Antileishmanial Activity of 4,8-Dimethoxynaphthalenyl Chalcones on Leishmania amazonensis.

Leishmaniasis is a neglected tropical disease caused by Leishmania species. Available therapeutic options have several limitations. The drive to develop new, more potent, and selective antileishmanial agents is thus a major goal. Herein we report the synthesis and the biological activity evaluation against promastigote and amastigote forms of Leishmania amazonensis of nine 4,8-dimethoxynaphthalenyl chalcones. Compound ((E)-1-(4,8-dimethoxynaphthalen-1-yl)-3-(4-nitrophenyl)prop-2-en-1-one), 4f, was the most promising with an IC50 = 3.3 ± 0.34 µM (promastigotes), a low cytotoxicity profile (CC50 = 372.9 ± 0.04 µM), and a high selectivity index (SI = 112.6). Furthermore, 4f induced several morphological and ultrastructural changes in the free promastigote forms, loss of plasma membrane integrity, and increased reactive oxygen species (ROS). An in silico analysis of drug-likeness and ADME parameters suggested high oral bioavailability and intestinal absorption. Compound 4f reduced the number of infected macrophages and the number of amastigotes per macrophage, with an IC50 value of 18.5 ± 1.19 µM. Molecular docking studies with targets, ARG and TR, showed that compound 4f had more hydrogen bond interactions with the ARG enzyme, indicating a more stable protein-ligand binding. These results suggest that 4,8-dimethoxynaphthalenyl chalcones are worthy of further study as potential antileishmanial drugs.

Different conformations and packing motifs in the crystal structures of four thio-phene-carbohydrazide-pyridine derivatives.

The crystal structures of four thio-phene-carbohydrazide-pyridine derivatives, viz. N'-[(E)-pyridin-3-yl-methyl-idene]thio-phene-2-carbohydrazide, C11H9N3OS, (I), N'-[(E)-pyridin-2-yl-methyl-idene]thio-phene-2-carbohydrazide, C11H9N3OS, (II), N-methyl-N'-[(E)-pyridin-2-yl-methyl-idene]thio-phene-2-carbohydrazide, C12H11N3OS, (III) and N'-[(E)-pyridin-2-yl-methyl-idene]-2-(thio-phen-2-yl)ethano-hydrazide, C12H11N3OS, (IV) are described. The dihedral angles between the thio-phene ring and the pyridine ring are 21.4 (2), 15.42 (14), 4.97 (8) and 83.52 (13)° for (I)-(IV), respectively. The thio-phene ring in (IV) is disordered over two orientations in a 0.851 (2):0.149 (2) ratio. Key features of the packing include N-H⋯Np (p = pyridine) hydrogen bonds in (I), which generate C(7) chains propagating in the [001] direction; N-H⋯Np links also feature in (II), but in this case they lead to C(6) [001] chains; in (IV), classical amide (C4) N-H⋯O links result in [010] chains; in every case adjacent mol-ecules in the chains are related by 21 screw axes. There are no classical hydrogen bonds in the extended structure of (III). Various weak C-H⋯X (X = O, N, S) inter-actions occur in each structure, but no aromatic π-π stacking is evident. The Hirshfeld surfaces and fingerprint plots for (I)-(IV) are compared.

Synthesis and trypanocidal activity of novel pyridinyl-1,3,4-thiadiazole derivatives.

Herein, we present the design, synthesis and trypanocidal evaluation of sixteen new 1,3,4-thiadiazole derivatives from N-aminobenzyl or N-arylhydrazone series. All derivatives were assayed against the trypomastigote form of Trypanosoma cruzi, showing IC50 values ranging from 3 to 226 µM, and a better trypanocidal profile was demonstrated for the 1,3,4-thiadiazole-N-arylhydrazones (3a-g). In this series, the 2-pyridinyl fragment bound to the imine subunit of the hydrazine moiety presented pharmacophoric behavior for trypanocidal activity. Compounds 2a, 11a and 3e presented remarkable activity and excellent selectivity indexes. Compound 2a was also active against the intracellular amastigote form of T. cruzi. Moreover, its corresponding hydrochloride, compound 11a, showed the most promising profile, producing phenotypic changes similar to those caused by posaconazole, a well-known inhibitor of sterol biosynthesis. Thus, 1,3,4-thiadiazole derivative 11a could be considered a good prototype for the development of new drug candidates for Chagas disease therapy.

Crystal structures of 3ß,19-dihydroxyandrost-5-en-17-one, 5, and its monohydrate, [(5).H2O]: A survey of the structures of related di- and tri-substituted hydroxy derivatives and their solvated compounds.

The crystal structures of 3ß,19-dihydroxyandrost-5-en-17-one, 5, and its monohydrate, [((5).H2O]], are reported. The monohydrate, isolated from a solution of 5 in 50% aqueous methanol, recrystallizes in the orthorhombic space group, P212121, while that of the anhydrous compound, isolated from solutions of THF, Me2CO, EtOAc or dry MeOH, recrystallizes in the monoclinic space group, P21. Apart from the different orientation of the 3-HO group, the conformations of the steroid molecules in 5 and [(5).H2O]: are similar. The two-dimensional structure of 5 consists of sheets of molecules formed from strong classical O3-H3⋯O19(OH) and O19-H19···O3(OH), augmented by weaker C-H⋯O hydrogen bonds. Noticeably the presence of the C19 hydroxyl group results in the replacement of the O3-H3⋯O17(one) hydrogen bonds as the strongest intermolecular interaction found in the stable polymorphs of the mono-hydroxylated compound, 3ß-hydroxyandrost-5-en-17-one (dehydroepiandrosterone). An additional structural difference between 3ß-hydroxyandrost-5-en-17-one and 3ß,19-dihydroxyandrost-5-en-17-one is that the steroid molecules are most strongly linked head-to-tail in the former but head-to-middle fashion in the latter. In the three dimensional structure of [((5).H2O]], each steroid molecule is directly connected to another by a O19-H19⋯O3(OH) hydrogen bond and indirectly to two others via the water molecule. Each water molecule forms three hydrogen bonds, namely O3-H3⋯Ow, Ow-Hw1⋯O17 and Ow-Hw2⋯O19. As found for most hydrated steroids, the hydrate molecules have strong influences on the structure. In addition to the reporting of the crystal structures of 5 and [(5).H2O], we report on a survey of the crystal structures of related di- and tri- hydroxy-17-one derivatives as well as solvated compounds.

Different packing motifs mediated by weak inter-actions and polymorphism in the crystal structures of five 2-(benzyl-idene)benzosuberone derivatives.

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 23.79 (3) for (I), 24.60 (4) for (II), 33.72 (4) for (III), 29.93 (8) for (IV) and 21.81 (7)° for (V). Key features of the packing include pairwise C-H⋯O hydrogen bonds for (II) and (IV), and pairwise C-H⋯N hydrogen bonds for (V), which generate inversion dimers in each case. The packing for (I) and (III) feature C-H⋯O hydrogen bonds, which lead to [010] and [100] chains, respectively. Weak C-H⋯π inter-actions consolidate the structures and weak aromatic π-π stacking is seen in (II) [centroid-centroid separation = 3.8414 (7) Å] and (III) [3.9475 (7) Å]. A polymorph of (I) crystallized from a different solvent has been reported previously [Dimmock et al. (1999 ▸) 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.

Racemic mefloquinium chloro-difluoro-acetate: crystal structure and Hirshfeld surface analysis.

In the racemic title mol-ecular salt, C17H17F6N2O+·C2ClF2O3- (systematic name: 2-{[2,8-bis-(tri-fluoro-meth-yl)quinolin-4-yl](hy-droxy)meth-yl}piperidin-1-ium chloro-difluoro-acetate), the cation, which is protonated at the piperidine N atom, has the shape of the letter, L, with the piperidin-1-ium group being approximately orthogonal to the quinolinyl residue [the Cq-Cm-Cm-Na (q = quinolinyl; m = methine; a = ammonium) torsion angle is 177.79 (18)°]. An intra-molecular, charge-assisted ammonium-N-H⋯O(hydrox-yl) hydrogen bond ensures the hy-droxy-O and ammonium-N atoms lie to the same side of the mol-ecule [Oh-Cm-Cm-Na (h = hydrox-yl) = -59.7 (2)°]. In the crystal, charge-assisted hydroxyl-O-H⋯O-(carboxyl-ate) and ammonium-N+-H⋯O-(carboxyl-ate) hydrogen bonds generate a supra-molecular chain along [010]; the chain is consolidated by C-H⋯O inter-actions. Links between chains to form supra-molecular layers are of the type C-Cl⋯π(quinolinyl-C6) and the layers thus formed stack along the a-axis direction without directional inter-actions between them. The analysis of the calculated Hirshfeld surface points to the dominance of F⋯H contacts to the surface (40.8%) with significant contributions from F⋯F (10.5%) and C⋯F (7.0%) contacts.

Different mol-ecular conformations in the crystal structures of three 5-nitro-imidazolyl derivatives.

The crystal structures of (E)-1-methyl-5-nitro-1H-imidazole-2-carbaldehyde O-benzyl-oxime, C12H12N4O3, (I), (E)-1-methyl-5-nitro-1H-imidazole-2-carb-alde-hyde O-(4-fluoro-benz-yl) oxime, C12H11FN4O3, (II), and (E)-1-methyl-5-nitro-1H-imidazole-2-carbaldehyde O-(4-bromo-benz-yl) oxime, C12H11BrN4O3, (III), are described. The dihedral angle between the ring systems in (I) is 49.66 (5)° and the linking Nm-C-C=N (m = methyl-ated) bond shows an anti conformation [torsion angle = 175.00 (15)°]. Compounds (II) and (III) are isostructural [dihedral angle between the aromatic rings = 8.31 (5)° in (II) and 5.34 (15)° in (III)] and differ from (I) in showing a near-syn conformation for the Nm-C-C=N linker [torsion angles for (II) and (III) = 17.64 (18) and 8.7 (5)°, respectively], which allows for the occurrence of a short intra-molecular C-H⋯N contact. In the crystal of (I), C-H⋯N hydrogen bonds link the mol-ecules into [010] chains, which are cross-linked by very weak C-H⋯O bonds into (100) sheets. Weak aromatic π-π stacking inter-actions occur between the sheets. The extended structures of (II) and (III) feature several C-H⋯N and C-H⋯O hydrogen bonds, which link the mol-ecules into three-dimensional networks, which are consolidated by aromatic π-π stacking inter-actions. Conformational energy calculations and Hirshfeld fingerprint analyses for (I), (II) and (III) are presented and discussed.

Evaluation of 1,3-benzoxathiol-2-one Derivatives as Potential Antifungal Agents.

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.

The 1:1 co-crystal of 2-bromo-naphthalene-1,4-dione and 1,8-di-hydroxy-anthracene-9,10-dione: crystal structure and Hirshfeld surface analysis.

The asymmetric unit of the title co-crystal, C10H5BrO2·C14H8O4 [systematic name: 2-bromo-1,4-di-hydro-naphthalene-1,4-dione-1,8-dihy-droxy-9,10-di-hydro-anthracene-9,10-dione (1/1)], features one mol-ecule of each coformer. The 2-bromo-naphtho-quinone mol-ecule is almost planar [r.m.s deviation of the 13 non-H atoms = 0.060 Å, with the maximum deviations of 0.093 (1) and 0.099 (1) Šbeing for the Br atom and a carbonyl-O atom, respectively]. The 1,8-di-hydroxy-anthra-quinone mol-ecule is planar (r.m.s. deviation for the 18 non-H atoms is 0.022 Å) and features two intra-molecular hy-droxy-O-H⋯O(carbon-yl) hydrogen bonds. Dimeric aggregates of 1,8-di-hydroxy-anthra-quinone mol-ecules assemble through weak inter-molecular hy-droxy-O-H⋯O(carbon-yl) hydrogen bonds. The mol-ecular packing comprises stacks of mol-ecules of 2-bromo-naphtho-quinone and dimeric assembles of 1,8-di-hydroxy-anthra-quinone with the shortest π-π contact within a stack of 3.5760 (9) Šoccurring between the different rings of 2-bromo-naphtho-quinone mol-ecules. The analysis of the Hirshfeld surface reveals the importance of the inter-actions just indicated but, also the contribution of additional C-H⋯O contacts as well as C=O⋯π inter-actions to the mol-ecular packing.

Correction: Copper(ii) catalyzed synthesis of novel helical luminescent benzo[4,5]imidazo[1,2-a][1,10]phenanthrolines via an intramolecular C-H amination reaction.

Correction for 'Copper(ii) catalyzed synthesis of novel helical luminescent benzo[4,5]imidazo[1,2-a][1,10]phenanthrolines via an intramolecular C-H amination reaction' by Ramon Borges da Silva, et al., Org. Biomol. Chem., 2017, DOI: 10.1039/c6ob02508k.

N-(2-(arylmethylimino)ethyl)-7-chloroquinolin-4-amine derivatives, synthesized by thermal and ultrasonic means, are endowed with anti-Zika virus activity.

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.

Copper(ii) catalyzed synthesis of novel helical luminescent benzo[4,5]imidazo[1,2-a][1,10]phenanthrolines via an intramolecular C-H amination reaction.

In the present study a series of N-phenyl-1,10-phenanthroline-2-amine derivatives were obtained by heating 2-chlorophenanthroline with aniline derivatives under solvent free conditions in good to excellent yields. The N-phenyl-1,10-phenanthroline-2-amines were employed as substrates in a copper(ii)-catalyzed C-H amination reaction to give derivatives of the novel heterocyclic system benzo[4,5]imidazo[1,2-a][1,10]phenanthroline. The structure of these compounds was predicted to be helical by DFT calculations and single crystal X-ray diffraction of an example of this system confirmed the non-planar helical structure. The luminescence properties of the parent heterocyclic system were characterized.

N'-[(1E)-(5-Nitro-furan-2-yl)methyl-idene]thio-phene-2-carbohydrazide: crystal structure and Hirshfeld surface analysis.

In the title carbohydrazide, C10H7N3O4S, the dihedral angle between the terminal five-membered rings is 27.4 (2)°, with these lying to the same side of the plane through the central CN2C(=O) atoms (r.m.s. deviation = 0.0403 Å), leading to a curved mol-ecule. The conformation about the C=N imine bond [1.281 (5) Å] is E, and the carbonyl O and amide H atoms are anti. In the crystal, N-H⋯O hydrogen bonds lead to supra-molecular chains, generated by a 41 screw-axis along the c direction. A three-dimensional architecture is consolidated by thienyl-C-H⋯O(nitro) and furanyl-C-H⋯O(nitro) inter-actions, as well as π-π inter-actions between the thienyl and furanyl rings [inter-centroid distance = 3.515 (2) Å]. These, and other, weak inter-molecular inter-actions, e.g. nitro-N-O⋯π(thien-yl), have been investigated by Hirshfeld surface analysis, which confirms the dominance of the conventional N-H⋯O hydrogen bonding to the overall mol-ecular packing.

A kryptoracemic salt: 2-{[2,8-bis-(tri-fluoro-meth-yl)quinolin-4-yl](hy-droxy)meth-yl}piperidin-1-ium (+)-3,3,3-tri-fluoro-2-meth-oxy-2-phenyl-propanoate.

The asymmetric unit of the title salt, C17H17F6N2O(+)·C10H8F3O3 (-), comprises two piperidin-1-ium cations and two carboxyl-ate anions. The cations, each having an l-shaped conformation owing to the near orthogonal relationship between the quinolinyl and piperidin-1-ium residues, are pseudo-enanti-omeric. The anions have the same absolute configuration but differ in the relative orientations of the carboxyl-ate, meth-oxy and benzene groups. Arguably, the most prominent difference between the anions occurs about the Cq-Om bond as seen in the Cc-Cq-Om-Cm torsion angles of -176.1 (3) and -67.1 (4)°, respectively (q = quaternary, m = meth-oxy and c = carboxyl-ate). The presence of Oh-H⋯Oc and Np-H⋯Oc hydrogen bonds leads to the formation of a supra-molecular chain along the a axis (h = hy-droxy and p = piperidin-1-ium); weak intra-molecular Np-H⋯Oh hydrogen bonds are also noted. Chains are connected into a three-dimensional architecture by C-H⋯F inter-actions. Based on a literature survey, related mol-ecules/cations adopt a uniform conformation in the solid state based on the letter L.

Synthesis and Biological Activities of Camphor Hydrazone and Imine Derivatives.

Both sonochemical and classical methodologies have been employed to convert camphor, 1,7,7-trimethylbicyclo[2.2.1]heptan-2-one, C9H16C=O, into a number of derivatives including hydrazones, C9H16C=N-NHAr 3, imines, C9H16C=N-R 7, and the key intermediate nitroimine, C9H16C=N-NO2 6. Reactions of nitroamine 6 with nucleophiles by classical methods provided the desired compounds in a range of yields. In evaluations of activity against Mycobacterium tuberculosis, compound 7j exhibited the best activity (minimal inhibitory concentration (MIC) = 3.12 µg/mL), comparable to that of the antitubercular drug ethambutol. The other derivatives displayed modest antimycobacterial activities at 25-50 µg/mL. In in vitro tests against cancer cell lines, none of the synthesized camphor compounds exhibited cytotoxic activities.

Anti-tuberculosis evaluation and conformational study of N-acylhydrazones containing the thiophene nucleus.

A series of N-acylhydrazonyl-thienyl derivatives (compounds 2 and 3), mainly of the type 2-(aryl-CH=N-NHCOCH2 )-thiene (2: aryl = substituted-phenyl; 3: aryl = heteroaryl) were evaluated against Mycobacterium tuberculosis. Particularly active compound was 3 (heteroaryl = 5-nitrothien-2-yl or 5-nitrofuran-2-yl) with MIC values of 8.5 and 9.0 µM, respectively. Moderately active compounds were compound 3 (heteroaryl = pyridin-2-yl) and compound 2 containing aryl = 2- or 4-hydroxyphenyl groups, with MIC values between 170 and 408 µM. Compound 2 containing OMe, H, F, Cl, Br, CN, and NO2 substituents and compound 3 (heteroaryl = furan-2-yl, thien-2-yl, pyrrol-2-yl, imidazol-2-yl, pyridin-3-yl, and pyridin-4-yl) were all inactive. Clearly, there is no correlation of activity with the electronic effects of the substituents. The activities suggest different modes of biological action of the compounds having nitro-heteroaryl groups, on the one hand, and the 2-hydroxyphenyl or pyridin-2-yl substituents, on the other hand. Compounds having 2- or 4-hydroxyphenyl, 2-hydroxy-5-nitrophenyl, or 4-hydroxy-3-chlorophenyl were less cytotoxic than ethambutol. It is important to notice that compound 3 (aryl = 5-NO2 -furan-2-yl) exhibited a promising therapeutic index (TI = 1093.90), with a value 4.4 less than that of ethambutol. Compounds 2 and 3 exist in DMSO or MeOD solutions as mixtures of EC(O)N /EC=N and ZC(O)N /EC=N conformers.

Design, synthesis and biological evaluation of (E)-2-(2-arylhydrazinyl)quinoxalines, a promising and potent new class of anticancer agents.

A series of forty-seven quinoxaline derivatives, 2-(XYZC6H2CHN-NH)-quinoxalines, 1, have been synthesized and evaluated for their activity against four cancer cell lines: potent cytotoxicities were found (IC50 ranging from 0.316 to 15.749 µM). The structure-activity relationship (SAR) analysis indicated that the number, the positions and the type of substituents attached to the aromatic ring are critical for biological activity. The activities do not depend on the electronic effects of the substituents nor on the lypophilicities of the molecules. A common feature of active compounds is an ortho-hydroxy group in the phenyl ring. A potential role of these ortho-hydroxy derivatives is as N,N,O-tridentate ligands complexing with a vital metal, such as iron, and thereby preventing proliferation of cells. The most active compound was (1: X,Y=2,3-(OH)2, Z=H), which displayed a potent cytotoxicity comparable to that of the reference drug doxorubicin.

Mefloquine-oxazolidine derivatives: a new class of anticancer agents.

A series of 23 racemic mefloquine-oxazolidine derivatives, 4-[3-(aryl)hexahydro[1,3]oxazolo[3,4-a]pyridin-1-yl]-2,8-bis(trifluoromethyl)quinolines, derived from (R*, S*)-(±)-mefloquine and arenealdehydes, have been evaluated for their activity against four cancer cell lines (HCT-8, OVCAR-8, HL-60, and SF-295). Good cytotoxicities have been determined with IC50 values ranging from 0.59 to 4.79 µg/mL. In general compounds with aryl groups having strong electron-releasing substituents, such as HO and MeO, or electron-rich heteroaryl groups, for example imidazol-2-y-l, are active. However, other factors such as steric effects may play a role. As both the active and non-active conformations of the mefloquine-oxazolidine derivatives are similar, it is concluded that molecular conformations do not play a significant role either. This study is the first to evaluate mefloquine derivatives as antitumor agents. The mefloquine-oxazolidine derivatives are considered to be useful leads for the rational design of new antitumor agents.

Syntheses and antimycobacterial activities of [(2S,3R)-2-(amino)-4-(arenesulfonamido)-3-hydroxy-1-phenylbutane derivatives.

The syntheses of hydroxyethylsulfonamides, (2S,3R)-tert-butyl N-[4-(N-benzyl-4-R-phenylsulfonamido)-3- hydroxy-1-phenylbutan-2-yl]carbamates and (5) (2S,3R)-2-amino-4-[N-benzyl-4-R-benzenesulfonamido]-3-hydroxy-1- phenylbutane hydrochlorides (6), derived from (2S,3S)-Boc-phenylalanine epoxide, are reported. None of the compounds, containing the Boc group, showed activity against M. tuberculosis ATTC 27294, while compounds 6 did, with the most active compounds having R = p-Cl, p-Br and p-Me. Results indicate that the presence of a free amino group at C2 and the sulphonamide moiety are important for biological activity. The antimycobacterial activity of compounds 6 correlated well with the calculated lipophilicities, but not with the electronic effects of the substituents, R. All compounds 6 were highly cytotoxic against the hepatoma cell lineage Hep G2 A16. The X-ray crystal structure of compound [(6: R = Me).H2O] is also reported. In the propeller-like conformation adopted by the cation, the amino and hydroxy groups have a cis arrangement, and thus are suitably placed to form 5- membered chelates.

Synthesis and trypanocidal activity of novel 2,4,5-triaryl-N-hydroxylimidazole derivatives.

Herein, we report the design, synthesis and trypanocidal activity of some novel trisubstituted imidazole derivatives. These heterocyclic derivatives were structurally planned by exploring the concept of molecular hybridisation between two arylhydrazones derived from megazol, which has potent trypanocidal activity. The trypanocidal activity of these triarylimidazole derivatives was evaluated against infective trypomastigote forms of T. cruzi and the derivative 2'-(4-bromophenyl)-1-methyl-5'-phenyl-1H,3'H-2,4'-biimidazol-3'-ol showed moderate biological activity (IC50 = 23.9 µM) when compared to benznidazole, a standard trypanocidal drug. These compounds did not present cytotoxic effects at concentrations near the trypanocidal IC50, being considered a good starting point for the development of new anti-Chagas drug candidates.