Structural Rigidification of N-Aryl-pyrroles into Indoles Active against Intracellular and Drug-Resistant Mycobacteria.

A series of indolyl-3-methyleneamines incorporating lipophilic side chains were designed through a structural rigidification approach and synthesized for investigation as new chemical entities against Mycobacterium tuberculosis (Mtb). The screening led to the identification of a 6-chloroindole analogue 7j bearing an N-octyl chain and a cycloheptyl moiety, which displayed potent in vitro activity against laboratory and clinical Mtb strains, including a pre-extensively drug-resistant (pre-XDR) isolate. 7j also demonstrated a marked ability to restrict the intracellular growth of Mtb in murine macrophages. Further assays geared toward mechanism of action elucidation have thus far ruled out the involvement of various known promiscuous targets, thereby suggesting that the new indole 7j may inhibit Mtb via a unique mechanism.

Synthesis and Biological Evaluation of Amidinourea Derivatives against Herpes Simplex Viruses.

Current therapy against herpes simplex viruses (HSV) relies on the use of a few nucleoside antivirals such as acyclovir, famciclovir and valacyclovir. However, the current drugs are ineffective against latent and drug-resistant HSV infections. A series of amidinourea compounds, designed as analogues of the antiviral drug moroxydine, has been synthesized and evaluated as potential non-nucleoside anti-HSV agents. Three compounds showed micromolar activity against HSV-1 and low cytotoxicity, turning to be promising candidates for future optimization. Preliminary mode of action studies revealed that the new compounds act in an early stage of the HSV replication cycle, just after the viral attachment and the entry phase of the infection.

Development of photoactivable phenanthroline-based manganese(I) CO-Releasing molecules (PhotoCORMs) active against ESKAPE bacteria and bacterial biofilms.

The synthesis and biological evaluation of a series of phenanthroline-based visible-light-activated manganese(I) carbon-monoxide-releasing molecules (PhotoCORMs) against ESKAPE bacteria and bacterial biofilms is reported. Four carbonyl compounds of general formula fac-[Mn(N∧N)(CO)3(L)] have been synthesized and characterized. Despite being thermally stable in the absence of light, these PhotoCORMs readily release CO upon blue (435-450 nm) LED light irradiation as confirmed by spectrophotometric CO releasing experiments (Mb Assay). The antibacterial activity of the four PhotoCORMs has been investigated against a panel of ESKAPE bacteria. The compounds 1-3 were found to be effective antibacterials at low concentrations against multidrug-resistant Klebsiella pneumoniae and Acinetobacter baumannii when photoactivated with blue-light. In addition, the PhotoCORMs 1-2 were found to inhibit the formation of Klebsiella pneumoniae and Acinetobacter baumannii bacterial biofilms at low concentrations (MIC = 4-8 µg/mL), turning out to be promising candidates to combat antimicrobial resistance. The antibacterial and biofilm inhibitory effect of the PhotoCORMs is plausibly due to the release of CO as well as the formation of phenanthroline photo-by-products as revealed by spectroscopy and microbiology experiments.

A facile and regioselective multicomponent synthesis of chiral aryl-1,2-mercaptoamines in water followed by monoamine oxidase (MAO-N) enzymatic resolution.

A facile microwave assisted three-component protocol allows the synthesis of chiral aryl-1,2-mercaptoamines in water in a few minutes with high yields, bypassing the use of toxic aziridine intermediates. The chiral 1,2-mercaptoamines were then deracemized through enzymatic resolution of the racemates using monoamine oxidase (MAO-N) biocatalysts.

Switching on the activity of 1,5-diaryl-pyrrole derivatives against drug-resistant ESKAPE bacteria: Structure-activity relationships and mode of action studies.

Antibiotic resistance represents a major threat worldwide. Gram-positive and Gram-negative opportunistic pathogens are becoming resistant to all known drugs mainly because of the overuse and misuse of these medications and the lack of new antibiotic development by the pharmaceutical industry. There is an urgent need to discover structurally innovative antibacterial agents for which no pre-existing resistance is known. This work describes the identification, synthesis and biological evaluation of a novel series of 1,5-diphenylpyrrole compounds active against a panel of ESKAPE bacteria. The new compounds show high activity against both wild type and drug-resistant Gram + ve and Gram-ve pathogens at concentrations similar or lower than levofloxacin. Microbiology studies revealed that the plausible target of the pyrrole derivatives is the bacterial DNA gyrase, with the pyrrole derivatives displaying similar inhibitory activity to levofloxacin against the wild type enzyme and retaining activity against the fluoroquinolone-resistant enzyme.

Highly Sensitive and Selective Molecular Probes for Chromo-Fluorogenic Sensing of Carbon Monoxide in Air, Aqueous Solution and Cells.

Optical sensing offers a low-cost and effective means to sense carbon monoxide in air and in solution. This contribution reports the synthesis of a new series of vinyl complexes [Ru(CH=CHR)Cl(CO)(TBTD)(PPh3 )2 ] (R=aryl, TBTD=5-(3-thienyl)-2,1,3-benzothiadiazole) and shows them to be highly sensitive and selective probes for carbon monoxide in both solution and air. Depending on the vinyl substituent, chromogenic and fluorogenic responses signalled the presence of this invisible, odourless, tasteless and toxic gas. Adsorbing the complexes on silica produced colorimetric probes for the 'naked eye' detection of CO in the gas phase with a limit of detection as low as 8 ppm in some cases, while the release of the TBTD fluorophore allowed detection at much lower concentrations through the fluorescence response. Structural data were obtained by single-crystal X-ray diffraction techniques, while the photophysical behaviour was explored computationally using TD-DFT experiments. The systems were also shown to be selective for CO over all other gases tested, including water vapour and common organic solvents. By introducing a poly(ethylene)glycol chain to the vinyl functionality, water compatibility was achieved and these non-cytotoxic complexes were employed in the sensing of CO in HeLa cells, offering a simple and rapid system for sensing this gasotransmitter in this challenging medium.

Photo-biocatalytic One-Pot Cascades for the Enantioselective Synthesis of 1,3-Mercaptoalkanol Volatile Sulfur Compounds.

The synthesis of enantiomerically pure 1,3-mercaptoalkanol volatile sulfur compounds through a one-pot photo-biocatalytic cascade reaction is described. Two new KRED biocatalysts with opposite enantioselectivity were discovered and proved to be efficient on a wide range of substrates. The one-pot cascade reaction combining photocatalytic thio-Michael addition with biocatalytic ketoreduction in an aqueous medium provides a green and sustainable approach to enantiomerically pure 1,3-mercaptoalkanols in high yields with excellent enantioselectivity.

Ex Vivo Tracking of Endogenous CO with a Ruthenium(II) Complex.

A two-photon fluorescent probe based on a ruthenium(II) vinyl complex is capable of selectively detecting carbon monoxide in cells and ex vivo using mice with a subcutaneous air pouch as a model for inflammation. This probe combines highly selective and sensitive ex vivo detection of endogenous CO in a realistic model with facile, inexpensive synthesis, and displays many advantages over the widely used palladium-based systems.

Synthesis and Reactivity of Propargylamines in Organic Chemistry.

Propargylamines are a versatile class of compounds which find broad application in many fields of chemistry. This review aims to describe the different strategies developed so far for the synthesis of propargylamines and their derivatives as well as to highlight their reactivity and use as building blocks in the synthesis of chemically relevant organic compounds. In the first part of the review, the different synthetic approaches to synthesize propargylamines, such as A3 couplings and C-H functionalization of alkynes, have been described and organized on the basis of the catalysts employed in the syntheses. Both racemic and enantioselective approaches have been reported. In the second part, an overview of the transformations of propargylamines into heterocyclic compounds such as pyrroles, pyridines, thiazoles, and oxazoles, as well as other relevant organic derivatives, is presented.

The stepwise generation of multimetallic complexes based on a vinylbipyridine linkage and their photophysical properties.

The versatile rhenium complex [ReCl(CO)3(bpyC[triple bond, length as m-dash]CH)] (HC[triple bond, length as m-dash]Cbpy = 5-ethynyl-2,2'-bipyridine) is used to generate a series of bimetallic complexes through the hydrometallation of [MHCl(CO)(BTD)(PPh3)2] (M = Ru, Os; BTD = 2,1,3-benzothiadiazole). The ruthenium complex [Ru{CH[double bond, length as m-dash]CH-bpyReCl(CO)3}Cl(BTD)(CO)(PPh3)2] was characterised structurally. Ligand exchange reactions with bifunctional linkers bearing oxygen and sulfur donors provide access to tetra- and pentametallic complexes such as [{M{CH[double bond, length as m-dash]CH-bpyReCl(CO)3}(CO)(PPh3)2}2(S2CNC4H8NCS2)] and Fe[C5H4CO2M{CH[double bond, length as m-dash]CH-bpyReCl(CO)3}(CO)(PPh3)2]2. The effect of the group 8 metal on the photophysical properties of the rhenium centre was investigated using the complexes [Ru{CH[double bond, length as m-dash]CH-bpyReCl(CO)3}Cl(BTD)(CO)(PPh3)2] and [M{CH[double bond, length as m-dash]CH-bpyReCl(CO)3}{S2P(OEt)2}(CO)(PPh3)2] (M = Ru, Os). This revealed the quenching of the rhenium-based emission in favour of weak radiative processes based on the Ru and Os centres. The potential for exploiting this effect is illustrated by the reaction of [Ru{CH[double bond, length as m-dash]CH-bpyReCl(CO)3}Cl(CO)(BTD)(PPh3)2] with carbon monoxide, which results in a 5-fold fluorescence enhancement in the dicarbonyl product, [Ru{CH[double bond, length as m-dash]CH-bpyReCl(CO)3}Cl(CO)2(PPh3)2], as the quenching effect is disrupted.

Chromo-fluorogenic probes for carbon monoxide detection.

The sensing of carbon monoxide (CO) using electrochemical cells or semiconducting metal oxides has led to inexpensive alarms for the home and workplace. It is now recognised that chronic exposure to low levels of CO also poses a significant health risk. It is perhaps surprising therefore that the CO is used in cell-signalling pathways and plays a growing role in therapy. However, the selective monitoring of low levels of CO remains challenging, and it is this area that has benefited from the development of probes which give a colour or fluorescence response. This feature article covers the design of chromo-fluorogenic probes and their application to CO sensing in air, solution and in cells.

Ruthenium(II) and osmium(II) vinyl complexes as highly sensitive and selective chromogenic and fluorogenic probes for the sensing of carbon monoxide in air.

The detection of carbon monoxide in solution and air has been achieved using simple, inexpensive systems based on the vinyl complexes [M(CHCHR)Cl(CO)(BTD)(PPh3 )2 ] (R=aryl, BTD=2,1,3-benzothiadiazole). Depending on the nature of the vinyl group, chromogenic and fluorogenic responses signalled the presence of this odourless, tasteless, invisible, and toxic gas. Solutions of the complexes in CHCl3 underwent rapid change between easily differentiated colours when exposed to air samples containing CO. More significantly, the adsorption of the complexes on silica produced colorimetric probes for the naked-eye detection of CO in the gas phase. Structural data for key species before and after the addition of CO were obtained by means of single X-ray diffraction studies. In all cases, the ruthenium and osmium vinyl complexes studied showed a highly selective response to CO with exceptionally low detection limits. Naked-eye detection of CO at concentrations as low as 5 ppb in air was achieved with the onset of toxic levels (i.e., 100 ppm), thus resulting in a remarkably clear colour change. Moreover, complexes bearing pyrenyl, naphthyl, and phenanthrenyl moieties were fluorescent, and greater sensitivities were achieved (through turn-on emission fluorescence) in the presence of CO both in solution and air. This behaviour was explored computationally using time-dependent density functional theory (TDDFT) experiments. In addition, the systems were shown to be selective for CO over all other gases tested, including water vapour and common organic solvents. Supporting the metal complexes on cellulose strips for use in an existing optoelectronic device allows numerical readings for the CO concentration to be obtained and provision of an alarm system.

Multimetallic complexes and functionalized nanoparticles based on unsymmetrical dithiocarbamate ligands with allyl and propargyl functionality.

The new, unsymmetrical dithiocarbamate ligands, KS2CN(CH2CH═CH2)Me and KS2CN(CH2C≡CH)Me, are formed from the respective amines on reaction with KOH and carbon disulfide. The homoleptic complexes [Ni{S2CN(CH2CH═CH2)Me}2] and [M{S2CN(CH2C≡CH)Me}2] (M = Ni, Pd, Pt) are formed on reaction with suitable metal precursors. Conversion between the two pendant functionalities was confirmed by hydrogenation of [Ni{S2CN(CH2C≡CH)Me}2] to yield [Ni{S2CN(CH2CH═CH2)Me}2]. The monodithiocarbamate compounds of group 8, 10, and 11 metals, [Ru{S2CN(CH2CH═CH2)Me}(dppm)2](+), [Ru(CH═CHC6H4Me-4){S2CN(CH2CH═CH2)Me}(CO)(PPh3)2], [Ni{S2CN(CH2CH═CH2)Me}(dppp)](+), and [Au{S2CN(CH2CH═CH2)Me}(PPh3)] were formed successfully. Using KS2CN(CH2C≡CH)Me, the complex [Ru{S2CN(CH2C≡CH)Me}(dppm)2](+) was obtained from cis-[RuCl2(dppm)2]. One palladium example, [Pd{S2CN(CH2C≡CH)Me}(PPh3)2](+), was also isolated in low yield. However, under the typical conditions employed, a rearrangement reaction prevented isolation of further group 10 propargyl-dithiocarbamate products. Over the extended reaction time required, Me(HC≡CCH2)NCS2(-) was found to undergo a remarkable, atom-efficient cyclization to form the thiazolidine-2-thione, H2C═CCH2N(Me)C(═S)S, in high yield, with MeC═CHN(Me)C(═S)S as the minor product. The reactivity of the pendant triple bonds in [Ni{S2CN(CH2C≡CH)Me}2] was probed in the reaction with [RuH(CO)(S2P(OEt)2)(PPh3)2] to form the trimetallic example [Ni{S2CN(Me)CH2CH═CHRu(CO)(S2P(OEt)2)(PPh3)2}2], while the copper(I) catalyzed reaction with benzylazide yielded the triazole product, [Ni{S2CN(Me)CH2(C2HN3)Bz}2]. KS2CN(CH2C≡CH)Me was also used to prepare the gold nanoparticles, Au@S2CN(CH2C≡CH)Me. Structural studies are reported for [Ru(CH═CHC6H4Me-4){S2CN(CH2CH═CH2)Me}(CO)(PPh3)2] and [Ru{S2CN(CH2C≡CH)Me}(dppm)2]PF6.

A chromo-fluorogenic synthetic "canary" for CO detection based on a pyrenylvinyl ruthenium(II) complex.

The chromo-fluorogenic detection of carbon monoxide in air has been achieved using a simple, inexpensive system based on ruthenium(II). This probe shows exceptional sensitivity and selectivity in its sensing behavior in the solid state. A color response visible to the naked eye is observed at 5 ppb of CO, and a remarkably clear color change occurs from orange to yellow at the onset of toxic CO concentrations (100 ppm) in air. Even greater sensitivity (1 ppb) can be achieved through a substantial increase in turn-on emission fluorescence in the presence of carbon monoxide, both in air and in solution. No response is observed with other gases including water vapor. Immobilization of the probe on a cellulose strip allows the system to be applied in its current form in a simple optoelectronic device to give a numerical reading and/or alarm.

Ring-closing metathesis and nanoparticle formation based on diallyldithiocarbamate complexes of gold(I): synthetic, structural, and computational studies.

The gold(I) complexes [Au{S2CN(CH2CH═CH2)2}(L)] [L = PPh3, PCy3, PMe3, CN(t)Bu, IDip] are prepared from KS2CN(CH2CH═CH2)2 and [(L)AuCl]. The compounds [L2(AuCl)2] (L2 = dppa, dppf) yield [(L2){AuS2CN(CH2CH═CH2)2}2], while the cyclic complex [(dppm){Au2S2CN(CH2CH═CH2)2}]OTf is obtained from [dppm(AuCl)2] and AgOTf followed by KS2CN(CH2CH═CH2)2. The compound [Au2{S2CN(CH2CH═CH2)2}2] is prepared from [(tht)AuCl] (tht = tetrahydrothiophene) and the diallyldithiocarbamate ligand. This product ring-closes with [Ru(═CHPh)Cl2(SIMes)(PCy3)] to yield [Au2(S2CNC4H6)2], whereas ring-closing of [Au{S2CN(CH2CH═CH2)2}(PR3)] fails. Warming [Au2{S2CN(CH2CH═CH2)2}2] results in formation of gold nanoparticles with diallydithiocarbamate surface units, while heating [Au2(S2CNC4H6)2] with NaBH4 results in nanoparticles with 3-pyrroline dithiocarbamate surface units. Larger nanoparticles with the same surface units are prepared by citrate reduction of HAuCl4 followed by addition of the dithiocarbamate. The diallydithiocarbamate-functionalized nanoparticles undergo ring-closing metathesis using [Ru(═CHC6H4O(i)Pr-2)Cl2(SIMes)]. The interaction between the dithiocarbamate units and the gold surface is explored using computational methods to reveal no need for a countercation. Preliminary calculations indicate that the Au-S interactions are substantially different from those established in theoretical and experimental studies on thiolate-coated nanoparticles. Structural studies are reported for [Au{S2CN(CH2CH═CH2)2}(PPh3)] and [Au2{S2CN(CH2CH═CH2)2}2]. In the latter, exceptionally short intermolecular aurophilic interactions are observed.

Multimetallic complexes and functionalized gold nanoparticles based on a combination of d- and f-elements.

The new DO3A-derived dithiocarbamate ligand, DO3A-(t)Bu-CS2K, is formed by treatment of the ammonium salt [DO3A-(t)Bu]HBr with K2CO3 and carbon disulfide. DO3A-(t)Bu-CS2K reacts with the ruthenium complexes cis-[RuCl2(dppm)2] and [Ru(CH═CHC6H4Me-4)Cl(CO)(BTD)(PPh3)2] (BTD = 2,1,3-benzothiadiazole) to yield [Ru(S2C-DO3A-(t)Bu)(dppm)2](+) and [Ru(CH═CHC6H4Me-4)(S2C-DO3A-(t)Bu)(CO)(PPh3)2], respectively. Similarly, the group 10 metal complexes [Pd(C,N-C6H4CH2NMe2)Cl]2 and [PtCl2(PPh3)2] form the dithiocarbamate compounds, [Pd(C,N-C6H4CH2NMe2)(S2C-DO3A-(t)Bu)] and [Pt(S2C-DO3A-(t)Bu)(PPh3)2](+), under the same conditions. The linear gold complexes [Au(S2C-DO3A-(t)Bu)(PR3)] are formed by reaction of [AuCl(PR3)] (R = Ph, Cy) with DO3A-(t)Bu-CS2K. However, on reaction with [AuCl(tht)] (tht = tetrahydrothiophene), the homoleptic digold complex [Au(S2C-DO3A-(t)Bu)]2 is formed. Further homoleptic examples, [M(S2C-DO3A-(t)Bu)2] (M = Ni, Cu) and [Co(S2C-DO3A-(t)Bu)3], are formed from treatment of NiCl2·6H2O, Cu(OAc)2, or Co(OAc)2, respectively, with DO3A-(t)Bu-CS2K. The molecular structure of [Ni(S2C-DO3A-(t)Bu)2] was determined crystallographically. The tert-butyl ester protecting groups of [M(S2C-DO3A-(t)Bu)2] (M = Ni, Cu) and [Co(S2C-DO3A-(t)Bu)3] are cleaved by trifluoroacetic acid to afford the carboxylic acid products, [M(S2C-DO3A)2] (M = Ni, Cu) and [Co(S2C-DO3A)3]. Complexation with Gd(III) salts yields trimetallic [M(S2C-DO3A-Gd)2] (M = Ni, Cu) and tetrametallic [Co(S2C-DO3A-Gd)3], with r(1) values of 11.5 (Co) and 11.0 (Cu) mM(-1) s(-1) per Gd center. DO3A-(t)Bu-CS2K can also be used to prepare gold nanoparticles, Au@S2C-DO3A-(t)Bu, by displacement of the surface units from citrate-stabilized nanoparticles. This material can be transformed into the carboxylic acid derivative Au@S2C-DO3A by treatment with trifluoroacetic acid. Complexation with Gd(OTf)3 or GdCl3 affords Au@S2C-DO3A-Gd with an r(1) value of 4.7 mM(-1) s(-1) per chelate and 1500 mM(-1) s(-1) per object.