Synthesis and in vitro activity of new tetrahydronaphtho[1,2-b]azepine derivatives against Trypanosoma cruzi and Leishmania chagasi parasites

Series of 2-exo-aryl-1,4-epoxy-2,3,4,5-tetrahydronaphtho[1,2-b]azepines 3a–k and cis-2-aryl-4-hydroxy-2,3,4,5-tetrahydronaphtho[1,2-b]azepines 4a–j were synthesized and evaluated against free and intracellular live forms of Trypanosoma cruzi and Leishmania chagasi parasites using in vitro assays. Cell toxicity was also analyzed on Vero and THP-1 mammalian cell lines. The compounds 3c, 3f, and 4d were the most active against both live forms of T. cruzi parasites with low mammalian cell toxicity. Some compounds were active on free live forms of L. chagasi parasites but none was active on intracellular amastigotes of L. chagasi infecting THP-1 macrophages.     

Synthesis and biological evaluation of enantiomerically pure cyclopropyl analogues of combretastatin A4

To evaluate the influence of stereochemistry on biological activities of cis-cyclopropyl combretastatin A4 (CA4) analogues, we have prepared several cyclopropyl compounds in their pure enantiomeric forms. The key reactions in our synthesis are the cyclopropanation of a (Z)-alkenylboron compound bearing a chiral auxiliary, and the cross-coupling of both enantiomeric cyclopropyl trifluoroborate salts with aryl and olefinic halides. Three pairs of cis-cyclopropyl CA4 analogues were evaluated for their potential antivascular activities. The diarylcyclopropyl compounds with SR-configuration (?)-1b, (?)-2b and the cyclopropylvinyl enantiomer (+)-3a with RR-configuration were the most potent tubulin polymerization inhibitors. A correlation was noted between anti-tubulin activity and rounding up activity of endothelial cells. The cytotoxic activity on B16 melanoma cells was in the submicromolar range for most compounds, but unlike the anti-tubulin activity, there was no difference in cytotoxic activity between racemic and enantiomerically pure forms for the three series of compounds. Molecular docking studies within the colchicine binding site of tubulin were in good agreement with the tubulin polymerization inhibitory data and confirmed the importance of the configuration of the synthesized cis-cyclopropyl CA4 analogues for potential antivascular activities.     

Sulfonate and sulfamate derivatives possessing benzofuran or benzothiophene nucleus as potent carbonic anhydrase II/IX/XII inhibitors

In the current work, we report the discovery of new sulfonate and sulfamate derivatives of benzofuran- and benzothiophene as potent inhibitors of human carbonic anhydrases (hCAs) II, IX and XII. A set of derivatives, 1a–t, having different substituents on the fused benzofuran and benzothiophene rings (R = alkyl, cyclohexyl, aryl, NH₂, NHMe, or NMe₂) was designed and synthesized. Most of the derivatives exhibited higher potency than acetazolamide as inhibitors of the purified hCAII, IX and XII isoforms. The most potent inhibitors for hCAII, hCAIX and hCAXII were 1g, 1b and 1d with an IC₅₀ ± SEM values of 0.14 ± 0.03, 0.13 ± 0.03 and 0.17 ± 0.06 µM, respectively. In addition, compounds 1d and 1n exerted preferential inhibitory effect against hCAXII isozyme with good potencies. Some selected compounds were docked within the active pocket of these isozymes and binding of the molecules revealed that sulfonate and sulfamate rings were located towards the active cavity and compounds coordinated to zinc ions.     

Improved preparations of some per-O-acetylated aldohexopyranosyl cyanides

3,4,6-Tri-O-acetyl-1,2-O-[1-(exo-, endo-cyano)ethylidene]-α-d-galacto- (1a/b), -α-d-gluco- (2a/b), and -β-d-manno-pyranose (3a/b) were stereoselectively isomerized to the corresponding per-O-acetylated 1,2-trans-aldohexopyranosyl cyanides in 75, 16, and 62% yield, respectively, by treatment with boron trifluoride etherate in dry nitromethane. The corresponding per-O-acetylated 1,2-cis-aldohexopyranosyl cyanides were obtained concurrently in respective yields of 1.9, 0.9, and 4.8%. The per-O-acetylaldohexopyranosyl cyanide products were found stable to the reaction conditions and were readily isolated following completion of the rearrangement. It had previously been proved that reaction of 2,3,4,6-tetra-O-acetyl-α-d-manno- and -gluco-pyranosyl bromide with mercuric cyanide in nitromethane generates, in the ratio of ∼1:1, the desired 1,2-trans-glycosyl cyanides and the corresponding 1,2-O-(1-cyanoethylidene) isomers (3a/b and 2a/b, respectively). Treatment of these reaction-mixtures with boron trifluoride etherate in nitromethane effected the rearrangement of 3a/b and 2a/b, thereby facilitating the isolation, and increasing the overall yields, of the per-O-acetylated 1,2-trans-d-manno and -gluco-pyranosyl cyanides (58 and 30% total yield, respectively) relative to the earlier procedures. The boron trifluoride etherate-mediated reaction of per-O-acetyl-α- and -β-d-galacto, -α- and -β-d-gluco-, -α-d-manno-, and -2-deoxy-2-phthalimido-β-d-gluco-pyranoses with trimethylsilyl cyanide in nitromethane was also investigated. This reaction provides a “one-flask” synthesis of the corresponding per-O-acetylated 1,2-trans-aldohexopyranosyl cyanides in which 1,2-O-(1-cyanoethylidene) derivatives are isomerized in situ. Finally, improved preparations of the (not readily accessible) per-O-acetylated 1,2-cis-d-manno- and -gluco-pyranosyl cyanides are described. Thus, 2,3,4,6-tetra-O-acetyl-α- and -β-d-mannopyranosyl cyanide (48 and 16% total yield, respectively) and -α- and -β-d-glucopyranosyl cyanide (12 and 39% total yield, respectively) were synthesized by fusion of the corresponding -α-d-glycosyl bromides with mercuric cyanide.     

Microbially Mediated Formation of Benzonaphthothiophenes from Benzo[b]thiophenes

Studies of the microbial metabolism of benzo[b]thiophene (molecular weight 134) by three Pseudomonas isolates showed the formation of benzothiophene sulfoxide, benzothiophene sulfone, and a sulfur-containing metabolite with a molecular weight of 234. Desulfurization of the high-molecular-weight product with nickel boride gave 1-phenylnaphthalene, indicating that the metabolite was benzo[b]naphtho[1,2-d]thiophene. Similarly, the isolates were capable of producing the analogous dimethyl-substituted benzonaphthothiophenes from methylbenzothiophenes that had the methyl substitution on the benzene ring. The formation of benzo[b] naphtho[1,2-d]thiophene was also observed when a petroleum-degrading mixed culture was incubated with benzothiophene-supplemented Prudhoe Bay crude oil. Investigations into the mechanism of formation of these high-molecular-weight compounds showed that they resulted from an abiotic, Diels-Alder-type condensation of two molecules of the sulfoxide, which were microbially produced from the respective benzothiophene, with the subsequent loss of two atoms of hydrogen and oxygen and one atom of sulfur. The condensation products also formed from the sulfoxides of benzothiophene and methylbenzothiophenes when the sulfoxides were enzymatically synthesized by oxidation of the benzothiophene with horse heart cytochrome c and H₂O₂.     

Structure-based design,synthesis, and biological evaluation of lipophilic-tailed monocationic inhibitors of neuronal nitric oxide synthase

Selective inhibitors of neuronal nitric oxide synthase (nNOS) have the potential to develop into new neurodegenerative therapeutics. Recently, we described the discovery of novel nNOS inhibitors (1a and 1b) based on a cis-pyrrolidine pharmacophore. These compounds and related ones were found to have poor blood–brain barrier permeability, presumably because of the basic nitrogens in the molecule. Here, a series of monocationic compounds was designed on the basis of docking experiments using the crystal structures of 1a,b bound to nNOS. These compounds were synthesized and evaluated for their ability to inhibit neuronal nitric oxide synthase. Despite the excellent overlap of these compounds with 1a,b bound to nNOS, they exhibited low potency. This is because they bound in the nNOS active site in the normal orientation rather than the expected flipped orientation used in the computer modeling. The biphenyl or phenoxyphenyl tail is disordered and does not form good protein–ligand interactions. These studies demonstrate the importance of the size and rigidity of the side chain tail and the second basic amino group for nNOS binding efficiency and the importance of the hydrophobic tail for conformational orientation in the active site of nNOS.     

New hybrid molecules combining benzothiophene or benzofuran with rhodanine as dual COX-1/2 and 5-LOX inhibitors: Synthesis,biological evaluation and docking study

New molecular hybrids combining benzothiophene or its bioisostere benzofuran with rhodanine were synthesized as potential dual COX-2/5-LOX inhibitors. The benzothiophene or benzofuran scaffold was linked at position -2 with rhodanine which was further linked to various anti-inflammatory pharmacophores so as to investigate the effect of such molecular variation on the anti-inflammatory activity. The target compounds were evaluated for their in vitro COX/LOX inhibitory activity. The results revealed that, compound 5h exhibited significant COX-2 inhibition higher than celecoxib. Furthermore, compounds 5a, 5f and 5i showed COX-2 inhibitory activity comparable to celecoxib. Compound 5h showed selectivity index SI = 5.1 which was near to that of celecoxib (SI = 6.7). Compound 5h displayed LOX inhibitory activity twice than that of meclofenamate sodium. Moreover, compounds 5a, 5e and 5f showed significant LOX inhibitory activity higher than that of meclofenamate sodium. Compound 5h was screened for its in vivo anti-inflammatory activity using formalin-induced paw edema and gastric ulcerogenic activity tests. The results revealed that, it showed in vivo decrease in formalin-induced paw edema volume higher than celecoxib. It also displayed gastrointestinal safety profile as celecoxib. The biological results were also consistent with the docking studies at the active sites of the target enzymes COX-2 and 5-LOX. Also, compound 5h showed physicochemical, ADMET, and drug-like properties within those considered adequate for a drug candidate.     

Synthesis of C-glycopyranosylfuran derivatives by reaction of dialdehydes with cyanoacetamide

The reaction of diglycol- and thiodiglycol-aldehyde (1a,b) with cyanoacetamide yields cis-3,5-diacetoxy-4-carbamoyl-4-cyano-tetrahydropyran (2a) and -tetrahydrothiopyran (2b). When this reaction is applied to (2S)-2-(3-ethoxycarbonyl-2-methyl-5-furyl)-3,5-dihydroxy-1,4-dioxane (1c), (2S)-3,5-dihydroxy-2-(3-methoxycarbonyl-2-methyl-5-furyl)-1,4-dioxane (1d), and (2S,3R,5S)-2-(3-acetyl-2-methyl-5-furyl)-3,5-dihydroxy-1,4-dioxane (1e), 5-(3-carbamoyl-3-cyano-3-deoxy-β-d-xylo-pentopyranosyl)-3-ethoxycarbonyl-2-methylfuran (2c), 5-(2,4-di-O-acetyl-3-carbamoyl-3-cyano-3-deoxy-β-d-xylo-pentopyranosyl)-3-methoxycarbonyl-2-methylfuran (2e), and 3-acetyl-5-(2,4-di-O-acetyl-3-carbamoyl-3-cyano-3-deoxy-β-d-xylo-pentopyranosyl)-2-methylfuran (2f), respectively, are formed with (4S,5S)-4-carbamoyl-4-cyano-2-(3-ethoxycarbonyl-2-methyl-5-furyl)-5-hydroxy-5,6-dihydropyran (3a) and (4S,5S)-4-carbamoyl-4-cyano-5-hydroxy-2-(3-methoxycarbonyl-2-methyl-5-furyl)-5,6-dihydropyran (3b) as minor products. The dehydration of 2a,b, 5-(2,4-di-O-acetyl-3-carbamoyl-3-cyano-3-deoxy-β-d-xylo-pentopyranosyl)-3-ethoxycarbonyl-2-methylfuran (2d), 2e, and 2f yields cis-3,5-diacetoxy-4,4-dicyano-tetrahydropyran and -tetrahydrothiopyran (2l,m), and the 5-(2,4-di-O-acetyl-3,3-dicyano-3-deoxy-β-d-erythro-pentopyranosyl) derivatives (2n–p) of 3-ethoxycarbonyl-2-methylfuran, 3-methoxycarbonyl-2-methylfuran, and 3-acetyl-2-methylfuran, respectively.     

New structure–activity relationship studies in a series of N,N-bis(cyclohexanol)amine aryl esters as potent reversers of P-glycoprotein-mediated multidrug resistance (MDR)

As a continuation of previous research on a new series of potent and efficacious P-gp-dependent multidrug resistant (MDR) reversers with a N,N-bis(cyclohexanol)amine scaffold, we have designed and synthesized several analogs by modulation of the two aromatic moieties linked through ester functions to the N,N-bis(cyclohexanol)amine, aiming to optimize activity and to extend structure–activity relationships (SAR) within the series. This scaffold, when esterified with two different aromatic carboxylic acids, gives origin to four geometric isomers (cis/trans, trans/trans, cis/cis and trans/cis).The new compounds were tested on doxorubicin-resistant erythroleukemia K562 cells (K562/DOX) in the pirarubicin uptake assay. Most of them resulted in being potent modulators of the extrusion pump P-gp, showing potency values ([I]_0.5) in the submicromolar and nanomolar range. Of these, compounds 2b, 2c, 3d, 5a–d and 6d, showed excellent efficacy with a α_max close to 1. Selected compounds (2d, 3a, 3b, 5a–d) were further studied to evaluate their doxorubicin cytotoxicity potentiation (RF) on doxorubicin-resistant erythroleukemia K562 cells and were found able to enhance significantly doxorubicin cytotoxicity on K562/DOX cells.The results of both pirarubicin uptake and the cytotoxicity assay, indicate that the new compounds of the series are potent P-gp-mediated MDR reversers. They present a structure with a mix of flexible and rigid moieties, a property that seems critical to allow the molecules to choose the most productive of the several binding modes possible in the transporter recognition site.In particular, compounds 5c and 5d, similar to the already reported analogous isomers 1c and 1d,²⁹ are potent and efficacious modulators of P-gp-dependent MDR and may be promising leads for the development of MDR-reversal drugs.     

Discovery and optimization of a new class of pyruvate kinase inhibitors as potential therapeutics for the treatment of methicillin-resistant Staphylococcus aureus infections

A novel series of bis-indoles derived from naturally occurring marine alkaloid 4 were synthesized and evaluated as inhibitors of methicillin-resistant Staphylococcus aureus (MRSA) pyruvate kinase (PK). PK is not only critical for bacterial survival which would make it a target for development of novel antibiotics, but it is reported to be one of the most highly connected ‘hub proteins’ in MRSA, and thus should be very sensitive to mutations and making it difficult for the bacteria to develop resistance. From the co-crystal structure of cis-3-4-dihydrohamacanthin B (4) bound to S. aureus PK we were able to identify the pharmacophore needed for activity. Consequently, we prepared simple direct linked bis-indoles such as 10b that have similar anti-MRSA activity as compound 4. Structure–activity relationship (SAR) studies were carried out on 10b and led us to discover more potent compounds such as 10c, 10d, 10k and 10m with enzyme inhibiting activities in the low nanomolar range that effectively inhibited the bacteria growth in culture with minimum inhibitory concentrations (MIC) for MRSA as low as 0.5 μg/ml. Some potent PK inhibitors, such as 10b, exhibited attenuated antibacterial activity and were found to be substrates for an efflux mechanism in S. aureus. Studies comparing a wild type S. aureus with a construct (S. aureus LAC Δpyk::Erm^R) that lacks PK activity confirmed that bactericidal activity of 10d was PK-dependant.     

New ruthenium(II) precursors with the tetradentate sulfur macrocycles tetrathiacyclododecane ([12]aneS4) and tetrathiacyclohexadecane ([16]aneS4) for the construction of metal-mediated supramolecular assemblies

The preparation and structural characterization of several new Ru(II) complexes in which four coordination positions are occupied by the sulfur atoms of a macrocycle, either 1,4,7,10-tetrathiacyclododecane ([12]aneS4) or 1,5,9,13-tetrathiacyclohexadecane ([16]aneS4), and the two others by relatively labile ligands (Cl⁻, , H₂O, dmso-S), are described:cis-[Ru([12]aneS4)(dmso-S)(H₂O)](CF₃SO₃)₂ (2a), cis-[Ru([12]aneS4)(dmso-S)(ONO₂)](NO₃) (2b), cis-[Ru([16]aneS4)Cl₂] (4), and trans-[Ru([16]aneS4)(dmso-S)(H₂O)](CF₃SO₃)₂ (5).The complexes of the larger [16]aneS4 macrocycle have a flexible coordination geometry, either cis or trans, that makes them unsuited for being used as precursors in metal-driven self-assembly processes.On the contrary, the [12]aneS4 complexes cis-[Ru([12]aneS4)(dmso-S)Cl]Cl (1) and, above all, its chlorido free derivatives cis-[Ru([12]aneS4)(dmso-S)(H₂O)](CF₃SO₃)₂ (2a) and cis-[Ru([12]aneS4)(dmso-S)(ONO₂)](NO₃) (2b) are potential precursors of the geometrically stable 90° bis-acceptor fragment cis-[Ru([12]aneS4)]²⁺.Preliminary results of their reactivity towards the linear linker pyrazine (pyz) showed that the nature of the isolated product depends on that of the counter-anion.When treated with pyz 2b afforded the dinuclear complex [{Ru([12]aneS4)(ONO₂)}₂(μ-pyz)](NO₃)₂ (8), while 2a gave the molecular triangle [{cis-Ru([12]aneS4)(μ-pyz)}₃](CF₃SO₃)₆ (9), both in low yields.The X-ray structures of compounds 2a, 2b, 4, 5, [{Ru([12]aneS4)Cl}₂(μ-pyz)]Cl₂ (7), 9, and of the sandwich complex[Ru([12]aneS3-S)₂](CF₃SO₃)₂ (3), in which only three sulfur atoms of each macrocycle are bound to ruthenium, are also described.     

Synthesis and evaluation of novel azetidine analogs as potent inhibitors of vesicular [3H]dopamine uptake

Lobelane analogs that incorporate a central piperidine or pyrrolidine moiety have previously been reported by our group as potent inhibitors of VMAT2 function. Further central ring size reduction of the piperidine moiety in lobelane to a four-membered heterocyclic ring has been carried out in the current study to afford novel cis-and trans-azetidine analogs. These azetidine analogs (15a–15c and 22a–22c) potently inhibited [³H]dopamine (DA) uptake into isolated synaptic vesicles (K_i ? 66 nM). The cis-4-methoxy analog 22b was the most potent inhibitor (K_i = 24 nM), and was twofold more potent that either lobelane (2a, K_i = 45 nM) or norlobelane (2b, K_i = 43 nM). The trans-methylenedioxy analog, 15c (K_i = 31 nM), was equipotent with the cis-analog, 22b, in this assay. Thus, cis- and trans-azetidine analogs 22b and 15c represent potential leads in the discovery of new clinical candidates for the treatment of methamphetamine abuse.     

Benzothieno[3,2-b]quinolinium and 3-(phenylthio)quinolinium compounds: Synthesis and evaluation against opportunistic fungal pathogens

Substitution around 5-methyl benzothieno[3,2-b]quinolinium (2) ring system was explored in order to identify positions of substitution that could improve its antifungal profile. The 3-methoxy (10b) was active against C. albicans, C. neoformans, and A. fumigatus and the 4-chloro (10f) analog showed moderate increases in anti-cryptococcal and anti-aspergillus activities. The effectiveness of 10b and 10f were validated in murine models of candidiasis and cryptococcosis, respectively. The efficacy of 10f in reducing brain cryptococcal infection and its observation in the brain of mice injected with this quaternary compound confirm the capacity of these compounds to cross the blood-brain barrier of mice. Overall, several of the chloro and methoxy substituted compounds showed significant improvements in activity against A. fumigatus, the fungal pathogen prevalent in patients receiving organ transplant. Opening the benzothiophene ring of 2 to form 1-(5-cyclohexylpentyl)-3-(phenylthio)quinolinium compound (3) resulted in the identification of several novel compounds with over 50-fold increases in potency (cf. 2) while retaining low cytotoxicities. Thus, compound 3 constitutes a new scaffold for development of drugs against opportunistic infections.     

Synthesis and characterization of ruthenium(II) complexes bearing the bis(2-pyridylmethyl)amine ligand

The reaction of [Ru(CO)₂Cl₂]_n with bis(2-pyridylmethyl)amine (bpma) in refluxing ethanol followed by anion exchange yields two products: cis,fac-[Ru(bpma)(CO)₂Cl]PF₆ (1a, 71%) and trans,fac-[Ru(bpma)(CO)₂Cl]PF₆ (1b, 29%). Reaction of 1a with AgBF₄ in acetone, followed by acetonitrile and then anion exchange gave cis,fac-[Ru(bpma)(CO)₂(CH₃CN)](PF₆)₂ (2a). In the same way, 1b afforded trans,fac-[Ru(bpma)(CO)₂(CH₃CN)](PF₆)₂ (2b). Reaction of depolymerized [Ru(CO)₂Cl₂]_n with bpma in ethanol at room temperature afforded cis,cis-[Ru(η²-bpma)(CO)₂Cl₂] (3). In refluxing ethanol, 3 was converted to cis,fac-[Ru(bpma)(CO)₂Cl]Cl (1a-Cl). Heating 3 in chlorobenzene afforded 1b-Cl, exclusively; heating 3 in ethylene glycol gave mainly 1a-Cl. Heating 1a-Cl in ethanol resulted in no isomerization, but heating in chlorobenzene gave a mixture of 3 and 1b-Cl. Anion exchange for PF₆ with 1a-Cl and 1b-Cl afforded 1a and 1b, respectively, whereas anion exchange for BPh₄ afforded 1a-BPh₄. Compounds 1a, 1b, 2a and 3 have been structurally characterized.     

Synthesis,biological evaluation and molecular modeling of novel selective COX-2 inhibitors: sulfide,sulfoxide, and sulfone derivatives of 1,5-diarylpyrrol-3-substituted scaffold

A novel series of 1,5-diarylpyrrol-3-sulfur derivatives (10–12) was synthesized and characterized by NMR and mass spectroscopy and x-ray diffraction. The biological activity of these compounds was evaluated in in vitro and in vivo tests to assess their COX-2 inhibitory activity along with anti-inflammatory and antinociceptive effect.Results showed that the bioisosteric transformation of previously reported alkoxyethyl ethers (9a-c) into the corresponding alkyl thioethers (10a-c) still leads to selective and active compounds being the COX-2 inhibitory activity for most of them in the low nanomolar range. The oxidation products of 10a,b were also investigated and both couple of sulfoxides (11a,b) and sulfones (12a,b) showed an appreciable COX-2 inhibitory activity. Molecular modeling studies were performed to investigate the binding mode of the representative compounds 10b, 11b, and 12b into COX-2 enzyme and to explore the potential site of metabolism of 10a and 10b due to the different in vivo efficacy. Among the developed compounds, compound 10b showed a significant in vivo anti-inflammatory and antinociceptive activity paving the way to develop novel anti-inflammatory drugs.     

Synthesis and biological evaluation of pyrano[4,3-b][1]benzopyranone derivatives as monoamine oxidase and cholinesterase inhibitors

A series of eighteen pyrano[4,3-b][1]benzopyranone derivatives (1a-9b) were synthesized, and structure-activity relationships of their monoamine oxidase (MAO) A and B, acetylcholinesterase (AChE), and butyrylcholinesterase (BChE) inhibitory activities were evaluated. Most of the synthesized compounds exhibited weak inhibitory activity toward MAO-A, whereas compounds 2a, 2b, 4a, 4b, 5a, 5b, 6a, 6b, 8a and 8b showed potent inhibitory activities toward MAO-B. Intriguingly, compounds 5a, 5b, and 8a showed inhibitory activities comparable to pargylin, used as a positive control for MAO-B. Substitution of butoxy at the C3 position or of chlorine at the C8 position of pyrano[4,3-b][1]benzopyranone increased the inhibitory activity of the compound toward MAO-B. The results of a molecular docking study supported this structural effect. Most of the compounds exhibited no or slight inhibitory activity toward AChE and BChE, with exo type compounds bearing a butoxy group, such as compounds 2b, 5b and 8b, showing weak but distinct inhibitory activities toward BChE. This report is the first to identify pyrano[4,3-b][1]benzopyranone derivatives as potent and selective MAO-B inhibitors. 3-Butoxy-8-chloro-pyrano[4,3-b][1]benzopyranone (5b) may be useful as a lead compound for the development of MAO-B inhibitors.     

Main group derivatives of a cyclometallated iron carbonyl anion. Crystal structures of Fe(CO)2{P(OPh)3}{(PhO)2POC6H4}(SnPh3) and two isomers of Fe(CO)2{P(OPh)3}{(PhO)2POC6H4}(I)

The iron hydrido complex HFe(CO)₂{P(OPh)₃}{(PhO)₂POC₆H₄} (1), was rapidly deprotonated by DBU or [BzMe₃N][OH] in THF to afford the new carbonyl iron anion [Fe(CO)₂{P(OPh)₃}{(PhO)₂POC₆H₄}]⁻ ([2]⁻), containing an ortho-metallated triphenyl phosphite ligand. Complex [2]⁻ reacted with triorganostannyl and plumbyl salts and with halogens to give the octahedral Fe^II compounds Fe(CO)₂{P(OPh)₃}{(PhO)₂POC₆H₄}(X) (X=SnPh₃, 3; SnMe₃, 4; PbPh₃, 5; PbMe₃, 6; Cl, 7; Br, 8; I, 9). The Group 14 complexes 3-6 were obtained in one isomeric form in which the P^III-donor atoms are mutually cis, the carbonyl ligands are cis and the P(OPh)₃ and MR₃ (M=Sn, Pb; R=Ph, Me) groups are trans as determined by solution-state IR, ³¹P and ¹³C NMR spectroscopic data. This geometry was confirmed for 3 by a single crystal X-ray diffraction study. The halide complexes, however, were obtained as a mixture of isomers. The major isomer (7, X=Cl; 8a, X=Br; 9a, X=I) has cis P atoms, trans CO groups and the halide located trans to the phosphorus atom of the ortho-metallated phosphite ligand. The structure of 9a was confirmed by an X-ray diffraction study. Two other isomers, designated 8b (X=Br) and 9b (X=I), with cis P atoms and cis CO groups were isolated from the reactions of [2]⁻ with Br₂ and I₂, respectively. The structure of the latter was established by X-ray crystallography and is related to 9a by exchange of the P(OPh)₃ ligand and a carbonyl group such that the metal-bound C atom of the five-membered metallacycle is trans to CO. The stereo-geometry of 8b could not be unambiguously assigned from the spectroscopic data; however, two of the seven possible geometric isomers were suggested as plausible structures.     

Synthesis,biological evaluation and docking study of N-(2-(3,4,5-trimethoxybenzyl)benzoxazole-5-yl) benzamide derivatives as selective COX-2 inhibitor and anti-inflammatory agents

A series of N-(2-(3,4,5-trimethoxybenzyl)-benzoxazole-5-yl)benzamide derivatives (3a–3n) was synthesized and evaluated for its in vitro inhibitory activity against COX-1 and COX-2. The compounds with considerable in vitro activity (IC₅₀ < 1 µM), were evaluated in vivo for their anti-inflammatory and ulcerogenic potential. Out of the fourteen newly synthesized compounds; 3b, 3d, 3e, 3h, 3l and 3m were found to be most potent COX-2 inhibitors in in vitro enzymatic assay with IC₅₀ in the range of 0.14–0.69 µM. In vivo anti-inflammatory activity of these six compounds (3b, 3d, 3e, 3h, 3l and 3m) was assessed by carrageenan induced rat paw edema method. The compound 3b (79.54%), 3l (75.00%), 3m (72.72%) and 3d (68.18%) exhibited significant anti-inflammatory activity than standard drug ibuprofen (65.90%). Ulcerogenic activity with histopathological studies was performed, and the screened compounds demonstrated significant gastric tolerance than ibuprofen. Molecular Docking study was also performed with resolved crystal structure of COX-2 to understand the interacting mechanisms of newly synthesized inhibitors with the active site of COX-2 enzyme and the results were found to be in line with the biological evaluation studies of the compounds.     

Design of hybrid molecules as antimycobacterial compounds: Synthesis of isoniazid-naphthoquinone derivatives and their activity against susceptible and resistant strains of Mycobacterium tuberculosis

Isoniazid-naphthoquinone hybrids were synthesized and evaluated against a susceptible (H₃₇Rv) strain and two isoniazid-resistant strains (INH_R1 and INH_R2) of Mycobacterium tuberculosis. The antimycobacterial activity of the derivatives was determined based on the resazurin microtiter assay and their cytotoxicity in adhered mouse monocyte macrophage J774.A1 cells (ATCC TIB-67). Of the twenty-two compounds evaluated against the three strains of M. tuberculosis, twenty-one presented some activity against the H₃₇Rv and INH_R1 (katG S315T) or INH_R2 (inhA C(−5)T) strains. Compounds 1a, 2a, and 8a were effective against the INH_R1 strain, and compounds 1a, 1b, 2a, 3a, 5a, 5b and 8a were effective against the INH_R2 strain, with MICs in the range of 3.12–6.25 µg/mL. Compounds 1b and 5b were the most active against H₃₇Rv, with MIC of 0.78 µg/mL. Based on the selectivity index, 1b and 5b can be considered safe as a drug candidate compounds. These results demonstrate that quinoidal compounds can be used as promising scaffolds for the development of new anti-TB drugs and hybrids with activity against M. tuberculosis-susceptible and INH-resistant strains.     

Practical and efficient synthesis of pyrano[3,2-c]pyridone,pyrano[4,3-b]pyran and their hybrids with nucleoside as potential antiviral and antileishmanial agents

A highly practical and efficient preparation of pyrano[3,2-c]pyridone and pyrano[4,3-b]pyran derivatives was developed via an ionic liquid mediated and promoted multi-component reaction of aldehyde (1), 4-hydroxy-pyridin-2(1H)-one or 4-hydroxy-2-pyranone (2), and malononitrile (3). As an application, a series of pyrimidine nucleoside-pyrano[3,2-c]pyridone or pyrano[4,3-b]pyran hybrids were efficiently obtained. These hybrid compounds were evaluated as potential antiviral and antileishmanial agents and showed encouraging biological activities.