Evaluation of trypanocidal properties of ferrocenyl and cyrhetrenyl N-acylhydrazones with pendant 5-nitrofuryl group.

Four N-acylhydrazones of general formulae [R1-C(O)-NH-N=C(R2)(5-nitrofuryl)] with (R1 = ferrocenyl or cyrhetrenyl and R2 = H or Me) are synthesized and characterized in solution and in the solid-state. Comparative studies of their stability in solution under different experimental conditions and their electrochemical properties are reported. NMR studies reveal that the four compounds are stable in DMSO­d6 and complementary UV-Vis studies confirm that they also exhibit high stability in mixtures DMSO:H2O at 37 °C. Electrochemical studies show that the half-wave potential of the nitro group of the N-acylhydrazones is smaller than that of the standard drug nifurtimox and the reduction process follows a self-protonation mechanism. In vitro studies on the antiparasitic activities of the four complexes and the nifurtimox against Trypanosoma cruzi and Trypanosoma brucei reveal that: i) the N-acylhydrazones have a potent inhibitory growth activity against both parasites [EC50 in the low micromolar (in T. cruzi) or even in the nanomolar (in T. brucei) range] and ii) cyrhetrenyl derivatives are more effective than their ferrocenyl analogs. Parallel studies on the L6 rat skeletal myoblast cell line have also been conducted, and the selectivity indexes determined. Three of the four N-acylhydrazones showed higher selectivity towards T. brucei than the standard drug nifurtimox. Additional studies suggest that the organometallic compounds are bioactivated by type I nitroreductase enzymes.

Spectroscopic Study of the E/Z Photoisomerization of a New Cyrhetrenyl Acylhydrazone: A Potential Photoswitch and Photosensitizer†.

The new cyrhetrenyl acylhydrazone [(CO)3 Re(η5 -C5 H4 )-C(O)-NH-N = C(CH3 )-(2-C4 H2 S-5-NO2 )] (E-CyAH) has been designed, synthesized and fully characterized to study the effect of having a cyrhetrenyl fragment (sensitizer) covalently bonded to an acylhydrazone moiety (switch), on its photophysical and photochemical properties. The crystal structure reveals that E-CyAH adopts an E-configuration around the iminic moiety [-N = C(CH3 )]. The absorption spectrum of E-CyAH displays two bands at 270 and 380 nm, which are mainly ascribed to π â†’ π* intraligand (IL) and dπ  â†’ π* metal-to-ligand charge transfer (MLCT) transitions, being consistent with DFT/TD-DFT calculations. Upon 365 nm irradiation, E-CyAH photoisomerizes to Z-CyAH, as evidenced by UV-Vis and 1 H-NMR spectral changes, with a quantum yield value ΦE -CyAH → Z -CyAH of 0.30. Z-CyAH undergoes a first-order thermal back-isomerization process, with a relatively short half-life τ1/2 of 277 min. Consequently, E-CyAH was quantitatively recovered after 24 h, making it a fully reversible T-type molecular photoswitch. This remarkable behavior allows us to measure the individual photophysical properties for both isomers. In addition, E-CyAH and Z-CyAH efficiently photosensitize the generation of singlet oxygen (O2 (1 Δg )) with good yield (ΦΔ  = 0.342).

Novel multifunctional and multitarget homo- (Fe2) and heterobimetallic [(Fe,M) with M = Re or Mn] sulfonyl hydrazones.

The synthesis and characterization of the novel ferrocenyl sulfonyl hydrazide [Fe(η5-C5H5){(η5-C5H4)-S(O)2-NH-NH2}] (2) is reported. Additional studies on its reactivity using acetone or the ferrocenyl-, cyrhetrenyl- or cymantrenyl-aldehydes have allowed us to isolate and characterize [Fe(η5-C5H5){(η5-C5H4)-S(O)2-NH-N[double bond, length as m-dash]CMe2}] (3), the bis(ferrocenyl) derivative [Fe(η5-C5H5){[(η5-C5H4)-S(O)2-NH-N[double bond, length as m-dash]CH-(η5-C5H4)]Fe(η5-C5H5)}] (4) and the heterodimetallic compounds [Fe(η5-C5H5){[(η5-C5H4)-S(O)2-NH-N[double bond, length as m-dash]CH-(η5-C5H4)]M(CO)3}] with M = Re (5a) or Mn (5b). The X-ray crystal structures of compounds 3, 5a and 5b are also reported. A comparative study of their electrochemical and spectroscopic properties is also described. Additional computational calculations based on the DFT methodology have allowed us to elucidate the effect produced by the replacement of the terminal -NH2 (in 2) by the -N[double bond, length as m-dash]CMe2 (in 3) and -N[double bond, length as m-dash]CHR (in 4, 5a and 5b) moieties on the electronic distribution and to explain the differences detected in their electrochemical properties and absorption spectra. In vitro cytotoxicity studies of compounds 2, 4, 5a and 5b on the HCT-116 (colon), MCF7 and MDA-MB231 (breast) cancer cell lines reveal that compound 2 has no significant activity (IC50 > 100 µM), while its derivatives 4, 5a and 5b proved to be active in the three cancer cell lines selected in this study. The growth inhibition potency of compounds 5a and 5b against the triple negative MDA-MB231 breast cancer cell line is similar (or slightly) greater than that of cisplatin. Moreover, compounds 2, 4, 5a and 5b are less toxic than cisplatin in the normal and non-tumoral BJ fibroblasts, and the heterodimetallic complexes 5a and 5b with selective index >2.1 show an outstanding selective toxicity towards the MDA-MB231 cancer cells.

A novel type of organometallic 2-R-2,4-dihydro-1H-3,1-benzoxazine with R = [M(η5-C5H4)(CO)3] (M = Re or Mn) units. Experimental and computational studies of the effect of substituent R on ring-chain tautomerism.

The syntheses, characterization, X-ray crystal structures, electrochemical properties and anticancer and antichagasic activities of the first examples of 2-substituted 2,4-dihydro-1H-3,1-benzoxazines with half-sandwich organometallic arrays, [M(η5-C5H4)(CO)3] (M = Re or Mn), at position-2 are described. Experimental and computational studies based on DFT calculations on the open forms [Schiff bases of general formulae R-CH[double bond, length as m-dash]N-C6H4-2-CH2OH] (5), with R = ferrocenyl (a), phenyl (b), cyrhetrenyl (c) or cymantrenyl (d), and their tautomeric forms (2-substituted 2,4-dihydro-1H-3,1 benzoxazines) have allowed us to establish the influence of substituents a-d and solvents on: (a) the extent of tautomeric equilibria (5a-5d) ↔ (6a-6d) and (b) their electrochemical properties and the electronic distribution on the open and closed forms. Despite the formal similarity between 6c and 6d, their anticancer and antiparasitic activities are markedly different. Compound 6d is inactive in the HCT116, MDA-MB231 and MCF7 cancer cell lines, but 6c shows moderate activity in the latter cell line, while the Mn(i) complex (6d) is a more potent anti-Trypanosoma cruzi agent than its Re(i) analogue (6c).

Synthesis and antimalarial activities of rhenium bioorganometallics based on the 4-aminoquinoline structure.

A bioorganometallic approach to malaria therapy led to the discovery of ferroquine (FQ, SSR97193). To assess the importance of the electronic properties of the ferrocenyl group, cyclopentadienyltricarbonylrhenium analogues related to FQ, were synthesized. The reaction of [N-(7-chloro-4-quinolinyl)-1,2-ethanodiamine] with the cyrhetrenylaldehyde complexes (η(5)-C(5)H(4)CHO)Re(CO)(3) and [η(5)-1,2-C(5)H(3)(CH(2)OH)(CHO)]Re(CO)(3) produces the corresponding imine derivatives [η(5)-1,2-C(5)H(3)(R)(CHN-CH(2)CH(2)NH-QN)]Re(CO)(3) R=H 3a; R=CH(2)OH 3b; QN=N-(7-Cl-4-quinolinyl). Reduction of 3a and 3b with sodium borohydride in methanol yields quantitatively the amine complexes [η(5)-1,2-C(5)H(3)(R)(CH(2)-NH-CH(2)CH(2)NH-QN)]Re(CO)(3) R=H 4a; R=CH(2)OH 4b. To establish the role of the cyrethrenyl moiety in the antimalarial activity of this series, purely organic parent compounds were also synthesized and tested. Evaluation of antimalarial activity measured in vitro against the CQ-resistant strains (W2) and the CQ-susceptible strain (3D7) of Plasmodium falciparum indicates that these cyrhetrene conjugates are less active compared to their ferrocene and organic analogues. These data suggest an original mode-of-action of FQ and ferrocenyl analogues in relationship with the redox pharmacophore.

Heterobimetallic Re=Pd complexes bridged by eta(1):eta(5)-Ph(2)PC(5)H(4) ligand. Synthesis, electronic and crystal structure of (CO)(2)(PR(3))(eta(5)-C(5)H(4)PPh(2))Re-PdCl(2), R = Me and OMe.

The new rhenium complexes (eta(5)-C(5)H(4)PPh(2))Re(CO)(2)(PR(3)) (R = Me (1) and OMe (2)) were prepared photochemically from (eta(5)-C(5)H(4)PPh(2))Re(CO)(3) in the presence of PMe(3) or P(OMe)(3). Further reaction of these ligands with PdCl(2)(NCPh)(2) in chloroform, produces the heterobimetallic complexes (CO)(2)(PMe(3))(eta(5)-C(5)H(4)PPh(2))Re-PdCl(2) (3) and (CO)(2)(P(OMe)(3))(eta(5)-C(5)H(4)PPh(2))Re-PdCl(2) (4). IR spectroscopy reveals that both complexes possess a Re-Pd interaction which was confirmed by X-ray crystallography (Re-Pd bond distance = 2.762 A in and 2.774 A in ). Relativistic functional density theory calculations have also been carried out in order to probe the bonding in these compounds.

Synthesis, reactivity and molecular structure of phosphino tetramethyl cyclopentadienyl complex (eta5: eta1-C5Me4CH2PPh2)Re(CO)2.

The fulvene complex (eta(6)-C(5)Me(4)CH(2))Re(C(6)F(5))(CO)(2) reacts at the exocyclic methylene carbon with potassium diphenylphosphide to yield the anionic species [(eta(5)-C(5)Me(4)CH(2)PPh(2))Re(C(6)F(5))(CO)(2)](-) (). Protonation of with HCl at 0 degrees C produces the hydride complex trans-(eta(5)-C(5)Me(4)CH(2)PPh(2))Re(C(6)F(5))(H)(CO)(2) (). Thermolysis of a hexanes solution of , under nitrogen atmosphere, produces the chelated complex (eta(5):eta(1)-C(5)Me(4)CH(2)PPh(2))Re(CO)(2) () in good yield. The thermolysis under a CO atmosphere affords a mixture of the complexes (eta(5):eta(1)-C(5)Me(4)CH(2)PPh(2))Re(CO)(2) () and (eta(5)-C(5)Me(4)CH(2)PPh(2))Re(CO)(3) (). The reaction of with two electron donor ligands yields (eta(5)-C(5)Me(4)CH(2)PPh(2))Re(CO)(2)(L) (, L = CO; , L = PMe(3); , L = (t)BuNC). Complex also reacts with I(2), HBF(4) and MeOTf to yield the cationic compounds trans-[(eta(5):eta(1)-C(5)Me(4)CH(2)PPh(2))Re(R)(CO)(2)](+) (, R = I; , R = H; , R = Me). Upon treatment with chloroform, the hydride complex converts to the corresponding chloro derivative . The trans stereochemistry for complexes have been assigned on basis of nu(CO) IR intensities and (13)C-NMR chemical shifts. The reaction of the cationic complexes (, ) with KI and Me(3)NO.2H(2)O yields the neutral species cis-(eta(5):eta(1)-C(5)Me(4)CH(2)PPh(2))Re(I)(R)(CO) (, R = I, , R = Me). The molecular structure of and have been determined by X-ray crystallography.