One-Pot Multicomponent Synthesis of Methoxybenzo[h]quinoline-3-carbonitrile Derivatives; Anti-Chagas, X-ray, and In Silico ADME/Tox Profiling Studies.

Several methoxybenzo[h]quinoline-3-carbonitrile analogs were designed and synthesized in a repositioning approach to developing compounds with anti-prostate cancer and anti-Chagas disease properties. The compounds were synthesized through a sequential multicomponent reaction of aromatic aldehydes, malononitrile, and 1-tetralone in the presence of ammonium acetate and acetic acid (catalytic). The effect of the one-pot method on the generation of the target product has been studied. The compounds were in vitro screened against bloodstream trypomastigotes of T. cruzi (NINOA and INC-5 strains) and were most effective at showing a better activity profile than nifurtimox and benznidazole (reference drugs). A study in silico on absorption, distribution, metabolism, excretion, and toxicity (ADME/Tox) profiling to help describe the molecular properties related to the pharmacokinetic aspects in the human body of these compounds was reported. In addition, X-ray data for the compound 2-Amino-5,6-dihydro-4-(3-hydroxy-4-methoxy-phenyl)-8-methoxybenzo[h]quinoline-3-carbonitrile 6 was being reported. Spectral (IR, NMR, and elemental analyses) data on all final compounds were consistent with the proposed structures.

4-(Dimethyl-amino)phenyl ethynyl telluride.

The title compound, C(10)H(11)NTe, is the first organyl ethynyl telluride, R-Te-C C-H, to be structurally characterized. In the L-shaped mol-ecule, the aryl moiety, viz. Me(2)NC(6)H(4)Te, is almost perpendicular to the Te-C C-H fragment. The Te-Csp(2) bond [2.115 (3) Å] is significantly longer than the Te-Csp bond [2.041 (4) Å]. The Te-C C group is approximately linear [Te-C-C = 178.5 (4)° and C C = 1.161 (5) Å], while the coordination at the Te atom is angular [C-Te-C = 95.92 (14)°]. In the crystal structure, there are Csp-H⋯N hydrogen bonds which are perpendicular to the CNMe(2) group; the N atom displays some degree of pyramidalization. Centrosymmetrically related pairs of mol-ecules are linked by Te⋯π(ar-yl) inter-actions, with Te⋯Cg = 3.683 (4) Šand Csp-Te⋯Cg = 159.1 (2)° (Cg is the centroid of the benzene ring). These inter-actions lead to the formation of zigzag ribbons which run along c and are approximately parallel to (110).

Synthesis, antimalarial activity, structure-activity relationship analysis of thieno-[3,2-b]benzothiazine S,S-dioxide analogs.

An improved procedure for the synthesis of 3-amino-9-arylsubstituted-thieno[3,2-b]benzothiazine S,S-dioxide 2-decarboxylated is reported. Thieno-[3,2-b]benzothiazine S,S-dioxide derivatives were investigated for their abilities to inhibit beta-hematin formation, hemoglobin hydrolysis and in vivo for their efficacy in rodent Plasmodium berghei. Compounds 5j-o were the most promising as inhibitors of hemoglobin hydrolysis, however, the compounds are not as efficient as chloroquine. A structure-activity relationship (SAR) study was carried out in this series. Our results allow us to determine the minimal structural requirements to produce the biological response.

Twinning by merohedry in bis(4-methoxyphenyl)tellurium(IV) diiodide dimethyl sulfoxide hemisolvate.

Green crystals of the title compound, C(14)H(14)I(2)O(2)Te x 0.5 C(2)H(6)OS, space group P3(2), show twinning by merohedry (class II). The asymmetric unit contains two organotellurium molecules and one dimethyl sulfoxide (DMSO) molecule. The crystal structure displays secondary Te...I and Te...O(DMSO) bonds that lead to [(4-MeOC(6)H(4))(2)TeI(2)](2) x DMSO supramolecular units in which the two independent organotellurium molecules are bridged by the DMSO O atom. In addition to these secondary bonds, I...I interactions link translationally equivalent organotellurium molecules to form nearly linear ...I-Te-I...I-Te-I... chains. These chains are crosslinked, forming two-dimensional arrays parallel to (001). The crystal packing consists of a stacking of these sheets, which are related by the 3(2) axis. This study describes an unusual dimeric arrangement of X-Te-X groups.

(2E)-2-(2,4-Dichloro-phenyl-sulfon-yl)-3-(3-methoxy-anilino)-3-(methyl-sulfan-yl)acrylonitrile.

The title compound, C(17)H(14)Cl(2)N(2)O(3)S(2), and the 4-methyl-anilino analogue reported in the following paper have been used as starting materials to develop benzothia-zine derivatives with anti-malarial activity. The mol-ecule displays an E (trans) configuration about the central double bond. Due to conjugation in the C=C-C N group, the putative single bond shows a significant shortening [1.421 (3) Å]. The mol-ecule has a six-membered ring involving an intra-molecular N-H⋯O(sulfon-yl) bond, which is an example of resonance-assisted hydrogen bonding. There is also an intra-molecular N-H⋯Cl hydrogen bond. In the crystal structure, bonds of the C-H⋯O(sulfon-yl) type form chains that run along [101], while N-H⋯O(sulfon-yl) bonds connect centrosymmetrically related molecules in pairs of these chains, forming ribbons. Comparison of the N⋯O distances in the intra- and inter-molecular N-H⋯O(sulfon-yl) bonds reveals that the π-bond co-operativity results in a strengthening of the intra-molecular hydrogen bond. There are also π-π inter-actions between benzene rings of pairs of centrosymmetrically related mol-ecules [centroid-centroid distance = 3.8612 (13) Å], as well as C-H⋯π interactions.

(2E)-2-(2,4-Dichloro-phenyl-sulfon-yl)-3-(4-methyl-anilino)-3-(methyl-sulfan-yl)acrylonitrile.

The title compound, C(17)H(14)Cl(2)N(2)O(2)S(2), and the 3-methoxy-anilino analogue reported in the preceding paper have been used as starting materials to develop benzothia-zine derivatives with anti-malarial activity. The mol-ecule displays an E (trans) configuration about the central double bond. Due to conjugation in the C=C-C N group, the putative single bond shows a significant shortening [1.418 (3) Å]. The mol-ecule has a six-membered ring involving an intra-molecular N-H⋯O(sulfon-yl) bond, which is an example of resonance-assisted hydrogen bonding. In the crystal structure, bonds of the C-H⋯O(sulfon-yl) and C-H⋯N(cyano) types form double layers of mol-ecules parallel to (01). Within these layers there are π-π inter-actions between benzene rings of pairs of centrosymmetrically related mol-ecules, with distances of 3.7969 (12) Šbetween centroids. C-H⋯π interactions are also present.

(2,2'-Bipyridine)bis-(triphenyl-phosphine)copper(I) nitrate chloro-form solvate hemihydrate.

In the title compound, [Cu(C(10)H(8)N(2))(C(18)H(15)P)(2)]NO(2)·CHCl(3)·0.5H(2)O, the Cu atom is tetra-hedrally coordinated by a bidentate 2,2'-bipyridine ligand and two PPh(3) ligands. The Cu-N and Cu-P distances are similar to those observed in similar compounds. The range of coordination angles shows a moderate distortion from ideal tetra-hedral geometry. The bipyridine ligand is twisted [14.2 (4)°] about the ring-ring C-C bond. The nitrate anion and the water and chloro-form mol-ecules of solvation are disordered. In the crystal structure, there are O(water)-H⋯O(nitrate), C-H⋯O(water) and C-H⋯O(nitrate) hydrogen bonds.

Synthesis, crystal structure and effect of indeno[1,2-b]indole derivatives on prostate cancer in vitro. Potential effect against MMP-9.

A highly regiospecific synthesis of a series of indenoindoles is reported, together with X-ray studies and their activity against human prostate cancer cells PC-3 and LNCaP in vitro. The most effective compound 7,7-dimethyl-5-[(3,4-dichlorophenyl)]-(4bRS,9bRS)-dihydroxy-4b,5,6,7,8,9bhexahydro-indeno[1,2-b]indole-9,10-dione 7q reduced the viability in both cell lines in a time and dose-dependent manner. Inhibitory effects were also observed on the adhesion, migration, and invasion of the prostate cancer cells as well as on clonogenic possibly by inhibition of MMP-9 activity. Molecular docking of 7q and 6k into MMP-9 human active site was also performed to determine the probable binding mode.

Synthesis, in vitro antifungal activity and mechanism of action of four sterol hydrazone analogues against the dimorphic fungus Paracoccidioides brasiliensis.

The design and synthesis of novel sterol hydrazone analogues (9, 10, 11 and 12) are described, followed by their evaluation as inhibitors of fungal growth, using Paracoccidioides brasiliensis as the biological tester. Compounds 9, 10, 11 and 12 generated a dose-dependent effect in fungal growth, particularly 9, 11 and 12, which were active at nanomolar concentrations (100 nM). When P. brasiliensis in its pathogenic yeast-like phase was treated individually with each of the aforementioned compounds at concentrations that reduced growth rate around 50%, the analysis of sterol composition in the resulting surviving cells demonstrated a 50% reduction of the final sterols brasicasterol and ergosterol, and concomitant increase in the levels of lanosterol. These results indicate that these compounds inhibit the enzyme Δ(24)-sterol methyl transferase (SMT), in a manner dependent on the stereochemical location of the hydrazone group. Compound 12, instead, induced a good antiproliferative activity not associated with blockage of any step in the pathway to sterol biosynthesis, suggesting a different mode of action. The X-ray crystal structure of H1 was determined to obtain information regarding the rings and side chain conformation of the sterol hydrazones. Comparison of the inhibitory effects of sterol hydrazones (9-12) and azasterols (AZA1-AZA3) on SMT with the molecular electrostatic potential, negative isopotential energy surfaces (-10 kcal/mol) and local ionization potential calculated via DFT methods, showed that changes in the electronic moiety introduced by the N and O atoms were not as important as the additional flexibility of the side chain introduced by an extra methylene group.

Synthesis and antimalarial activity of pyrazolo and pyrimido benzothiazine dioxide derivatives.

A series of phenylsubstituted pyrazolo and pyrimido benzothiazine dioxide derivatives were synthesized and investigated for their abilities to inhibit beta-hematin formation, hemoglobin hydrolysis and in vivo for their antimalarial efficacy in rodent Plasmodium berghei. Compounds 3-amino-7-chloro-9-(2'-methylphenyl)-1,9-dihydro-pyrazolo-[4,3-b]benzothiazine 4,4-dioxide 2b and 2,4-diamino-8-chloro-10H-phenyl-pyrimido-[5,4-b]benzothiazine 5,5-dioxide 3a were the most promising as inhibitors of hemoglobin hydrolysis, however, their effect as inhibitors of beta-hematin formation was marginal, except for compound 3-amino-7-chloro-9-(3'-chlorophenyl)-1,9dihydro-pyrazolo-[4,3-b]benzothiazine 4,4-dioxide 2g. The most active compound to emerge from the in vitro and in vivo murine studies was 2b, suggesting an antimalarial activity via inhibition of hemoglobin hydrolysis, however, not as efficient as chloroquine.