Synthesis and biological evaluation of -n[4-(2-trans-[([2,6-diamino-4(3H)-oxopyrimidin-5-yl]methyl)thio]cyclobutyl)benzoyl] -l-glutamic acid a novel 5-thiapyrimidinone inhibitor of dihydrofolate reductase

The synthesis and biological evaluation of N-[4-(2-trans-[([2,6-diamino-4(3H)-oxopyrimidin-5-yl]methyl)thio]cyclobutyl)benzoyl]-L-glutamic acid (1) is reported. Compound 1 is a potent dihydrofolate reductase (DHFR) inhibitor (K_j = 12 nM) with excellent in vitro cell culture growth inhibition (L1210, IC₅₀ = 29 nM). Protection experiments showed that the cell growth inhibitory activity was due to DHFR inhibition. The key step in the synthesis was the coupling of a cyclobutylmethylthiol with the 5-bromo-2,6-diamino-4-oxopyrimidine ⁸.     

Synthesis of Some Novel 5-(Arylidene)-2-imino-3(pyridin-2-yl)thiazolidin-4-one Derivatives

Treatment of 2-aminopyridine ( 1 ) with chloroacetyl chloride in dry benzene gave 2-chloro-N-(pyridin-2-yl)acetamide ( 3 ), which on further reaction with potassium thiocyanate gave 2-imino-3-(pyridin-2-yl)thiazolidin-4-one ( 4 ) as an intermediate compound for the synthesis of pyridin-2-yl substituted 2-imino-thiazolidine-4-one derivatives. Cyclocondensation reaction of ( 4 ) with a series of aromatic aldehydes gave 5-arylidene derivatives of pyridin-2-yl substituted 2-imino-thiazolidine-4-ones 5a–j . ¹ H and ¹³C NMR spectroscopy, as well as elemental analyses, were used for the identification of these new compounds.     

DABCO mediated one pot synthesis of 2-(3-benzyl-2, 6-dioxo-3, 6-dihydropyrimidin-1[2H]-yl)-N-(4-(1, 3-dioxo-1H-benzo [de]isoquinolin-2[3H]-yl) aryl) acetamides as antimicrobial agents

We report herein DABCO mediated one pot synthesis of 2-(3-benzyl-2, 6-dioxo-3,6-dihydropyrimidin-1[2H]-yl)-N-(4-(1,3-dioxo-1H-benzo[de]isoquinolin-2[3H]-yl) aryl) acetamides ( 4a-j ). The silent features of this new one pot synthesis include the shorter reaction time, high yields, simple workup, and simultaneous formation of N-Amide and N-benzyl bonds in the one pot. The newly synthesized compounds ( 4a-j ) were characterized by different spectral techniques such as IR, ¹H-NMR, ¹³C-NMR, HRMS. All the synthesized compounds were evaluated for their anti-bacterial and anti-fungal activities. The anti-bacterial activities results reveal that the compounds 4a , 4g , 4i , and 4j are most active against S. aureus. In the case of B. subtilis the compounds 4a , 4i , and 4j are found to be most active. The compounds 4c , 4e , 4i , and 4j are most active against E. coli. In the case of P. aeruginosa 4a , 4i & 4j are found to be more active. On the other hand, the anti-fungal activity result shows that the compounds 4d , 4f , 4i , and 4j are more active against A. niger. The compounds 4a , 4d , 4i , and 4j are found to be more active against C. albicans.     

Design,synthesis and antibacterial activity evaluation of novel 2-(4-((1-aryl-1H-1,2,3-triazol-4-yl)methoxy)phenyl)2-(2-oxoazetidin-1-yl)acetamide derivatives

In this paper, a novel series of 2-(4-((1-aryl-1H-1,2,3-triazol-4-yl)methoxy)phenyl)2-(2-oxoazetidin-1-yl)acetamide derivatives are synthesized in two steps. The first step involved Ugi multicomponent reaction of β-alanine, o-(propargyl)benzaldehyde and isocyanide derivatives. The product of this step, underwent a click 1,3-dipolar cycloaddition reaction with benzyl azide derivatives. The 2-(4-((1-aryl-1H-1,2,3-triazol-4-yl)methoxy)phenyl)2-(2-oxoazetidin-1-yl)acetamide product was characterized and their antibacterial activities were evaluated against various G-positive (Staphylococcus aureus and Bacillus subtilis) and G-negative (Pseudomonas aeruginosa and Escherichia coli) bacteria, using minimal inhibition concentration. The compounds showed very good antimicrobial activity and a number of products have been more active than ciprofloxacin.     

Synthesis and insecticidal activities of O,O-dialkyl-2-[3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carbonyloxy] (aryl) methylphosphonates

A series of novel O,O-Dialkyl-2-[3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carbonyloxy](aryl) methy-lphosphonates I-1–14 were designed and synthesized. The structures of all the title compounds were confirmed by ¹H-NMR, ¹³C-NMR, ³¹P-NMR, IR and elemental analysis. Their insecticidal activities against Mythimna separata and Plutella xylostella were evaluated. The results of bioassays indicated that the title compounds exhibited 20–80% larvicidal activity against Mythimna separata at 1000 mg/L.     

Synthesis and Antimicrobial Activities of Novel Series of 1-((4-Methyl-2-Substituted Thiazol-5-yl)Methyleneam INO)-2-Substituted Isothiourea Derivatives

A novel series of 1-((4-methyl-2-substituted thiazol-5-yl)methyleneamino)-2-substituted isothiourea derivatives was synthesized by alkylation of (Z/E)-1-((4-methyl-2-substituted thiazol-5-yl)methylene)thiosemicarbazide with alkylhalide in acetone. All the newly synthesized compounds were characterized by spectral (IR, ¹H NMR, ¹³C NMR, and mass spectrometry) methods. The newly synthesized compounds were screened for in vitro antimicrobial activity. Most of the compounds show moderate to excellent antimicrobial activity.

[Supplementary materials are available for this article. Go to the publisher's online edition of Phosphorus, Sulfer, and Silicon and the Related Elements for the following free supplemental files: Additional figures and tables.]     

超声法合成新型3-(5-氯/苯氧基-3-甲基-1-苯基-4-吡唑基)异噁唑N-取代苯基去甲去氢斑蝥酰亚胺衍生物

去甲去氢斑蝥素与取代芳胺反应得到了一系列N-取代苯基去甲去氢斑蝥酰亚胺, 再与5-氯/苯氧基-4-(α-氯-α-肟基甲基)-3-甲基-1-苯基吡唑甲酰基氯代肟发生1,3-偶极环加成反应生成一系列未见报道的3-(5-氯/苯氧基-3-甲基-1-苯基-4-吡唑基)异噁唑N-取代苯基去甲去氢斑蝥酰亚胺衍生物. 所合成化合物经元素分析, IR, ¹H NMR, ¹H-¹HCOSY, NOESY确证结构.     

Design,synthesis and biological evaluation of novel N1,N8-bis(((4-((5-aryl-1,3,4-oxadiazol-2-yl)methoxy)phenyl)amino)oxy)-1-naphthamide derivatives

A new series of 1,8-bis(4-((5-phenyl-1,3,4-oxadiazol-2-yl) methoxy)-substituted aryl) naphthalene-1,8-dicarboxamide derivatives (6a–j) were synthesized in the presence of POCl₃ and obtained good yields. All the synthesized novel compounds were characterized by IR, ¹H NMR, ¹³C NMR, HRMS spectroscopic data and elemental analysis. All the synthesized compounds evaluated for their antibacterial and antifungal activities. The antibacterial activity screened against Gram-positive bacteria Staphylococcus aureus and Gram-negative bacteria Escherichia coli and used standard reference drug ciprofloxacin. The antifungal activity screened against two pathogenic fungal strains Aspergillus niger and Candida albicans used a reference standard drug Voriconazole. All these compounds (6a–j) demonstrate good antibacterial and antifungal activity. Among them, compounds 6h and 6c show highest antibacterial and antifungal activity.     

Synthesis,studies and in vitro antibacterial activity of some 5-(thiophene-2-yl)-phenyl pyrazoline derivatives

In the present investigation, a novel series of pyrazolines 2a–2d were synthesized by the cyclization of various -1-[2-(alkoxy) phenyl]-3-(thiophen-2-yl) prop-2-en-1-one 1a–1d with N-substituted phenyl hydrazine and thiosemicarbazide in the presence of CH₃COOH and NaOH in ethanol which lead to the formation of new pyrazolines. The structures of these compounds were elucidated by, IR, ¹H-NMR, ¹³C-NMR, ESI-MS spectral data and their purities were confirmed by elemental analyes. The in vitro antibacterial activity of these compounds was evaluated against two Gram-positive and two Gram-negative bacteria Aeromonas hydrophila, Yersinia enterocolitica, Listeria monocytogenes, and Staphylococcus aureus by microdilution method and then the minimum inhibitory concentration (MIC) of these compounds was determined. The results showed that compounds 1-[2-(benzyloxy) phenyl]-5-(thiophen-2-yl)-1-phenyl-4,5-dihydro-1H-pyrazol-4-yl (2b) and 1-[2-(naphthalen-2-ylmethoxy) phenyl]-5-(thiophene-2-yl)-1-phenyl-4,5-dihydro-1H-pyrazole-4-yl (2d) showed most promising antibacterial activity as compared to the antibiotics gentamicin and tetracycline in (Table 1, Table 2).     

Palladium complex of 6-(2-hydroxy-5-methylphenyl)-3-(pyridin-2-yl)-1,2,4-triazin-5(2<Emphasis Type="Italic">H</Emphasis>)-one: Synthesis,structure, and catalytic activity

Palladium(II) complex with 6-(2-hydroxy-5-methylphenyl)-3-(pyridin-2-yl)-1,2,4-triazin-5(2H)-one was synthesized for the first time. The ligand was prepared from 3-(pyridin-2-yl)-1,2,4-triazin-5(2H)-one and 4-methylphenol via nucleophilic substitution of hydrogen (S_N^H reaction). The complex was readily soluble in basic medium, and it effectively catalyzed Mizoroki-Heck reaction.     

Synthesis and characterization of novel 2-(1-benzyl-3-[4-fluorophenyl]-1H-pyrazol-4-yl)-7-fluoro-4H-chromen-4-one derivatives

Novel 1-benzyl-3-(4-fluorophenyl)-1H-pyrazole-4-carbaldehydes 3a to 3e were synthesized via Vilsmeier-Haack reaction of the appropriate 1-benzyl-2-(1-(4-fluorophenyl)ethylidene)hydrazines, derived from 4-fluoroacetophenone 1 with substituted 2-benzylhydrazines 2a to 2e . The base catalyzed condensation of 1-benzyl-3-(4-fluorophenyl)-1H-pyrazole-4-carbaldehydes 3a to 3e with 1-(4-fluoro-2-hydroxyphenyl)ethanone 4 gave (E)-3-(1-benzyl-3-(4-fluorophenyl)-1H-pyrazol-4-yl)-1-(4-fluoro-2-hydroxyphenyl)prop-2-en-1-ones 5a to 5e . On cyclization with dimethyl sulfoxide (DMSO)/I₂, compounds 5a to 5e gave 2-(1-benzyl-3-(4-fluorophenyl)-1H-pyrazol-4-yl)-7-fluoro-4H-chromen-4-ones 6a to 6e . Structures of all novel compounds were confirmed by infrared (IR), proton nuclear magnetic resonance (¹H NMR), carbon nuclear magnetic resonance (¹³C NMR), and mass spectral data. All the synthesized compounds were screened for their antibacterial activities.     

Synthesis and characterization of diorganotin(IV) complexes of tridentate Schiff bases: crystal structure of [N-(3-hydroxypyridine-2-yl)-5-chlorosalicylideneiminato]dimethyltin(IV)

Some five-coordinated dimethyltin(IV) complexes of the type Me₂SnL (where L is the anion of a bifunctional tridentate Schiff base) were synthesized. These Schiff bases are N-(3-hydroxypyridine-2-yl)-3-methoxysalicylideneimine, HOC₆H₃OCH₃CH=NC₅H₃NOH (1), N-(3-hydroxypyridine-2-yl)-3-ethoxysalicylideneimine, HOC₆H₃OC₂H₅CH=NC₅H₃NOH (2), N-(3-hydroxypyridine-2-yl)-5-chlorosalicylideneimine, HOC₆H₃ClCH=NC₅H₃NOH (3), and N-(3-hydroxypyridine-2-yl)-3-methoxy-5-bromosalicylideneimine, HOC₆H₂OCH₃BrCH=NC₅H₃NOH (4). Dimethyltin(IV) complex of 3 (3a) was characterized by single crystal X-ray diffraction method and a coordination geometry that is nearly halfway between trigonal–bipyramidal and square pyramidal arrangement was found. Dimethyltin complexes of (1), (2), and (4) were also prepared and characterized by the comparison of their elemental analysis and ¹H-NMR-, IR-, UV- and mass spectral data with those of (3a). For example, in the ¹H-NMR spectra, the ²J(¹¹⁹Sn-¹H) in the Sn-CH₃ moiety have values between 80 Hz and 90 Hz, typical of five-coordinated tin species. By using these values in Lockart’s Equations, H₃C–Sn–CH₃ angles in the complexes were estimated to lie between 130° and 145°. X-ray diffraction value for 3a, confirms this estimate within 3.4% relative deviation (129.7° exp. Vs. 134.9° estimate).     

Design,synthesis and evaluation of 2-(4-(substituted benzoyl)-1,4-diazepan-1-yl)-N-phenylacetamide derivatives as a new class of falcipain-2 inhibitors

The cysteine protease, falcipain-2 is an important drug target in human malaria parasite Plasmodium falciparum. A new series of 2-(4-(substituted benzoyl)-1,4-diazepan-1-yl)-N-phenylacetamide derivatives 5(a–t) were designed as per pharmacophoric requirements of falcipain-2 inhibitors using ligand-based approach. The target compounds were synthesized from the key intermediate, 2-(1,4-Diazepan-1-yl)-N-phenylacetamide, by coupling it with appropriate carboxylic acids using carbodiimide chemistry. Structural features of target compounds were characterized by spectral data (¹H NMR, and mass) and elemental analyses. The purity of the final compounds was confirmed by HPLC. The compounds were tested for their in vitro falcipain-2 inhibitor activity on recombinant falcipain-2 enzyme. Five compounds 5b, 5g, 5h, 5j, 5k showed good inhibitory activity (>60%), against falcipain-2 at 10 μM concentration, and fifteen compounds showed weak to moderate inhibitor activity. Compound 5g, the most potent compound from this series showed 72% inhibition at 10 μM concentrations.     

Novel one-pot multicomponent synthesis of (E)-2-(benzylideneamino)-5-mercapto-4H-1,2,4-triazol-3-yl)-2,3-dihydrophthalazine-1,4-dione derivatives

Abstract

An expeditious, one-pot multicomponent reaction has been developed for the synthesis of (E)-2-(benzylideneamino)-5-mercapto-4H-1,2,4-triazol-3-yl)-2,3-dihydrophthalazine-1,4-dione derivatives. Condensation of 4-amino-5-hydrazino-4H-1,2,4-triazole-3-thiol with phthalic anhydride and aromatic aldehyde afforded the (E)-2-(benzylideneamino)-5-mercapto-4H-1,2,4-triazol-3-yl)-2,3-dihydrophthalazine-1,4-diones in acetic acid medium with excellent yields. All the synthesized compounds were characterized by their analytical and spectral data.     

Synthesis and antimicrobial activity of 2-(4-(benzo[d]thiazol-5-ylsulfonyl)piperazine-1-yl)-N-substituted acetamide derivatives

A new series of 2-(4-(benzo[d]thiazol-5-ylsulfonyl)piperazin-1-yl)-N-substituted acetamide (5a-5k) compounds have been synthesized, and these compounds were characterized with spectral data like IR, NMR, and Mass spectroscopy. All compounds were evaluated in vitro for their efficacy as antimicrobial against Gram-positive and Gram-negative pathogenic bacterial strains such as Staphylococcus aureus, Bacillus subtilis, Escherichia coli and Pseudomonas aeruginosa using ciprofloxacin as a standard and fungal strains like Candida albicans and Aspergillus fumigatus as compared with standard drug Clotrimazole, and Molecular docking study shows that all these compounds were having good to excellent correlation binding energy as compared with binding energy of standard drugs.     

4-(色酮-3-基)-3-乙氧羰基-1,4,5,6,7,8-六氢-5-氧代-2,7,7-三甲基喹啉的一步合成

报道了用3-甲酰基色酮、5,5-二甲基-1,3-环己二酮、乙酰乙酸乙酯与醋酸铵一步法合成4-(色酮-3-基)-3-乙氧羰基-1,4,5,6,7,8-六氢-5-氧代-2,7,7-三甲基喹啉类化合物, 对其结构进行了表征, 并分析了代表性化合物2f的晶体结构. 2f晶体属于单斜晶系, P2/c空间群, 所得晶胞参数为: a＝2.0255(4) nm, b＝0.9132(2) nm, c＝1.4066(3) nm, β＝121.60(3)°, V＝2.2159(8) nm³, Z＝4, D_c＝1.335 g/cm³, μ＝0.209 mm^－1, F(000)＝736, R₁＝0.0556, wR₂＝0.1248.     

N-烷基/芳基-N'-(4-芳基噻唑-2-基)-N"-糖基胍的合成及生物活性研究

2,3,4,6-四-O-乙酰基-β-D-吡喃葡萄糖基异硫氰酸酯(1)与2-氨基-4-取代苯基噻唑(2a～2b)反应, 生成糖基硫脲衍生物3a～3b, 再在伯胺存在下经氯化汞脱硫, 得到一系列新的N-烷基/芳基-N'-(4-芳基噻唑-2-基)-N"-糖基胍类化合物(4a～4e, 5a～5e). 所有新化合物的结构均经IR, ¹H NMR, MS谱和元素分析证实, 所得产物均为β-构型. 生物活性测试结果表明, 化合物4b和5d对HIV-1 PR表现出了较高的抑制活性.     

Synthesis and biological evaluation of novel 2-(substituted isoxazol-4-yl)-5-arylamino-1,3,4-oxadiazoles

A series of 2-(5-methyl-3-(4-chloro/trifluoromethylphenyl)isoxazol-4-yl)-5-arylamino-1,3,4-oxadiazoles were synthesized from 4-chloro/trifluoromethyl benzaldehyde, ethyl acetoacetate, hydroxylamine hydrochloride, hydrazine hydrate, and aryl isocyanate by multi-step reactions. The structures of the target compounds were elucidated by IR, ¹H NMR, MS, and elemental analysis. All these compounds were tested for in vitro antifungal activities against Botrytis cinerea and Rhizoctonia cerealis by the mycelium growth rate method, and the results indicated that some compounds displayed high antifungal activity against Botrytis cinerea.     

Synthesis of 4-(pyrazol-5-yl)-1,2,4-triazole-3-thiones

Condensation of pyrazolyl isothiocyanates 2 with N-substituted hydrazines provided the 2-methyl/phenyl-4-(pyrazol-5-yl)thiosemicarbazides 3 . Cyclization of 3 with formic acid-acetic anhydride or with triethyl orthoacetate-acetic anhydride provided 4-(pyrazol-5-yl)-l,2,4-triazole-3-thiones 4a-f and 5-methyl-4-(pyrazol-5-yl)-1,2,4-triazole-3-thiones 4g-I respectively.     

Synthesis and antimycobacterial screening of new 4-(4-(1-benzyl-1H-1,2,3-triazol-4-yl)-1-phenyl-1H-pyrazol-3-yl)quinoline derivatives

A new series of 4-(4-(1-benzyl-1H-1,2,3-triazol-4-yl)-1-phenyl-1H-pyrazol-3-yl)quinoline ( 6a-t ) have been synthesized by a click reaction of 4-(4-ethynyl-1-phenyl-1H-pyrazol-3-yl)quinoline ( 4a-d ) with a substituted benzyl azide ( 5a-e ). The starting alkyne derivatives 4a-d are obtained from Bestmann-Ohira reaction of 1-phenyl-3-(quinolin-4-yl)-1H-pyrazole-4-carbaldehyde and dimethyl(1-diazo-2-oxopropyl)phosphonate. The newly synthesized compounds are screened against M. tuberculosis H37Ra dormant and active, Escherichia coli, Pseudomonas fluorescence, Staphylococcus aureus and Bacillus subtilis strains at 30 μg/mL concentration. Most of the screened compounds showed good to moderate antibacterial activity against S. aureus, B. subtilis, and Mycobacterium tuberculosis H37Ra strains. The synthesized derivatives of quinolinyl-pyrazole-4-carbaldehyde and quinolinyl-pyrazole-4-ethyne reportd good to moderate activity against both strains of M. tuberculosis H37Ra. Ten derivatives of quinolinyl-pyrazole presented good activity against B. subtilis. These results suggested that further optimization and development of quinolinyl-pyrazolyl-1,2,3-triazole moeity could serve as lead compounds for antimycobacterial activity.