Synthesis and anti‐HIV activity of new chiral 1,2,4‐triazoles and 1,3,4‐thiadiazoles

5‐substituted 4‐(4‐chlorophenyl)‐4H‐1,2,4‐triazol‐3‐thiones 3 and 2‐substituted 5‐(4‐chlorophenylamino)‐1,3,4‐thiadiazoles 4 were prepared from the intermediate thiosemicarbazides 2 under basic and acidic conditions, respectively. The thiosemicarbazides, in turn, were prepared by the reaction of hydrazides 1 with 4‐chlorophenylisothiocyanate in MeOH. Some of the new synthesized compounds were assayed against HIV‐1 and HIV‐2 in MT‐4 cells. All the compounds were inactive except 3f , which showed an EC₅₀ value of 23.9 μg/mL and 9.9 μg/mL against HIV‐1 and HIV‐2 with a therapeutic index of 3 and 7, respectively. It means that compound 3f was cytotoxic to MT‐4 cells at CC₅₀ of 72.7 μg/mL in both strains. © 2007 Wiley Periodicals, Inc. Heteroatom Chem 18:316–322, 2007; Published online in Wiley InterScience ( www.interscience.wiley.com ). DOI 10.1002/hc.20282     

Ring‐opening polymerization of benzylated 1,6‐anhydro‐β‐D‐lactose and specific biological activities of sulfated (1→6)‐α‐D‐lactopyranans

A new anhydro disaccharide monomer, 1,6‐anhydro‐2,3‐di‐o‐benzyl‐4‐o‐(2′,3′,4′,6′‐tetra‐o‐benzyl‐β‐D ‐galactopyranosyl)‐β‐D ‐glucopyranose (benzylated 1,6‐anhydro lactose (LSHBE)), was synthesized from D ‐lactose to investigate the polymerizability and biological activities of the resulting branched polysaccharides. The ring‐opening polymerization of LSHBE was carried out with phosphorus pentafluoride as a catalyst under high vacuum to give a stereoregular benzylated (1 → 6)‐α‐D ‐lactopyranan. The molecular weights of poly(LSHBE)s increased with an increase in the amount of CH₂Cl₂ solvent, and polymerization temperatures were affected in both molecular weights and yields of the polymers. The copolymerization of LSHBE with benzylated 1,6‐anhydro‐β‐D ‐glucopyranose (LGTBE) gave the corresponding copolysacchrides having different proportions of lactose and glucose units in good yields. After debenzylation to recover hydroxyl groups and then sulfation, sulfated homopoly(lactose)s and copoly(lactose and glucose)s were obtained. Sulfated homopoly(lactose)s had moderate anti‐HIV (EC₅₀ = 5.9 and 1.3 μg/mL) and blood anticoagulant activities (AA = 18 and 13 unit/mg), respectively. Sulfated copoly(lactose and glucose) having 15 mol % lactose units gave high anti‐HIV and blood anticoagulant activities of 0.3 μg/mL and 54 unit/mg, respectively. These biological results suggest that the distance between branched units on the main chain plays an important role in the anti‐HIV and blood anticoagulant activities. © 2008 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 47: 913–924, 2009     

Design,Synthesis, and in vitro Antimicrobial Activity of New Furan/Thiophene‐1,3‐Benzothiazin‐4‐one Hybrids

This study presents the design, synthesis, spectral analysis, and in vitro antimicrobial evaluation of a new series of furan/thiophene‐1,3‐benzothiazin‐4‐one hybrids ( 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 ). New compounds were obtained by cyclization reaction of N‐substituted furan/thiophene‐2‐carboxamide derivatives ( 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 ) with thiosalicylic acid. All synthesized compounds were screened for their in vitro antimicrobial activities using the broth microdilution method. Nine of the synthesized compounds showed good activity against Gram‐positive, Gram‐negative bacteria, and yeasts belonging to Candida spp. (MIC = 7.81–500 μg/mL), especially against Staphylococcus spp. (MIC = 15.62–62.5 μg/ml), Bacillus spp. (MIC = 7.81–62.5 μg/mL), Bordetella bronchiseptica ATCC 4617 (MIC = 62.5–125 μg/mL), and fungistatic activity against Candida spp. (MIC = 62.5–125 μg/mL).     

Synthesis and anti‐HIV activity of new 2‐thiolumazine and 2‐thiouracil metal complexes

A series of new Cu(II), Pt(II), VO(II), Fe(II), and Co(II) complexes ( 1‐‐5 ) with 3‐methyl‐6,7‐diphenyllumazine are described. Similarly, complexes from 2‐thiouracil with Cu(II) ( 6,7 ) and Pt(II) ( 8 ) have been prepared and characterized by spectroscopic methods. All the complexes were assayed for their anti‐HIV‐1 and HIV‐2 activity by examination of their inhibition of HIV‐induced cytopathogenicity in MT‐4 cells. Compound 3 was found to be the most active inhibitor against HIV‐2 in cell culture (EC₅₀ = >18.9 μ g/mL, selectivity index (SI) = 3), which provided a good lead for further optimization. Compounds 6 and 7 exhibited some activity (EC₅₀ = >7.12 μ g/mL and >2.23 μ g/mL) against HIV‐1 and HIV‐2, but no selectivity was observed (SI <1). © 2010 Wiley Periodicals, Inc. Heteroatom Chem 22:44–50, 2011; View this article online at wileyonlinelibrary.com . DOI 10.1002/hc.20654     

Novel 5‐Methyl‐2‐[(un)substituted phenyl]‐4‐{4,5‐dihydro‐ 3‐[(un)substituted phenyl]‐5‐(1,2,3,4‐tetrahydroisoquinoline‐2‐yl)pyrazol‐1‐yl}‐oxazole Derivatives: Synthesis and Anticancer Activity

Eleven novel 5‐methyl‐2‐[(un)substituted phenyl]‐4‐{4,5‐dihydro‐3‐[(un)substituted phenyl]‐5‐(1,2,3,4‐tetrahydroisoquinoline‐2‐yl)pyrazol‐1‐yl}‐oxazole derivatives were synthesized and characterized by elemental analysis, ESI‐MS, ¹H NMR and ¹³C NMR. All of the compounds have been screened for their antiproliferative activities against PC‐3 cell (human prostate cancer) and A431 cell (human epidermoid carcinoma cancer) lines in vitro. The results revealed that compounds 4g , 4j and 4k exhibited the strong inhibitory activities against the PC‐3 cell lines (with IC₅₀ values of 2.8±0.11, 3.1±0.10 and 3.0±0.06 μg/mL, respectively).     

Synthesis and Antiviral Bioactivity of Novel 2‐Substituted Methlthio‐5‐(4‐Amino‐2‐Methylpyrimidin‐5‐yl)‐1,3,4‐Thiadiazole Derivatives

A series of novel 2‐substituted methlthio‐5‐(4‐amino‐2‐methylpyrimidin‐5‐yl‐)‐1,3,4‐thiadiazole derivatives were synthesized, characterized and evaluated for antiviral activities against tobacco mosaic virus (TMV). The preliminary biological results indicated that most compounds exhibit excellent antiviral activity against TMV in vivo. Among these compounds, compounds 9c , 9i , and 9p displayed the similar curative effect against TMV (EC₅₀ = 287.05–322.47 µg/mL) to that of the commercial agent Ningnanmycin (EC₅₀ = 301.83 µg/mL). In particular, compound 9d demonstrated the best curative effect against TMV (EC₅₀ = 266.21 µg/mL), which was better than that of commercial Ningnanmycin.     

Facile Heterocyclic Synthesis and Antibacterial Activity of Substituted Isoxazol‐5(4H)‐ones

An efficient, simple, and green procedure for the synthesis of isoxazol‐5(4H)‐one derivatives are described here through a convenient one‐pot, three‐component reaction at room temperature. The title compounds are isolated in high to excellent yields and after short reaction times, and are characterized by various spectroscopic methods such as IR, ¹H NMR, and ¹³C NMR. The synthesized compounds 4a–c and 4e–i were tested for their in vitro activity against a panel of Gram‐positive and Gram‐negative bacteria, demonstrating their ability to inhibit microorganisms with a zone of inhibition ranging from 15 to 30 mm, minimum inhibitory concentration between 250 and 900 μg/mL, and minimum bacterial concentration between 700 and 1000 μg/mL.     

Synthesis of novel N‐alkyl/aryl‐N′‐(4‐arylthiazol‐2‐yl)‐N″‐xylosyl guanidines

The reaction of 2,3,4‐tri‐O‐acetyl‐β‐D‐xylopyranosyl isothiocyanate ( 1 ) and 2‐amino‐4‐arylthiazoles ( 2 ) gave xylosylthioureas 3 . These thiourea derivatives reacted with alkyl/aryl amine in the presence of HgCl₂ to give a new series of N‐alkyl/aryl‐N″‐(4‐arylthiazol‐2‐yl)‐N″‐xylosyl guanidines 4 . Some of the synthesized guanidines were screened for their biological activity. © 2007 Wiley Periodicals, Inc. Heteroatom Chem 18:688–694, 2007; Published online in Wiley InterScience ( www.interscience.wiley.com ). DOI 10.1002/hc.20379     

Synthesis of novel 5‐aryl‐1H‐tetrazoles

In this study phenylselenocyanate and some of its derivatives (o‐Cl, p‐Cl, p‐Br, o‐NO₂, p‐NO₂, o‐CH₃, p‐CH₃, o‐COOH, p‐COOH, p‐OCH₃ substituted) were synthesized ( 3a–3j ). The synthesized compounds were converted to 5‐aryl‐1H‐tetrazole ( 4a–4j ), by Et₃N ċ HCl‐NaN₃ in toluene, which are a new series of phenylselanyl‐1H‐tetrazoles. The structure of all the presently synthesized compounds were confirmed using spectroscopic methods (FTIR, ¹H NMR, MS). © 2007 Wiley Periodicals, Inc. Heteroatom Chem 18:255–258, 2007; Published online in Wiley InterScience ( www.interscience.wiley.com ). DOI 10.1002/hc.20293     

Synthesis and properties of polyimides derived from 1,4‐bis(4‐aminophenoxy)‐2‐(6‐oxido‐6H‐dibenz[c,e] [1,2]oxaphosphorin‐6‐yl) phenylene

A new phosphorus‐containing aromatic diamine, 1,4‐bis(4‐aminophenoxy)‐2‐(6‐oxido‐6H‐dibenz[c,e] [1,2]oxaphosphorin‐6‐yl) phenylene ( 3 ) was synthesized by the nucleophilic aromatic substitution of 2‐(6‐oxido‐6H‐dibenz[c,e] [1,2]oxaphosphorin‐6‐yl)‐1,4‐dihydroxy phenylene ( 1 ) with 4‐fluoronitrobenzene, followed by catalytic hydrogenation. Light color, flexible, and creasable polyimides with high molecular weight, high glass transition, high thermal stability, improved organosolubility, and good oxygen plasma resistance were synthesized from the condensation of ( 3 ) with various aromatic dianhydrides in N,N‐dimethylacetamide, followed by thermal imidization. The number‐average molecular weights of polyimides are in the range of 7.0–8.3 × 10⁴ g/mol, and the weight‐average molecular weights are in the range of 12.5–16.5 × 10⁴ g/mol. The T_gs of these polyimides range from 230 to 304 °C by differential scanning calorimetry and from 228 to 305 °C by DMA. These polyimides are tough and flexible, with tensile strength at around 100 MPa. The degradation temperatures (T_d 5%) and char yields at 800 °C in nitrogen range from 544 to 597 °C and 59–65 wt %, respectively. Polyimides 5c and 5e , derived from OPDA and 6FDA, respectively, with the cutoff wavelength of 347 and 342 μm, respectively, show very light color. These polyimides also exhibit good oxygen plasma resistance. © 2007 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 45: 2897–2912, 2007     

Synthesis and anti‐HIV activity of substituted 1,2,4‐triazolo‐thiophene derivatives

A new series of substituted 1,2,4‐triazoles bearing thiophene molecules 8 and 10 has been synthesized from cycloaddition of thiophene 3‐and 2‐carbonitriles 5 and 9 , respectively, with the reactive cumulene intermediates 4 . The newly synthesized products have been evaluated for their anti‐HIV activity. © 2007 Wiley Periodicals, Inc. Heteroatom Chem 18:443–448, 2007; Published online in Wiley InterScience ( www.interscience.wiley.com ). DOI 10.1002/hc.20319     

Synthesis and antimicrobial evaluation of new 1‐{[4‐(4‐Halogenophenyl)‐4H‐1,2,4‐ triazol‐3‐yl]sulfanyl}acetyl‐4‐substituted thiosemicarbazides and products of their cyclization

By the reaction of hydrazides of 4‐(4‐halogenophenyl)‐4H‐1,2,4‐triazol‐3‐yl‐sulfanyl acetic acid with isothiocyanate, 1‐acyl‐4‐substituted thiosemicarbazide derivatives ( 7–19 ) were obtained. The cyclization of compounds ( 7–19 ) in the presence of 2% NaOH led to the formation of compounds ( 20–26 ) containing two 1,2,4‐triazole rings connected by a methylenesulfanyl group. The new compounds were tested for their in vitro antimicrobial activity. Some of the tested compounds ( 9, 12, 18, 21, 22 ) showed activity against the reference strains of Gram‐positive bacteria with the MIC (minimal inhibitory concentration) = 125 to >1000 μg/mL. © 2011 Wiley Periodicals, Inc. Heteroatom Chem 23:117–121, 2012; View this article online at wileyonlinelibrary.com . DOI 10.1002/hc.20758     

Simple HPLC‐UV for the quantification of a new leishmanicidal candidate (E)‐1‐4(trifluoromethyl) benzylidene)‐5‐(2‐4‐dichlorozoyl) carbonylhydrazine (LASSBio‐1736) in rat plasma for pharmacokinetics assessment

In this study, a sensitive HPLC‐UV assay was developed and validated for the determination of LASSBio‐1736 in rat plasma with sodium diclofenac as internal standard (IS). Liquid–liquid extraction using acetonitrile was employed to extract LASSBio‐1736 and IS from 100 μL of plasma previously basified with NaOH 0.1 M. Chromatographic separation was carried on Waters Spherisorb^®S5 ODS2 C₁₈ column (150 × 4.6 mm, 5 μm) using an isocratic mobile phase composed by water with triethylamine 0.3% (pH 4), methanol and acetonitrile grade (45:15:40, v/v/v) at a flow rate of 1 mL/min. Both LASSBio‐1736 and IS were eluted at 4.2 and 5 min, respectively, with a total run time of 8 min only. The lower limit of quantification was 0.2 μg/mL and linearity between 0.2 and 4 μg/mL was obtained, with an R² > 0.99. The accuracy of the method was >90.5%. The relative standard deviations intra and interday were <6.19 and <7.83%, respectively. The method showed the sensitivity, linearity, precision, accuracy and selectivity required to quantify LASSBio‐1736 in preclinical pharmacokinetic studies according to the criteria established by the US Food and Drug Administration and European Medicines Agency. Copyright © 2016 John Wiley & Sons, Ltd.     

Design,Synthesis, and Herbicidal Activities of 3‐Aryl‐4‐substituted‐5‐[3‐(trifluoromethyl)phenoxy]‐1,2,4‐triazoles

In order to find novel bleaching herbicide lead compounds, a series of novel 3‐aryl‐4‐substituted‐5‐[3‐(trifluoromethyl)phenoxy]‐1,2,4‐triazoles were designed and synthesized by the multi‐step reactions. N‐(Arylformamido)phenylthioureas undergo ring closure in the presence of sodium hydroxide to generate 3‐aryl‐4‐substituted‐4H‐[1,2,4]triazol‐5‐thiols 1 , which reacted with methyl sulfate in the presence of K₂CO₃ to give 3‐aryl‐5‐methylsulfanyl‐4‐substituted‐4H‐[1,2,4]triazoles 2 . The target compounds 4 were synthesized by the oxidation of 2 in the presence of H₂O₂ and Na₂WO₄, followed by the substitution with 3‐(trifluoromethyl)phenol in moderate to good yields. Their structures were confirmed by IR, ¹H NMR, EI–MS, and elemental analyses. The preliminary bioassay indicated that some of them displayed moderate to good selective herbicidal activity against Brassica campestris L at the concentration of 100 µg/mL. Compounds 4c and 4i possessed 75.0% and 82.6% inhibition against Brassica campestris L at the concentration of 100 µg/mL. However, the target compounds 4 showed weak herbicidal activity against Echinochloa crus‐galli at the concentration of 100 and 10 µg/mL.     

Synthesis and anti‐HIV activity of n‐(3‐amino‐3,4‐dihydro‐4‐oxopyrimidin‐2‐yl)‐4‐chloro‐2‐mercapto‐5‐methylbenzenesulfonamide derivatives

A series of N‐(3‐amino‐3,4‐dihydro‐4‐oxopyrimidin‐2‐yl)‐4‐chloro‐2‐mercapto‐5‐methylbenzenesulfonamide derivatives 10‐17 have been synthesized as potential anti‐HIV agents. The in vitro anti‐HIV‐1 activity of these compounds has been tested at the national Cancer Institute (Bethesda, MD), and the structure‐activity relationships are discussed. The selected N‐[3‐amino‐3,4‐dihydro‐6‐(tert‐butyl)‐4‐oxothieno[2,3‐e]pyrimidin‐2‐yl]‐4‐chloro‐2‐metcapto‐5‐methylbenzenesulfonamide ( 14 ) showed good anti‐HIV‐1 activity with 50% effective concentration (EC₅₀) value of 15 μM and weak cytotoxic effect (IC₅₀ = 106 μM).     

Efficient Synthesis of Novel 3‐Phenyl‐5‐thioxo‐3,4,5,6‐tetrahydroimidazo[4,5‐c]pyrazole‐2(1H)‐carbothioamide Derivatives Using a CeO2–MgO Catalyst and Evaluation of Antimicrobial Activity

Imidazo[4,5‐c ]pyrazole derivatives ( 3a–f , 4a–f , and 5a–f ) were efficiently synthesized by one‐pot three‐component reactions using CeO₂–MgO as the catalyst. The synthesized compounds were characterized by IR, ¹H NMR, ¹³C NMR, and mass spectroscopic analyses. The in vitro antimicrobial activity of the synthesized compounds against various bacterial and fungal strains was screened. Compound 3b was highly active [minimum inhibitory concentration (MIC): 0.5 μg/mL] against Gram‐positive Staphylococcus aureus , and compounds 3b , 3f , 4d , and 4e were highly active (MIC: 0.5, 2, 2, and 0.5 μg/mL, respectively) against Gram‐negative Pseudomonas aeruginosa and Klebsiella pneumoniae , relative to standard ciprofloxacin in the antibacterial activity screening. Compounds 3b and 4f were highly active (MIC: 4 and 0.5 μg/mL, respectively) against Aspergillus fumigatus and Microsporum audouinii in the antifungal activity screening compared with the clotrimazole standard.     

Design,Synthesis and In Vitro Anti‐mycobacterial Activity of Propylene‐1H‐1,2,3‐triazole‐4‐methylene‐tethered Isatin‐moxifloxacin Hybrids

Ten propylene‐1H‐1,2,3‐triazole‐4‐methylene‐tethered isatin‐moxifloxacin hybrids 5a–j were synthesized via Cu‐promoted azide‐alkyne cycloaddition reaction, and screened for their in vitro anti‐mycobacterial activities against Mycobacterium tuberculosis H₃₇Rv and multidrug‐resistant tuberculosis. The results showed that all the synthesized hybrids [minimum inhibitory concentration (MIC): 0.25–4.0 μg/mL] displayed considerable activities against the tested two strains, but all less active than the parent moxifloxacin (MIC: 0.10 and 0.12 μg/mL). The resistance index of the most targets was around 1, suggesting this kind of hybrids could reduce the cross–resistance to some extent. Among them, hybrid 5 g was found most active against Mycobacterium tuberculosis H₃₇Rv with MIC of 0.39 μg/mL, which was comparable with rifampicin (MIC: 0.39 μg/mL), while conjugate 5a (MIC: 0.25 μg/mL) was 128– > 512 times more active than rifampicin (MIC: 32 μg/mL) and isoniazid (MIC: >128 μg/mL) against multidrug‐resistant tuberculosis.     

Synthesis and in vitro antibacterial evaluation of 1‐substituted‐4‐ethoxycarbonylmethylthiosemicarbazides and products of their dehydrocyclization

A series of s‐triazoles and thiohydantoines were synthesized by dehydrocyclization of 1‐substituted‐4‐ethoxycarbonylmethylthiosemicarbazides. The molecular structure proposed for s‐triazoles was confirmed by the X‐ray crystal structure analysis of one compound that was prone to crystallization. All compounds were tested in vitro for their antibacterial activity. Some of them showed low levels of activity against Gram‐positive species, MIC range 100–400 μg/mL or higher. © 2010 Wiley Periodicals, Inc. Heteroatom Chem 21:131–138, 2010; Published online in Wiley InterScience ( www.interscience.wiley.com ). DOI 10.1002/hc.20597     

Study on the Color Reaction of Silver with 2‐(2‐Quinolylazo)‐5‐Dimethylaminoaniline and its Application

A new chromogenic reagent, 2‐(2‐quinolylazo)‐5‐dimethylaminoaniline (QADMAA) was synthesized. A highly sensitive, selective and rapid method for the determination of silver based on the rapid reaction of silver(I) with QADMAA was developed. In the presence of pH = 6.5 sodium citrate‐sodium hydroxide buffer solution and sodium dodecyl sulfonate (SDS) medium, QADMAA reacts with silver to form a violet complex of a molar ratio 1:2 (silver to QADMAA). The molar absorptivity of the complex is 1.26 × 10⁵ L. mol^?1.cm^?1 at 570 nm. Beer's law is obeyed in the range of 0.01–0.6 μg/mL. The relative standard deviation for eleven replicate samples of 0.2 μg/mL silver is 1.76%. This method was applied to the determination of silver in water with good results.     

Chemoselective synthesis of thieno[3,2‐c][1,8]naphthyridin‐4(5H)‐ones by tandem cyclization

A number of the thieno[3,2‐c][1,8]‐naphthyridin‐4(5H)‐ones are chemoselectively synthesized from 4‐(4′‐aryloxybut‐2′‐ynylthio)‐1‐phenyl‐1,8‐naphthyridin‐2(1H)‐ones in 82–90% yield by the formation of sulfoxide, followed by [2,3] and [3,3]sigmatropic rearrangement and an intramolecular Michael addition. © 2007 Wiley Periodicals, Inc. Heteroatom Chem 18:87–92, 2007; Published online in Wiley InterScience ( www.interscience.wiley.com ). DOI 10.1002/hc.20234