Exploring antimalarial potential: Conjugating organometallic moieties with organic fragments for enhanced efficacy.

In the search for novel ligands with efficacy against various diseases, particularly parasitic diseases, molecular hybridization of organometallic units into biologically active scaffolds has been hailed as an appealing strategy in medicinal chemistry. The conjugation to organometallic fragments can be achieved by an appropriate linker or by directly coordinating the existing drugs to a metal. The success of Ferroquine (FQ, SR97193), an effective chloroquine-ferrocene conjugate currently undergoing the patient-exploratory phase as a combination therapy with the novel triaminopyrimidine ZY-19489 for malaria, has sparked intense interest in organometallic compound drug discovery. We present the evolution of organometallic antimalarial agents over the last decade, focusing on the parent moiety's class and the type of organometallics involved. Four main organometallic antimalarial compounds have been chosen based on conjugated organic moieties: existing antimalarial drugs, other clinical drugs, hybrid drugs, and promising scaffolds of thiosemicarbazones, benzimidazoles, and chalcones, in particular. The presented insights contribute to the ongoing discourse on organometallic compound drug development for malaria diseases.

Integration of Paramagnetic Diruthenium Complexes into an Extended Chain by Heterometallic Metal-Metal Bonds with Diplatinum Complexes.

We successfully obtained a paramagnetic one-dimensional (1D) chain complex [{Ru2(O2CCH3)4}{Pt2(piam)2(NH3)4}2]n(PF6)4n·4nH2O (2; piam = pivalamidate) extended by metal-metal bonds. Compound 2 comprises two types of metal species, ruthenium and platinum, where an acetate-bridged dinuclear ruthenium complex (i.e., [Ru2]) and a pivalamidate-bridged platinum complex (i.e., [Pt2]) are connected by axial metal-metal bonds, forming an attractive quasi-1D infinite chain that can be expressed as -{[Pt2]-[Ru2]-[Pt2]}n-. Such axial metal-metal bonds are attributed to the interaction between the highest occupied molecular orbital (HOMO) and the lowest unoccupied molecular orbital (LUMO) along the z axis, where both the HOMO in [Pt2(II,II)] and the LUMO in [Ru2(II,II)] are σ* orbitals associated with metal cores. The crystal structure and X-ray photoelectron spectrum for 2 reveal that metal oxidation states are -{[Pt2(II,II)]-[Ru2(II,II)]-[Pt2(II,II)]}n-, where [Ru2(II,II)] can have an electronic configuration of σ(2)π(4)δ(2)δ*(2)π*(2) or σ(2)π(4)δ(2)π*(4). The magnetic susceptibility of 2 has a µeff [∝(χT)(1/2)] value of 2.77 µB per [Pt2(II,II)]-[Ru2(II,II)]-[Pt2(II,II)] unit at 300 K, showing that two unpaired electrons lie on π*(Ru2). Magnetic measurements performed at temperatures of 2-300 K indicate that S = 1 Ru2(II,II) units are weakly antiferromagnetically coupled (zJ = -1.4 cm(-1)) with a large zero-field splitting (D = 221 cm(-1)).

Solution-phase synthesis and biological evaluation of triostin A and its analogues.

Triostin A is a biosynthetic precursor of echinomycin which is one of the most potent hypoxia inducible factor 1 (HIF-1) inhibitors. An improved solution-phase synthesis of triostin A on a preparative scale has been achieved in 17.5% total yield in 13 steps. New analogues of triostin A with various aromatic chromophores, oxidized intra-peptide disulfide bridges and diastereoisomeric cyclic depsipeptide cores were also successfully synthesized. All analogues had a significant inhibitory effect on HIF-1 transcriptional activation in hypoxia and cytotoxicity on MCF-7 cells, with the exception of the derivatives containing a naphthalene chromophore or a thiosulfonate bridge. For the first time, triostin A, echinomycin and the thiosulfinate analogue of triostin A have been revealed to inhibit not only DNA binding of HIF-1 but also HIF-1α protein accumulation in MCF-7 cells. Furthermore, the thiosulfinate analogue and triostin A exhibited a hypoxia-selective cytotoxicity on MCF-7 cells. The improved solution-phase synthetic procedure described herein will contribute to the development of diverse bicyclic depsipeptide drug candidates with the potential to act as novel anti-cancer agents targeting hypoxic tumor microenvironments.

Solution-phase microwave assisted parallel synthesis, biological evaluation and in silico docking studies of N,N'-disubstituted thioureas derived from 3-chlorobenzoic acid.

A facile and robust microwave-assisted solution phase parallel synthesis protocol was exercised for the development of a 38-member library of N,N'-disubstituted thiourea analogues (1-38) by using an identical set of conditions. The reaction time for synthesis of N,N'-disubstituted thiourea analogues was drastically reduced from a reported duration of 8-12h for conventional methods to only 1.5-2.0min. All the derivatives (1-38) were characterized by physico-analytical techniques such as elemental analysis in combination with FT-IR, (1)H, (13)C NMR and by single crystal XRD analysis have also been performed. These compounds were screened for their in vitro urease inhibition activities. Majority of compounds exhibited potent urease inhibition activities, however, the most significant activity was found for 16, with an IC50 value of 1.23±0.1µM. Furthermore, the synthesized compounds were screened for their cytotoxic potential against lungs cancer cell lines. Cell culture studies demonstrated significant toxicity of the compounds on the cell lines, and the levels of toxicity were altered in the presence of various side groups. The molecular docking studies of the most potent inhibitors were performed to identify the probable binding modes in the active site of the urease enzymes. These compounds have a great potential and significance for further investigations.

α-Hydroxy and α-Oxo Selenoamides: Synthesis via Nucleophilic Selenocarbamoylation of Carbonyl Compounds and Characterization.

Carbonyl compounds were added to selenocarbamoyllithiums to generate α-hydroxy and α-oxo selenoamides. Their conformations were determined by X-ray analyses. These compounds adopted conformations that were almost identical to those of ordinary amides. Unlike the consistency of the chemical shifts of the C═Se groups of the selenoamides in (13)C NMR spectra and the (1)J coupling constants of the C═Se groups, the substituents far from the selenium atom influenced the chemical shifts in (77)Se NMR.

Mixed valency in quadruple hydrogen-bonded dimers of bis(biimidazolate)dirhodium complexes.

Dirhodium complexes with biimidazole (H2bim) ligands [Rh2(O2CR)2(H2bim)2Cl2] (R = Bu ([1Cl2]), Pr ([2Cl2])), [Rh2(O2CBu)2(H2bim)2](PF6)2 ([1](PF6)2), [Rh2(O2CBu)2(H2bim)2(PPh3)2](PF6)2 ([1(PPh3)2](PF6)2), and [Rh2(O2CPr)2(H2bim)2(PPh3)2]Cl2 ([2(PPh3)2]Cl2) have been synthesized. Deprotonation of the biimidazole complexes afforded the quadruply hydrogen-bonded dimers of the biimidazolate complexes [Rh2(O2CR)2(Hbim)2(PPh3)2]2 (R = Bu ([1'(PPh3)2]2) and Pr ([2'(PPh3)2]2)). Complementary hydrogen bonds between the Hbim(-) ligands are not coplanar because the Hbim(-) ions in one dirhodium complex are not parallel (the dihedral angle between them is ca. 15°). A cyclic voltammogram of [1'(PPh3)2]2 shows two sets of two consecutive oxidation waves in CH2Cl2. The one-electron-oxidized species of [1'(PPh3)2]2 showed no intervalence charge-transfer band in the electronic spectrum and an axially symmetrical ESR spectrum with hyperfine structure because of two phosphorus atoms. These observations show that the odd electron is localized in a σ(Rh-Rh) orbital on one dirhodium unit. Theoretical calculations indicate that an oxidized complex [Rh2(O2CMe)2(bim)2(PMe3)2](-) hydrogen bonded with a biimidazole complex [Rh2(O2CMe)2(H2bim)2(PMe3)2](2+) was a stable mixed-valence complex.

Two types of heterometallic one-dimensional alignment composed of acetamidate-bridged dirhodium and pivalamidate-bridged diplatinum complexes.

Two types of heterometallic one-dimensional chains, [{Rh2(acam)4}{Pt2(piam)2(NH3)4}2]n(CF3SO3)4n·2nMeOH (2, where acam = acetamidate, piam = pivalamidate) and [{Rh2(acam)4}{Pt2(piam)2(NH3)4}]n(CF3CO2)2n·2nEtOH (3), have been synthesized and characterized by single-crystal X-ray analyses. The chain structures in 2 and 3 are composed of two kinds of dinuclear complexes, [Rh2(acam)4] (i.e., [Rh2]) and [Pt2(piam)2(NH3)4] (i.e., [Pt2]), where Rh and Pt atoms are axially linked by metal-metal bonds. In 2 and 3, each complex is one-dimensionally aligned as -{[Rh2]-[Pt2]-[Pt2]}n- or -{[Rh2]-[Pt2]}n-, respectively, in which different alignments are caused by different isomers of [Pt2] that are HH (head-head) and HT (head-tail) orientation of piam ligands and their hydrogen bonding modes. Considering the crystal structures and X-ray photoelectron spectra (XPS) measurements in 2 and 3, the oxidation states of the metal atoms are -{[Rh2(II,II)]-[Pt2(II,II)]-[Pt2(II,II)]}n- and -{[Rh2(II,II)]-[Pt2(II,II)]}n-, which are unchanged from those in the starting compounds. The diffuse reflectance spectra show that LUMOs are M-M σ-type orbitals. The gap between filled and vacant σ-type orbitals in 3 is narrower than that in 2, and is attributed to the relative higher destabilized filled σ-type orbitals caused by lower numbers of linking platinum atoms.

Crystal structure of di-chlorido-[2-(1H-imidazol-2-yl-κN (3))imidazolato-κN]bis-(tri-n-butyl-phosphane-κP)rhodium(III).

In the title compound, [Rh(C6H5N4)Cl2(C12H27P)2], the Rh(III) ion is chelated by the singly deprotonated 2,2'-biimidazolate (Hbim(-)) ligand and coordinated by two chloride ions and two tri-n-butyl-phosphane ligands. The chloride ions and N atoms of the Hbim(-) ligand lie in a plane where the sum of X-Rh-X angles between cis sites is 360°. The phosphane ligands occupy the sites perpendicular to the plane, completing the overall distorted octahedral coordination sphere. The complex forms a self-complementary hydrogen-bonded dimer with the inversion-related complex through N-H⋯N hydrogen bonds.

Paramagnetic one-dimensional chains comprised of trinuclear Pt-Cu-Pt and paddlewheel dirhodium complexes with metal-metal bonds.

One-dimensional (1-D) chain complexes constructed by metal-metal bonds containing three types of metal species-platinum, rhodium, and copper-have been rationally synthesized and characterized by single-crystal X-ray analyses and physical measurements. The paddlewheel or lantern type complex, [Rh2(O2CCH3)4] (i.e., [Rh2]), has a vacant σ* orbital which accepts the electrons from the filled dz(2) orbital of cis-[Pt(piam)2(NH3)2]·2H2O (1, i.e. [Pt], where piam = pivalamidate) to afford a tetranuclear complex, [{Rh2(O2CCH3)4}{Pt(piam)2(NH3)2}2]·2H2O (2). Compound 2 forms a linear alignment as [Pt]-[Rh2]-[Pt] with unbridged Rh-Pt bonds, where the oxygen atoms of the piam ligands in the [Pt] are noncoordinated, showing the capability of binding another metal ion. Simply mixing [Rh2] and the heterometallic trinuclear complex [Pt2Cu(piam)4(NH3)4](PF6)2 (3, i.e. [Pt-Cu-Pt]) in a ratio of 1:1 in MeOH, EtOH, or Me2CO affords [{Rh2(O2CCH3)4}{Pt2Cu(piam)4(NH3)4}]n(PF6)2n (4), [{Rh2(O2CCH3)4}{Pt2Cu(piam)4(NH3)4}]n(PF6)2n (5), or [{Rh2(O2CCH3)4}{Pt2Cu(piam)4(NH3)4}]n(PF6)2n·6nMe2CO (6), respectively. Compounds 4-6 form infinite chains with the repetition of -{[Rh2]-[Pt-Cu-Pt]}n-, which to our knowledge, are the first examples of heterometallic 1-D chains comprised of three types of metal species with direct metal-metal bonds. The CF3CO2(-), ClO4(-), and water molecules influence the crystal packing to form an octanuclear complex of [{Rh2(O2CCH3)4}{Pt2Cu(piam)4(NH3)4}2](CF3CO2)2(ClO4)2·2H2O (7) with [Pt-Cu-Pt]-[Rh2]-[Pt-Cu-Pt] alignment. Considering the crystal structures and X-ray photoelectron spectra (XPS) measurements in 4-7, the oxidation states of the metal atoms are -{[Rh2(II,II)]-[Pt(II)-Cu(II)-Pt(II)]}n- or [Pt(II)-Cu(II)-Pt(II)]-[Rh2(II,II)]-[Pt(II)-Cu(II)-Pt(II)], which are unchanged from those in the starting compounds. Electron paramagnetic resonance spectra of 4-7 show axially symmetric spectra with g∥ > g⊥, indicating that the HOMO (SOMO) is a Cu d(x(2)-y(2)) orbital. In 7, the hyperfine coupling in the spectrum indicates that the unpaired spin on Cu is perturbed by the Pt atoms.

The Staudinger reaction with 2-imino-1,3-thiaselenanes toward the synthesis of C4 spiro-ß-lactams.

The Staudinger ketene-imine [2 + 2] cycloaddition reaction for conversion of α-heteroatom-substituted exocyclic imines to C4 heterocyclic spiro-ß-lactams has rarely been investigated due to their instability. Herein, we describe the Staudinger reaction between ketenes and α-selenium-substituted exocyclic imines to synthesize C4 spiro-ß-lactams.

1-(2-Chloro-benzo-yl)-3-(2-trifluoro-methyl-phen-yl)thio-urea.

The dihedral angle between the benzene rings in the title compound, C15H10ClF3N2OS, is 54.02 (4)°. An intra-molecular N-H⋯O hydrogen bond occurs. In the crystal, N-H⋯S hydrogen bonds link the mol-ecules into inversion dimers.

1-(2-Chloro-benzo-yl)-3-(3-meth-oxy-phen-yl)thio-urea.

The title compound, C15H13ClN2O2S, exists in the solid state in its thione form with typical thio-urea C-S and C-O bonds lengths as well as shortened C-N bonds. An intra-molecular N-H⋯O hydrogen bond stabilizes the mol-ecular conformation. In the crystal, N-H⋯S hydrogen bonds link the mol-ecules into centrosymmetric dimers.

1-(2-Chloro-benzo-yl)-3-(pyrimidin-2-yl)thio-urea.

In the title compound, C12H9ClN4OS, the carbonyl group is at a cis position with respect to the thio-urea unit. The dihedral angle between the phenyl and pyrimidine ring is 16.49 (6)°. An intra-molecular N-H⋯N hydrogen bond stabilizes the mol-ec-ular conformation. In the crystal, N-H⋯N, C-H⋯O and C-H⋯S hydrogen bonds generate chains along the bc axis.

Synthesis, structures and reactions of acylsulfenyl iodides with theoretical investigations.

A series of acylsulfenyl iodides (RCOSI) were synthesized by the reactions of carbothioic acid group 11-16 element derivatives with iodine or N-iodosuccinimides in moderate to good yields. The structure of the PhCOSI was nearly square planar based on the X-ray analysis, where the C[double bond, length as m-dash]O⋯I distance (3.153(5) Å) was significantly shorter than the sum of the van der Waals radii of the atoms (Σr vdW), indicating close contact within the molecule. The distances between an iodine atom and the neighbouring two iodine atoms were also less than Σr vdW, perhaps due to the energy lowering effect of the interactions. The acylsulfenyl iodides readily reacted with alkenes and alkynes to give the expected addition products in moderate to good yields at approximately 0 °C. A new synthesis of acylated sulfines, sulfenamides and sulfenochalcogenides using acylsulfenyl iodides is also described. Theoretical calculations were performed on PhCOSI with the Sapporo-TZP(+1s1p) basis sets at the MP2 level, which perfectly reproduced the observed structures. Similar calculations were performed on the reactions, exemplified by those of MeCOSI and CH2[double bond, length as m-dash]CH2, together with those of MeSI and CH2[double bond, length as m-dash]CH2. Mechanisms for both reactions were proposed, which were very similar. The proposed mechanism for the former was understood based on that of the latter. For both mechanisms, the episulfuranes and episulfonium ions played an important role. The dynamic and static nature of the bonds in the COSI group of PhCOSI and MeCOSI were elucidated based on QTAIM dual functional analysis.

1-(2-Chloro-benzo-yl)-3-(2,3-dimethyl-phen-yl)thio-urea.

The dihedral angle between the two phenyl groups in the title compound, C16H15ClN2OS, is 14.88 (4)°. An intra-molecular N-H⋯O hydrogen bond occurs. In the crystal, pairs of N-H⋯S hydrogen bonds link the mol-ecules into centrosymmetric dimers.

1-Benzoyl-3-(2,4,5-trichloro-phen-yl)thio-urea.

The benzene and phenyl rings in the title compound, C(14)H(9)Cl(3)N(2)OS, form a dihedral angle of 40.98 (6)°. The mol-ecule exists in the thione form with typical thio-urea C-S [1.666 (2) Å] and C-O [1.227 (3) Å] bond lengths as well as shortened C-N bonds [1.345 (3) and 1.386 (2) Å]. An intra-molecular N-H⋯O hydrogen bond stabilizes the mol-ecular conformation. In the crystal, pairs of N-H⋯S hydrogen bonds link the mol-ecules into centrosymmetric dimers.

1-Benzoyl-3-(4-n-butyl-phen-yl)thio-urea.

The dihedral angle between the benzoyl and phenyl groups in the title compound, C(18)H(20)N(2)OS, is 30.57 (4)°. The crystal packing is characterized by N-H⋯O hydrogen bonds. In the crysta, pairs of N-H⋯S hydrogen bonds link the molecules into inversion dimers.

One-dimensionally extended paddlewheel dirhodium complexes from metal-metal bonds with diplatinum complexes.

We have succeeded in obtaining unique one-dimensional (1D) chain complexes (1, 2, and 3) comprised of two types of metal species: rhodium and platinum. These compounds are constructed from a dinuclear rhodium complex (i.e., [Rh(2)]) and a pivalamidate-bridged platinum complex (i.e., [Pt(2)]), forming an attractive quasi-1D infinite chain, expressed as -{[Rh(2)]-[Pt(2)]-[Pt(2)]}(n)-. Interestingly, the bridging ligands of [Rh(2)] can be varied with trifluoroacetate, acetate, and acetamidate groups, indicating the possibility of electronic structure modulation in the 1D chain.

Synthesis, crystal structure, and characterization of a heterometallic one-dimensional complex with metal-metal bonds.

The quasi-one-dimensional chain [{PtRh(TCM)(2)(NH(3))(2)Cl(2.5)}(2){Pt(2)(PVM)(2)(NH(3))(4)}(2)](n)(PF(6))(6n).2nH(2)O (Chain-2; TCM = Cl(3)CCONH(-), PVM = (t)BuCONH(-)), which consists of Pt and Rh atoms, has been obtained from two dinuclear compounds, [Pt(2)(PVM)(2)(NH(3))(4)](PF(6))(2).H(2)O (1) and [PtRh(TCM)(2)(NH(3))(2)Cl(3)] (2). Single-crystal X-ray analysis showed that the dinuclear compounds stack with metal-metal bonds to form octameric units, Pt-Rh-Pt-Pt-Pt-Pt-Rh-Pt (Pt(6)Rh(2)), that are bridged by the Cl(-) ion to be a quasi-one-dimensional chain. Elemental analysis, X-ray photoelectron spectroscopy, electron paramagnetic resonance (EPR), and magnetic susceptibility measurements showed that Chain-2 has a mixed valency and one unpaired electron per octameric Pt(6)Rh(2) unit. Taking into account the small observed g(av) value (g(av) = 2.01 at room temperature) obtained by EPR measurement and B3LYP density functional theory calculations of the model complex, oxidation states of the octameric unit are postulated to be Pt(3+)-Rh(2.5+)-Pt(2+)-Pt(2+)-Pt(2+)-Pt(2+)-Rh(2.5+)-Pt(3+), where the EPR isotropic signal showed that the unpaired electron resides in the Rh d(xy) orbitals (delta* orbitals in Pt-Rh dinuclear parts) and hops from one Rh atom to another.

Two-step adsorption on jungle-gym-type porous coordination polymers: dependence on hydrogen-bonding capability of adsorbates, ligand-substituent effect, and temperature.

A preliminary study of isopropanol (IPA) adsorption/desorption isotherms on a jungle-gym-type porous coordination polymer, [Zn(2)(bdc)(2)(dabco)](n) (1, H(2)bdc = 1,4-benzenedicarboxylic acid, dabco =1,4-diazabicyclo[2.2.2]octane), showed unambiguous two-step profiles via a highly shrunk intermediate framework. The results of adsorption measurements on 1, using probing gas molecules of alcohol (MeOH and EtOH) for the size effect and Me(2)CO for the influence of hydrogen bonding, show that alcohol adsorption isotherms are gradual two-step profiles, whereas the Me(2)CO isotherm is a typical type-I isotherm, indicating that a two-step adsorption/desorption is involved with hydrogen bonds. To further clarify these characteristic adsorption/desorption behaviors, selecting nitroterephthalate (bdc-NO(2)), bromoterephthalate (bdc-Br), and 2,5-dichloroterephthalate (bdc-Cl(2)) as substituted dicarboxylate ligands, isomorphous jungle-gym-type porous coordination polymers, {[Zn(2)(bdc-NO(2))(2)(dabco)]·solvents}(n) (2 ⊃ solvents), {[Zn(2)(bdc-Br)(2)(dabco)]·solvents}(n) (3 ⊃ solvents), and {[Zn(2)(bdc-Cl(2))(2)(dabco)]·solvents}(n) (4 ⊃ solvents), were synthesized and characterized by single-crystal X-ray analyses. Thermal gravimetry, X-ray powder diffraction, and N(2) adsorption at 77 K measurements reveal that [Zn(2)(bdc-NO(2))(2)(dabco)](n) (2), [Zn(2)(bdc-Br)(2)(dabco)](n) (3), and [Zn(2)(bdc-Cl(2))(2)(dabco)](n) (4) maintain their frameworks without guest molecules with Brunauer-Emmett-Teller (BET) surface areas of 1568 (2), 1292 (3), and 1216 (4) m(2) g(-1). As found in results of MeOH, EtOH, IPA, and Me(2)CO adsorption/desorption on 2-4, only MeOH adsorption on 2 shows an obvious two-step profile. Considering the substituent effects and adsorbate sizes, the hydrogen bonds, which are triggers for two-step adsorption, are formed between adsorbates and carboxylate groups at the corners in the pores, inducing wide pores to become narrow pores. Interestingly, such a two-step MeOH adsorption on 2 depends on the temperature, attributed to the small free-energy difference (ΔF(host)) between the two guest-free forms, wide and narrow pores.