities: antitubercular and anticancer. METHODS: A series of Schiff bases (3-12) derived from p-nitrophenylethylenediamine (1) as well as N1,N2-bis(4-nitrophenyl)ethane-1,2-diamine (2) were synthetized and assayed for their action against Mycobacterium tuberculosis H37Rv strain and the human tumour cell lines SF-295 (glioblastoma multiforme), HCT-116 (colon adenocarcinoma) and OVCAR-8 (ovarian cancer). RESULTS: Among the compounds that showed antimycobacterial effects, 4 was more active than ethambutol, the antitubercular drug used as positive control. Also, compounds 1, 8, 10 and 12 were able to reduce strongly the viability of the tumour cell lines at 5 µgmL-1. CONCLUSION: According to studies, some modifications on p-nitrophenylethylenediamine (1) were an effective strategy to obtain compounds with antiproliferactive activities. Also, Schiff base 4 proved to be the lead antitubercular compound.
ABSTRACT
In this study, the N,N,O metal chelator 2-pyridinecarboxaldehydeisonicotinoyl hydrazone (HPCIH, 1) and its derivatives 2-acetylpyridine-(HAPIH 2), 2-pyridineformamide-(HPAmIH, 3) and pyrazineformamide-(HPzAmIH, 4) were employed in the synthesis of four copper(II) complexes, [Cu(HPCIH)Cl2]·0.4H2O (5), [Cu(HAPIH)Cl2]·1.25H2O (6), [Cu(HPAmIH)Cl2]·H2O (7) and [Cu(HPzAmIH)Cl2]·1.25H2O (8). The compounds were assayed for their action toward Mycobacterium tuberculosis H37Rv ATCC 27294 strain and the human tumor cell lines OVCAR-8 (ovarian cancer), SF-295 (glioblastoma multiforme) and HCT-116 (colon adenocarcinoma). All copper(II) complexes were more effective in reducing growth of HCT-116 and SF-295 cells than the respective free hydrazones at 5 µg/mL, whereas only complex 7 was more cytotoxic toward OVCAR-8 lines than its ligand HPAmIH. 6 proved to be cytotoxic at submicromolar doses, whose IC50 values (0.39-0.86 µM) are similar to those ones found for doxorubicin (0.23-0.43 µM). Complexes 5 and 6 displayed high activity against M. tuberculosis (MIC = 0.85 and 1.58 µM, respectively), as compared with isoniazid (MIC = 2.27 µM), which suggests the compounds are attractive candidates as antitubercular drugs.