Synthesis, antimicrobial, and alkylating properties of 3-phosphonic derivatives of chromone

Dimethyl 2,6-dimethyl-4-oxo-4H-chromen-3-yl-phosphonate (1a) and dimethyl 6-methyl-2-phenyl-4-oxo-4H-chromen-3-yl-phosphonate (1b) were synthesized and reacted with primary aliphatic amines to yield title compounds 4-6. Their antibacterial properties against Gram-positive and Gram-negative bacteria strains were tested by the MIC method. Four of seventeen tested compounds (1d, 3, 4a, and 4b) exhibit detectable activity against S. aureus. Some representative examples of newly synthesized compounds were tested for their alkylating properties in vitro in the Preussmann test. Compounds 1a, 1c, 1d, 3, 5d, and 6a possess highly alkylating activity toward standard derivative 4-(4'-nitrobenzyl)pyridine (NBP).     

人参二醇衍生物的合成及其细胞毒活性研究

目的 为了获得细胞毒活性更强人参二醇衍生物 方法 利用生物电子等排原理制备3位胺基-人参二醇,再合成人参二醇3位胺基的肉桂酸类、NO供体类衍生物以及其它类型的人参二醇衍生物18个,其中有12个化合物未见文献报道,其结构均经过₁^H NMR, _¹3^C NMR核磁共振、质谱确证。这些化合物中的16个化合物用MTS法对人白血病细胞株HL-60、肝癌细胞株SMMC-7721、肺癌细胞株A-549、乳腺癌细胞株MCF-7、结肠癌细胞株SW480等肿瘤细胞株进行了细胞毒活性评价。结果 药理活性评价结果显示,化合物6c、7以及7j对五株肿瘤细胞均有较强的抑制活性,特别是化合物7对HL-6与SMMC-7721细胞抑制的IC₅₀分别为3.41,4.51 μM,显著优于人参二醇的细胞毒活性。结论 7和7j可以作为先导化合物进行更深入的研究。     

Synthesis,characterization, and antimicrobial activity of some new coumarin derivatives

A number of new [(4-methyl-2-oxo-2H-chromen-7-yl)amino]methylcoumarins (5a–c), benzofuran (6), and benzoxazol (7) were synthesized through the reaction of 7-amino-4-methylcoumarin (1) with a number of organic halides. In addition, series of N-substituted 2-[(4-methyl-2-oxo-2H-chromen-7-yl)oxy]acetohydrazide (11a–h) and (12a–d) were prepared from the reaction of 2-[(4-methyl-2-oxo-2H-chromen-7-yl)oxy]acetohydrazide (8) with corresponding heteroaryl/alkyl halides (2–4, 9, and 10). The synthesized compounds were characterized by elemental analysis and by spectroscopic techniques such as ¹H-NMR, ¹³C-NMR, and mass spectrometry and were tested for their in vitro antimicrobial activity. The newly synthesized compounds exerted significant inhibitory activity against the growth of tested bacterial strains and a few of them are found to be potent antimicrobial agents.     

Synthesis of some new biologically-active coumarin derivatives.

Coumarin and 6-nitrocoumarin hydrazones (2a,b), respectively, were prepared via the reaction of 2-thiocoumarin (1a,b) derivatives with hydrazine hydrate. The hydrazones were used as key intermediates for the preparation of some benzopyrano[2,3-c]pyrazoles (21-24) through the reaction of different acyl halides and subsequent cyclization in N,N-dimethylaniline. Benzopyrano[2,3-c]pyrazole-3-thione (25a,b) was prepared by the reaction of 1a with CS2 on which some alkylation, acylation and Mannich reactions were studied. Alternative procedures, other reactions and biological activity of some new compounds were given.     

Synthesis and cytotoxicity evaluation of novel podophyllotoxin derivatives

Seven benzylamino derivatives of podophyllotoxin 8a–8g were synthesized and their chemical structures were confirmed by IR, ¹H‐NMR, ¹³C‐NMR and ESI‐MS spectral analyses. Their abilities to inhibit the growth of cancer cells A549, HCT‐116 and HepG2, were investigated by MTT assay. Compound 8b possessed the highest cytotoxicity on cancer cell lines with average IC₅₀ values of 3.8 µM. All we synthetic compounds were cytotoxic against three cancer cell lines at the micromolar range, indicating podophyllotoxin derivatives with structural modification of benzylamino possess potent antitumor activity.     

Synthesis and preliminary screening of carbohydrazides and hydrazones of pyrrole derivatives as potential tuberculostatics

Five carbohydrazides and 19 hydrazones of carboxylic acids of pyrrole were synthesized as new structural analogs of known tuberculostatics, such as isoniazid (CAS 54-85-3) and its popular hydrazones. The preliminary screening against Mycobacterium tuberculosis H37Rv (ATCC 27294) at 6.25 microg/mL in 12B medium using a broth microdilution assay, the Microplate Alamar Blue Assay (MABA) registered higher inhibitory activity within the hydrazones series (up to 68 % inhibition) compared with that of the carbohydrazides (0-34 %). No simple relationship between the activity of a particular hydrazone and that of the parent carbohydrazide, or correlations with the structural features introduced by the carbonyl partner could be observed. So both most active hydrazones diethyl 5-(2-[(2,4-dimethyl-1H-3-pyrrolyl)carbonyl]hydrazonomethyl)-3-methyl-1H-2,4-pyrroledicarboxylate (22, 68 % inhibition) and ethyl 5-(4-chlorophenyl)-2-methyl-1-(2-2-1-(5-nitro-2-furyl)methylidene]hydrazino-2-oxoethyl)-1H-3-pyrrolecarboxylate (32, 55 %) originated from inactive carbohydrazides (1, 0 % and 7, 10 % respectively); ethyl 1-(2-2-[1-(3-ethoxy-4-hydroxyphenyl) methylidene] hydrazino-2-oxoethyl)-2-methyl-5-(4-nitrophenyl)-1H-3-pyrrolecarboxylate (30) showed 0 % inhibition, although derived from a hydrazide with 34 % activity. The condensation of six carbohydrazides with the same carbonyl reagent 5-nitrofurfural yielded hydrazones whose activity covered the wide range of 0-55 % inhibition.     

Synthesis and biological investigations of new thiazolidinone and oxadiazoline coumarin derivatives

Ethyl (coumarin-4-oxy)acetate 1 was prepared through the reaction of 4-hydroxycoumarin with ethyl bromoacetate. Compound 1 was allowed to react with hydrazine hydrate to produce coumarin-4-oxyacetic hydrazide 2. The synthesis of N-(arylidene and alkylidene)-coumarin-4-oxyacetic hydrazones 3-20 was performed. The preparation of 2-substituted-3-[(coumarin-4-oxy) acetamido]thiazolidinones 21-26 and 2-[(coumarin-4-oxy)methyl]-4-acetyl-5-substituted-delta2-1,3,4-oxadiazolines 27-33 was performed by the reaction of the hydrazones 3, 4, 7, 9, 12, 14 with mercaptoacetic acid and the hydrazones 3, 4, 5, 7, 12, 15, 16 with acetic anhydride, respectively. The antiviral activities, cytotoxicities and structure-activity relationship (SAR) towards different microorganisms of the prepared compounds were studied.     

Synthesis and antiallergic activity of novel chromone derivatives

Translated from Khimiko-farmatsevticheskii Zhurnal, Vol. 27, No. 1, pp. 41–43, January, 1993.     

Synthesis,cytotoxicity, and antiplasmodial and antitrypanosomal activity of new neocryptolepine derivatives

On the basis of the original lead neocryptolepine or 5-methyl-5H-indolo[2,3-b]quinoline, an alkaloid from Cryptolepis sanguinolenta, derivatives were prepared using a biradical cyclization methodology. Starting from easily accessible educts, this approach allowed the synthesis of hitherto unknown compounds with a varied substitution pattern. As a result of steric hindrance, preferential formation of the 3-substituted isomers over the 1-substituted isomers was observed when cyclizing N-(3-substituted-phenyl)-N'-[2-(2-trimethylsilylethynyl)phenyl]carbodiimides. All compounds were evaluated for their activity against chloroquine-sensitive as well as chloroquine-resistant Plasmodium falciparum strains, for their activity against Trypanosoma brucei and T. cruzi, and for their cytotoxicity on human MRC-5 cells. Mechanisms of action were investigated by testing heme complexation using ESI-MS, inhibition of beta-hematin formation, DNA interactions (DNA-methyl green assay and linear dichroism), and inhibition of human topoisomerase II. Neocryptolepine derivatives with a higher antiplasmodial activity and a lower cytotoxicity than the original lead have been obtained. This selective antiplasmodial activity was associated with inhibition of beta-hematin formation. 2-Bromoneocryptolepine was the most selective compound with an IC(50) value against chloroquine-resistant P. falciparum of 4.0 microM in the absence of cytotoxicity (IC(50) > 32 microM). Although cryptolepine, a known lead for antimalarials also originally isolated from Cryptolepis sanguinolenta, was more active (IC(50) = 2.0 microM), 2-bromoneocryptolepine showed a low affinity for DNA and no inhibition of human topoisomerase II, in contrast to cryptolepine. Although some neocryptolepine derivatives showed a higher antiplasmodial activity than 2-bromocryptolepine, these compounds also showed a higher affinity for DNA and/or a more pronounced cytotoxicity. Therefore, 2-bromoneocryptolepine is considered as the most promising lead from the present work for new antimalarial agents. In addition, 2-bromo-, 2-nitro-, and 2-methoxy-9-cyanoneocryptolepine exhibited antitrypanosomal activity in the micromolar range in the absence of obvious cytotoxicity.     

Synthesis, characterization, and biological evaluation of some N-aryl hydrazones and their 2,3-disubstituted-4-thiazolidinone derivatives

A series of 2,3-disubstituted 4-thiazolidinones 6 and 8a-p have been prepared by the cyclo condensation reaction of various substituted N-aryl hydrazones 5 and 7a–p with mercapto acetic acid. The intermediate N-aryl hydrazones 5 and 7a–p were synthesized by the condensation of 2-bromo-5-methoxy benzohydrazide 4 with 2 or various substituted aromatic aldehydes. The new Naphthalene-2-carboxaldehyde 2 has been synthesized by Vilsmeier-Haack reaction of naphthalen-1(2H)-one 1. The key starting compound 2-bromo-5-methoxy benzohydrazide 4 was prepared from methyl 2-bromo-5-methoxybenzoate 3 by the reaction with hydrazine hydrate in alcoholic medium. The formulae of the compounds were confirmed by elemental analyses and their structures were determined based on IR, ¹H-NMR, ¹³C-NMR, ¹³C-NMR-DEPT, and mass spectral data. The newly synthesized compounds were evaluated for their antioxidant, anti-inflammatory, and analgesic activities. The antibacterial activities of the newly synthesized compounds against E. coli ATCC 8739, S. aureus ATCC 6538, P. aeruginosa ATCC 1539, and Bacillus cereus, while the antifungal activities of the compounds against Candida albicans were tested. The acute cytotoxicity data of compounds 7h and 8a are tested and are found to be nontoxic up to 2,500 mg/kg.     

Synthesis and cytotoxicity evaluation of some 8-hydroxyquinoline derivatives.

Interest in Mannich bases of 8-hydroxyquinoline stems from reports of their high potency against human cancer cells. In the search for potential anticancer drug candidates, Mannich bases of 8-hydroxyquinoline (7-pyrrolidinomethyl-8-hydroxyquinoline, 7-morpholinomethyl-8-hydroxyquinoline, 7-piperidinomethyl-8-hydroxyquinoline and 7-diethylaminomethyl-8-hydroxyquinoline) were synthesised by reaction with various secondary amines and formaldehyde. They were prepared as hydrochlorides. The cytotoxic activity of 7-pyrrolidinomethyl-8-hydroxyquinoline, 7-morpholinomethyl-8-hydroxyquinoline and 7-diethylaminomethyl-8-hydroxyquinoline compounds in the National Cancer Institute in-vitro cancer cell line panel was determined. It was found that they exhibited substantial cytotoxic activity against leukaemia. The log concentration of 7-pyrrolidinomethyl-8-hydroxyquinoline, 7-morpholinomethyl-8-hydroxyquinoline and 7-diethylaminomethyl-8-hydroxyquinoline that inhibited 50% of 60 cell lines' growth were -4.81 M, -5.09 M and -5.35 M, respectively. Compound 7-pyrrolidinomethyl-8-hydroxyquinoline was selected for further in-vivo testing. The electrophysiological effect of 7-pyrrolidinomethyl-8-hydroxyquinoline also was tested in human myeloma cells (RPMI 8226). The outward current was voltage dependent, activating at -40 mV and believed to be the voltage-activated K+ current I(K(V)). 7-Pyrrolidinomethyl-8-hydroxyquinoline (1-30 microM) caused the inhibition of I(K(V)) in a concentration-dependent manner. The IC50 value of 7-pyrrolidinomethyl-8-hydroxyquinoline-induced inhibition of I(K(V)) is 23 microM. The GI50 value of 7-pyrrolidinomethyl-8-hydroxyquinoline-induced inhibition of cell growth is 14 microM. The results suggest that at least part of the cytotoxicity effect of 7-pyrrolidinomethyl-8-hydroxyquinoline on myeloma cells could be related to blockade of voltage-activated K+ channels.     

Synthesis and in vitro cytotoxicity evaluation of novel naphthindolizinedione derivatives

Novel 6,11-dioxo-6,11-dihydro-benzo[f]pyrido[1,2-a]indole-12-carboxamide derivatives and the corresponding 7,10-dihydroxy analogues were designed in accordance with Moore's and Pindur's theory and synthesized based on the structural similarity with known antitumour agents such as ellipticine, daunorubicin, mitoxantrone and 9-aminoacridine-4 carboxamide derivatives. These compounds, including structural variations of the amide side chain, were evaluated in the NCI panel of human tumour cell lines, from which 6,11-dioxo-6,11-dihydro-benzo[f]pyrido[1,2-a]indole-(2-dimethylamino-ethyl)-12-carboxamide 11a was found to be the most potent agent within the series. It showed good selectivity towards leukaemia, colon and renal cancer cell lines, with significant GI50 values, from lower than 10 nM to 0.2 microM. Moreover, its cytotoxicity against the adriamicine-resistant breast tumour cell line at a concentration lower than 1 microM turned out to be higher than the values using the clinical anticancer agents, daunorubicin and mitoxantrone.     

Synthesis, physicochemical characterization, and cytotoxic screening of new zirconium complexes with coumarin derivatives.

Zirconium complexes of mendiaxon, warfarin, coumachlor, and niffcoumar have been synthesized by reaction of the ligands with zirconium chloride in stoichiometric ratio 1:2. The formation of the complexes has been proved on the basis of elemental analysis, IR-spectroscopy, 1H-NMR spectroscopy, and thermal studies. Differential thermal analyses and thermogravimetric analyses have been applied to study the compositions of the new complexes. It is concluded that the lactone- and the keto-carbonyl groups of warfarin, coumachlor, and niffcoumar are bonded to the metal ion as bidentate ligands, but mendiaxon is bonded as monodentate ligand. Cytotoxic screening by MTT-assay was carried out. Among these compounds the zirconium complex of mendiaxon showed highest cytotoxic activity against human promyelocytic leukemic HL-60 cells. The inorganic salt was found to be active against this cell line.     

Synthesis, analgesic and anti-inflammatory evaluation of some new 3H-quinazolin-4-one derivatives

In this study, we have synthesized a series of 3H-quinazolin-4-ones in order to obtain new compounds with potential analgesic and anti-inflammatory activity. The structures of the newly synthesized compounds were confirmed by means of infrared, nuclear magnetic resonance and mass spectroscopy. Some compounds were evaluated for their analgesic and anti-inflammatory activities by writhing and carrageenan-induced rat paw edema tests, respectively. In comparison to the standard drug indomethacine, compounds 4, 6c, 12-14, 16, 18, 19, and 22 induced significant reduction in the writhing response while compounds 6c, 12, 14, 16, 18, and 22 produced a good dose-dependent anti-inflammatory activity. The best dual analgesic / anti-inflammatory relative activity was observed with compounds 6c, 14, 16, 18, and 22.     

Synthesis and evaluation of new oxamniquine derivatives

Oxamniquine derivatives were synthesized and evaluated as novel schistosomicide agents. Oxamniquine (1,2,3,4-tetrahydro-2-[[(1-methylethyl)amino]methyl]-7-nitro-6-quinolinemethanol) was submitted to the Mannich reaction, using formaldehyde, paraformaldehyde and acetaldehyde as reagents, and gave three unexpected products: two of them were cyclized on the alkylamine side chain and another etherified on the aminequinolinemethanol group. The three compounds were biologically evaluated using mice infected with Schistosoma mansoni and showed promising activities, but had higher toxicities. For studies on structure-activity relationships, results demonstrate that the side alkylamine group can be modified with preserved activity, but that this modification is associated with increased toxicity.     

Synthesis and antiinflammatory activity of coumarin derivatives

The synthesis of several coumarin Mannich bases is described. The structures of the synthesized compounds were confirmed by spectral and elemental analysis. Their lipophilicity was determined experimentally by RPTLC method. All compounds were evaluated for their antiinflammatory and antioxidant activity and for their ability to inhibit in vitro lipoxygenase. The derivatives were found to present antioxidant and antiinflammatory activities. The tested derivatives inhibited carraggeenin-induced hind paw edema. They also significantly suppressed the arthritis induced by Freund's adjuvant. Compound 10, the most active in vivo, was found to possess protective properties against adjuvant-induced arthritis in rats. The biological in vitro activities were concentration dependent. Hydrophilicity, the presence of a free 7-OH, and steric requirements for the substituent at position 8 are the most important factors in terms of SAR. An attempt was made to correlate several physicochemical properties of the molecules with their in vivo/in vitro activity.     

3-取代苯基苯并吡喃酮类化合物 的设计合成及抗肿瘤活性

目的 在7-甲氧基或7-羟基苯并吡喃酮的3位引入各种取代苯基,以发现抗肿瘤活性更强的异黄酮类化合物。方法 以丹皮酚和甲酸乙酯为原料,经多步反应制得关键中间体3-碘-7-甲氧基苯并吡喃酮(5),再经Suzuki coupling反应制得目标化合物,通过1H-NMR、MS和IR方法确定目标化合物的结构,部分化合物还进行了13C-NMR测定。选择人结肠癌细胞株HCT116和人肝癌细胞株7721为试验瘤株,以姜黄素和大豆异黄酮为阳性对照测定体外抗肿瘤活性。结果 设计合成的20个新目标化合物均有一定的体外抗肿瘤活性,其中化合物6, 9, 16和19的活性较好,与对照品姜黄素的IC50值相当, 明显优于对照品大豆异黄酮的IC50值。结论 可以通过引入不同的3-取代苯基改变异黄酮类化合物的抗肿瘤活性;在这类化合物的3位苯基上引入甲基、甲氧基或三氟甲基体积较小的基团似乎有利于其抗肿瘤活性。 关键词：化学合成; 苯并吡喃酮; Suzuki coupling偶联反应; 抗肿瘤活性