Specific effects of reactive thiol drugs on mitochondrial bioenergetics

In this minireview, the more recent findings about the effects of peculiar reactive thiol drugs on mitochondria are presented. These include the following compounds: metallo meso-tetrakis porphyrins, palladacycles, telluranes and phenothiazines. Metallo meso-tetrakis porphyrins can exhibit both beneficial and deleterious effects on mitochodria that are modulated by the central metal, cell location, and availability of axial ligands. Therefore, these compounds have the versatility to be used for cell and mitochondria protection and death. The antioxidant activity of manganese porphyrins is related to a glutathione peroxidase-like activity. By attacking exclusively the membrane protein thiol groups without glutathione depletion, palladacycles are able to induce mitochondrial permeability transition (MPT) and cytochrome c release in the absence of oxidative stress. In hepatoma cells, the mitochondrial action of palladacycles was able to induce apoptotic death. As opposed to palladacycles, telluranes and phenothiazines are able to conjugate the capacity to promote the MPT in a dose-dependent manner in association with efficient antioxidant activity toward lipids. These studies demonstrated that the action of drugs on mitochondrial bioenergetics can be modulated by peculiar reactivity with thiol groups. Therefore, they contribute to studies of toxicity as well as the design of new drugs.     

Study and Synthesis of Biologically Active Phenothiazines,their Sulfones,and Ribofuranosides

The present article describes the synthesis of new 10H-phenothiazines using the Smiles rearrangement. These synthesized phenothiazines on oxidation with 30% hydrogen peroxide in glacial acetic acid yield sulfones, and when treated with sugar give ribofuranosides. These compounds are evaluated for their anthelmintic and antimicrobial activities. The structural assignment of the synthesized compounds is made on the basis of elemental analysis and spectroscopic data.     

Hybrid Pharmacophore Design,Molecular Docking,Synthesis, and Biological Evaluation of Novel Aldimine‐Type Schiff Base Derivatives as Tubulin Polymerization Inhibitor

A series of hybrid aldimine‐type Schiff base derivatives including trimethoxyphenyl ring and 1,2,4‐triazole‐3‐thiol/thione were designed as tubulin inhibitors. The molecular docking simulations on tubulin complex (PDB: 1SA0) revealed that derivatives with nitro and/or chloro or dimethylamino substitutes (4‐nitro, 2‐nitro, 3‐nitro, 4‐Cl‐3‐nitro, and 4‐Me₂N) on the aldehyde ring were the best compounds with remarkable binding energies (?9.09, ?9.07, ?8.63, ?8.11, and ?8.07 kcal mol^?1, respectively) compared to colchicine (?8.12 kcal mol^?1). These compounds were also showed remarkable binding energies from ?10.66 to ?9.79 and ?10.12 to ?8.95 kcal mol^?1 on human (PDB: 1PD8) and Candida albicans (PDB: 3QLS) DHFR, respectively. The obtained results of cytotoxic activities against HT1080, HepG2, HT29, MCF‐7, and A549 cancer cell lines indicated that 4‐nitro and 2‐nitro substituted compounds were the most effective agents by mean IC₅₀ values of 11.84 ± 1.01 and 19.92 ± 1.36 μm , respectively. 4‐Nitro substituted compound (5 μm ) and 2‐nitro substituted compound (30 μm ) were able to strongly inhibit the tubulin polymerization compared to colchicine (5 μm ) and 4‐nitro substituted compound displayed IC₅₀ values of 0.16 ± 0.01 μm compared to that of colchicine (0.19 ± 0.01 μm ). This compound also showed the lowest MIC values on all tested microbial strains including three Gram‐positive, four Gram‐negative, and three yeast pathogens.     

Ammonium‐Charged Sterically Hindered Phenols with Antioxidant and Selective Anti‐Gram‐Positive Bacterial Activity

The increase in the resistance of pathogens, in particular Staphylococcus aureus, to the action of antibiotics necessitates the search for new readily available and non‐toxic drugs. In solving this problem, phenolic acylhydrazones have high potential. In this communication, the synthesis of quaternary ammonium compounds containing a differently substituted phenolic moiety has been performed. An initial study of antimicrobial activity showed that these compounds are highly selective against S. aureus and B. cereus. The highest activity (MIC 2.0 μm ) was shown by hydrazones containing a catechol fragment. These compounds are more than 3‐fold more active against S. aureus and 3–10‐fold more active against B. cereus than norfloxacin. Low hemolytic and high antioxidant activities of all new compounds were also established.     

Synthesis of functionalized amino acid derivatives as new pharmacophores for designing anticancer agents

A new series of functionalized amino acid derivatives N-substituted 1-N-(tert-butoxycarbonyl)-2,2-dimethyl-4-phenyl-5-oxazolidine carboxamide (1-17) and 1-N-substituted-3-amino-2-hydroxy-3-phenylpropane-1-carboxamide (18-34) were synthesized and evaluated for their in vitro cytotoxicity against human cancer cell lines. Compound 6 has shown interesting cytotoxicity (IC₅₀ = 5.67 μm) in ovarian cancer, while compound 10 exhibited promising cytotoxicity in ovarian (IC₅₀ = 6.1 μm) and oral (IC₅₀ = 4.17 μm) cancers. These compounds could be of use in designing new anti-cancer agents.     

Biocatalysis of nitro substituted styrene oxides by non-conventional yeasts

Yeast strains (410) from more than 45 different genera were screened for the enantioselective hydrolysis of nitro substituted styrene oxides. These strains included 262 yeasts with known epoxides hydrolase activity for various other epoxides. Epoxide hydrolase activity for p-nitrostyrene oxide (pNSO) (177 strains) and m-nitrostyrene oxide (mNSO) (148 strains) was widespread in the yeasts, while activity for o-nitrostyrene oxide (oNSO) was less ubiquitous (22 strains). The strains that displayed enantioselectivity in the hydrolysis of one or more of the nitro substituted styrene oxides (35 strains) were also screened against styrene oxide (SO). Rhodosporidium toruloides UOFS Y-0471 displayed the highest enantioselectivity for pNSO (ee 55%, yield 35%) while Rhodotorula glutinis UOFS Y-0653 displayed the highest enantioselectivity for mNSO (ee >98%, yield 29%), oNSO (ee 39%, yield 19%) and SO (ee >98%, yield 19%). (R)-Styrene oxide was preferentially hydrolysed to the corresponding (R)-diol with retention of configuration at the stereogenic centre. In the case of the nitro substituted styrene oxides the absolute configurations of the remaining epoxides and the formed diols were not established.     

Synthesis and evaluation of in vitro antiviral activity of 2-[3-(substituted phenyl)-4,5-dihydro-1H-5-pyrazolyl]benzofuran-3-yl chloride derivatives

3-Chlorobenzofuran-2-carbaldehyde was condensed with substituted acetophenone by using the Claisen-Schmidt condensation to obtain 3-(3-chlorobenzofuran-2-yl)-1-(substituted phenyl)-2-propen-1-one (2a-m) which upon further treatment with hydrazine hydrate gave 2-[3-(substituted phenyl)-4,5-dihydro-1H-5- pyrazolyl)benzofuran-3-yl chloride derivatives (3a-m). All the newly synthesized derivatives were evaluated in vitro for cytotoxicity and antiviral activity in Crandell-Rees Feline Kidney cell, human embryonic lung (HEL) cell, HeLa cell and Vero cell cultures against different viruses. Several compounds, i.e. 2f, 2g, 2i, 2m, 3b, 3d, 3g, 3h and 3m proved quite cytotoxic to the host cells (minimum cytotoxic concentration: 1-10 μg/mL). No specific antiviral activity [50% antivirally effective concentration (EC₅₀) ≥ 5-fold lower than the minimum cytototoxic concentration] was observed for any of the compounds.     

Design,synthesis and pharmacological screening of a series of N1-(substituted)aryl-5,7-dimethyl-2-(substituted)pyrido(2,3-d)pyrimidin-4(3H)-ones as potential histamine H1-receptor antagonists

A series of N₁-(substituted)aryl-5,7-dimethyl-2-(substituted)pyrido(2,3-d)pyrimidin-4(3H)-one was designed on the basis of the triangular pharmacophoric requirement of histamine H₁-receptor antagonists. The designed series was synthesized by cyclo-condensation of monoaryl thiourea with ethyl cyanoacetate in the presence of dry HCl gas to give N₁-(substituted aryl)-2-mercaptopyrimidine-4(3H)-one, which on cyclo-condensation with acetylacetone gave the pyridopyrimidinone. Further methylation of the mercapto group at C-2 with methyl iodide followed by nucleophilic displacement of the methylmercapto group by various amines gave the targeted compounds. All the synthesized compounds were screened for histamine H₁-receptor antagonistic activity by the in vitro method of inhibition of the isotonic contraction induced by histamine on isolated guinea pig ileum using cetirizine as a standard drug. All the compounds exhibited potent histamine H₁-receptor antagonistic activity with pA₂ values from 7.30– 9.75 (cetirizine, pA₂ value 9.40). The potent compounds were screened for their in vivo antihistaminic activity by protection of animal from asphyxic shock. The sedative potential of potent compounds was checked on albino mice by photoactometer and they had comparative sedative potential to the standard drug cetirizine. None of the compound exhibited anticholinergic activity in the in vitro rat ileum model.     

Synthesis,antimicrobial and antiviral activity of substituted benzimidazoles

In the present study we have synthesized (4-nitrophenyl)-[2-(substituted phenyl)-benzoimidazol-1-yl]-methanones, (2-bromophenyl)-[2-(substituted phenyl)-benzoimidazol-1-yl]-methanone analogues (1–14) and evaluated them for their antimicrobial and antiviral potential. The results of antimicrobial screening indicated that none of the synthesized compounds were effective against the tested bacterial strains. Compounds 3, 11, 13 and compounds 5, 11, 12 were found to be active against Aspergillus niger and Candida albicans respectively, and may be further developed as antifungal agents. Furthermore, evaluation against a panel of different viruses pointed out the selective activity of compounds 5 and 6 against vaccinia virus and Coxsackie virus B4.     

Highly enantiomeric reduction of acetophenone and its derivatives by locally isolated Rhodotorula glutinis

Ninety isolates of microorganisms belonging to different taxonomical groups (30 bacteria, 20 yeast, and 40 fungi) were previously isolated from various samples. These isolates were screened as reducing agents for acetophenone 1a to phenylethanol 2a . It was found that the isolate EBK‐10 was the most effective biocatalyst for the enantioselective bioreduction of acetophenone. This isolate was identified as Rhodotorula glutinis by the VITEK 2 Compact system. The various parameters (pH 6.5, temperature 32°C, and agitation 200 rpm) of the bioreduction reaction was optimized, which resulted in conversions up to 100% with >99% enantiomeric excesses (ee) of the S‐configuration. The preparative scale bioreduction of acetophenone 1a by R. glutinis EBK‐10 gave (S)‐1‐phenylethanol 2a in 79% yield, complete conversion, and >99% ee. In addition, R.glutinis EBK‐10 successfully reduced various substituted acetophenones. Chirality, 2010. © 2010 Wiley‐Liss, Inc.     

Evaluation of Antituberculosis Activity and in Silico Properties of Oxymethylene-cyclo-1,3-diones

Tuberculosis is a leading infectious disease that has infected one-third of the world's population and is more prevalent among people belonging to developing countries such as India and China. In the present study, a series of substituted oxymethylene-cyclo-1,3-diones was synthesized and screened for anti-tuberculosis activity against Mycobacterium tuberculosis H37Rv (M. tuberculosis). The compounds were synthesized by condensation of 1,3-cyclicdione, substituted phenols/ alcohols and triethyl orthoformate. The synthesized compounds were screened for anti-tuberculosis activity against M.tuberculosis H37Rv using Middlebrook 7H9 broth assay. Results demonstrated that among the synthesized library of molecules, two compounds 2-(2-hydroxyphenoxymethylene)-5,5-dimethylcyclohexane-1,3-dione and 5,5-dimethyl-2-(2-trifluoromethylphenoxymethylene)cyclohexane-1,3-dione were found to be most active against M. tuberculosis (MICs of 1.25 μg/mL⁻¹). The MICs of 2-(2,4-difluoro-phenoxymethylene)-5,5-dimethylcyclohexane-1,3-dione and 2-(2-bromophenoxymethylene)-5,5-dimethylcyclohexane-1,3-dione were found to be 5 and 10 μg mL⁻¹, respectively. Data from the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay showed that all the four most active compounds did not exhibit cytotoxicity against human cell lines. Molecular docking studies revealed that the most active compound targets mycobacterial InhA enzyme. In summary, the present study demonstrates the methodology for the synthesis of oxymethylene-cyclo-1,3-diones and identified two potential anti-tuberculosis compounds.     

A novel synthetic compound, (Z)-5-(3-hydroxy-4-methoxybenzylidene)-2-iminothiazolidin-4-one (MHY773) inhibits mushroom tyrosinase

As part of continued efforts for the development of new tyrosinase inhibitors, (Z)-5-(substituted benzylidene)-2-iminothiazolidin-4-one derivatives (1a – 1l) were rationally synthesized and evaluated for their inhibitory potential in vitro. These compounds were designed and synthesized based on the structural attributes of a β-phenyl-α,β-unsaturated carbonyl scaffold template. Among these compounds, (Z)-5-(3-hydroxy-4-methoxybenzylidene)-2-iminothiazolidin-4-one (1e, MHY773) exhibited the greatest tyrosinase inhibition (IC₅₀ = 2.87 μM and 8.06 μM for monophenolase and diphenolase), and outperformed the positive control, kojic acid (IC₅₀ = 15.59 and 31.61 μM). The kinetic and docking studies demonstrated that MHY773 interacted with active site of tyrosinase. Moreover, a melanin quantification assay demonstrated that MHY773 attenuates α-melanocyte-stimulating hormone (α-MSH) and 3-isobutyl-1-methylxanthine (IBMX)-induced melanin contents in B16F10 melanoma cells. Taken together, these data suggest that MHY773 suppressed the melanin production via the inhibition of tyrosinase activity. MHY773 is a promising for the development of effective pharmacological and cosmetic agents for skin-whitening.     

Synthesis and characterization of quinazoline derivatives: search for hybrid molecule as diuretic and antihypertensive agents

Abstract

To explore the pharmacological and structure–activity relationship of a series of N-substituted-(4-oxo-2-substituted-phenylquinazolin-3-(4H)-yl), substituted benzene sulfonamide derivatives (1–25) were synthesized from substituted anthranilic acids derived amino quinazolines and substituted benzene sulphonamides. All the synthesized compounds were evaluated for their diuretic (by Lipschitz et al. method), antihypertensive activity by non-invasive blood pressure (NIBP) using the tail-cuff method and anti-diabetic potential in rats. Six compounds showing significantly excellent activity were compared with metolazone, prazosin and diazoxide as standards. Compound N-[7-chloro-2-(4-methoxyphenyl)-4-oxoquinazolin-3(4H)-yl]-4 nitrobenzenesulfonamide (20) exhibited most potent of the series.     

3-Methyl-2-phenyl-1-substituted-indole derivatives as indomethacin analogs: design,synthesis and biological evaluation as potential anti-inflammatory and analgesic agents

In a new group of 3-methyl-2-phenyl-1-substituted-indole derivatives (10a–f), the indomethacin analogs were prepared via the Fisher indole synthesis reaction of propiophenone with appropriately substituted phenylhydrazine hydrochloride. This is followed by the insertion of the appropriate benzyl or benzoyl fragment. All the synthesized compounds were evaluated for their anti-inflammatory (in vitro and in vivo) and analgesic activities. The methanesulphonyl derivatives 10d, e and f showed the highest anti-inflammatory (in vitro and in vivo) and analgesic activities. In addition, molecular docking studies were performed on compounds 10a–f and the results were in agreement with that obtained from the in vitro COX inhibition assays. The significant anti-inflammatory and analgesic activities exhibited by 10d and 10e warrant continued preclinical development as potential anti-inflammatory and analgesic agents.     

Characterization of cyclic β-glucans of Bradyrhizobium by MALDI-TOF mass spectrometry

Periplasmic, cyclic β-glucans isolated from Bradyrhizobium elkanii, Bradyrhizobium liaoningense, and Bradyrhizobium yuanmingense strains have been investigated by means of Matrix-Assisted Laser Desorption/Ionization Time-of-Flight Mass Spectrometry (MALDI-TOF MS), 1D and 2D nuclear magnetic resonance (NMR), as well as standard chemical methods. These compounds are built of 10–13 d-glucose residues. The main fractions contain molecules assembled of 12 hexose units (M_w = 1945.363 Da). Glucose monomers are linked by β-(1→3) or β-(1→6) glycosidic bonds. The ratio of β-(1→3) to β-(1→6) linked glucose is approximately 1:2. Moreover, methylation analysis demonstrated the presence of terminal, non-reducing, as well as branched (i.e., 3- and 6-substituted) glucoses. Thus, the basic structure of the investigated compounds is similar to that of periplasmic oligosaccharides from Bradyrhizobium japonicum and Azorhizobium caulinodans strains. The analyzed cyclic β-glucans are substituted by phosphocholine (PC) (one or two residues per ring) and highly decorated with acetate and succinate. The substituents are arranged diversely in the population of cyclic β-glucan molecules. The concentrations of cyclic β-glucans in Bradyrhizobium periplasmic space are osmotically regulated and increase in response to a decrease of medium osmolarity.     

Synthesis And Biological Activity Of Substituted 4H-1,4-Benzothiazines,Their Sulfones,And Ribofuranosides

The present article describes the synthesis of new 4H-1,4-benzothiazines via condensation and oxidative cyclization of substituted 2-aminobenzenethiols with β-diketones/β-ketoesters in dimethyl sulfoxide. The oxidation of these synthesized 4H-1,4-benzothiazines with 30% hydrogen peroxide in glacial acetic acid yielded 4H-1,4-benzothiazine sulfones and the reaction of these synthesized benzothiazines with sugar (β-D-ribofuranose-1-acetate-2,3,5-tribenzoate) afforded the new ribofuranosides. These compounds were evaluated for their antioxidant and antimicrobial activities (using broth microdilution method). The structural assignments of the synthesized compounds were made on the basis of elemental analyses and spectroscopic data.     

Synthesis of substituted 5[H]phenanthridin-6-ones as potent poly(ADP-ribose)polymerase-1 (PARP1) inhibitors

1-, 2-, 3-, 4-, 8-, or 10-Substituted 5(H)phenanthridin-6-ones were synthesized and found to be potent PARP1 inhibitors. Among the 28 compounds prepared, some showed not only low IC₅₀ values (compound 1b, 10 nM) but also desirable water solubility characteristics. These properties, which are superior to the common PARP1 inhibitors such as benzamides and isoquinolin-1-ones, are essential for potential therapeutic usage. The variety of compounds allows SAR analysis of favored substituents and substituted positions on 5(H)phenanthridin-6-one ring.     

Synthesis and in vitro biological evaluation of new pyrimidines as glucagon-like peptide-1 receptor agonists

The therapeutic success of peptide glucagon-like peptide-1 (GLP-1) receptor agonists for the treatment of type 2 diabetes mellitus has inspired discovery efforts aimed at developing orally available small-molecule GLP-1 receptor agonists. In this study, two series of new pyrimidine derivatives were designed and synthesized using an efficient route, and were evaluated in terms of GLP-1 receptor agonist activity. In the first series, novel pyrimidines substituted at positions 2 and 4 with groups varying in size and electronic properties were synthesized in a good yield (78–90%). In the second series, the designed pyrimidine templates included both urea and Schiff base linkers, and these compounds were successfully produced with yields of 77–84%. In vitro experiments with cultured cells showed that compounds 3a and 10a (10^?15–10^?9 M) significantly increased insulin secretion compared to that of the control cells in both the absence and presence of 2.8 mM glucose; compound 8b only demonstrated significance in the absence of glucose. These findings represent a valuable starting point for the design and discovery of small-molecule GLP-1 receptor agonists that can be administered orally.     

1-Deoxy-d-galactonojirimycins with dansyl capped N-substituents as β-galactosidase inhibitors and potential probes for GM1 gangliosidosis affected cell lines

Two simple and reliably accessible intermediates, N-carboxypentyl- and N-aminohexyl-1-deoxy-d-galactonojirimycin were employed for the synthesis of a set of terminally N-dansyl substituted derivatives. Reaction of the terminal carboxylic acid of N-carboxypentyl-1-deoxy-d-galactonojirimycin with N-dansyl-1,6-diaminohexane provided the chain-extended fluorescent derivative. Employing bis(6-dansylaminohexyl)amine, the corresponding branched di-N-dansyl compound was obtained. Partially protected N-aminohexyl-1-deoxy-d-galactonojirimycin served as intermediate for two additional chain-extended fluorescent 1-deoxy-d-galactonojirimycin (1-DGJ) derivatives featuring terminal dansyl groups in the N-alkyl substituent. These new compounds are strong inhibitors of d-galactosidases and may serve as leads en route to pharmacological chaperones for GM1-gangliosidosis.     

Synthesis of a New Series of 1H‐Imidazol‐1‐yl Substituted 8‐Phenylxanthines as Adenosine Receptor Ligands

A new series of 1H‐imidazol‐1‐yl substituted 8‐phenylxanthine analogs has been synthesized to study the effects of the imidazole group on the binding affinity of compounds for adenosine receptors. Competition binding studies of these compounds were carried out in vitro with human cloned receptors using [³H]DPCPX and [³H]ZM 241385 as radioligands at A₁ and A_2A adenosine receptors, respectively. The effect of the substitution pattern of the (imidazolyl)alkoxy group on various positions of the phenyl ring at C(8) was also studied. The xanthine derivatives displayed varying degrees of affinity and selectivity towards A₁ and A_2A receptor subtypes despite a common but variedly substituted Ar C(8).