Synthesis, molecular modelling and biological evaluation of 4-amino-2(1H)-quinazolinone and 2,4(1H,3H)-quinazolidone derivatives as antitumor agents

A series of 6-benzoyl-, 6-arylthio- and 6-arylsulfonyl-4-amino-2(1H)-quinazolinones and -2,4(1H,3H)-quinazolinediones were prepared. They were evaluated in vitro for their cytotoxicity against the NCI-60 cancer cell lines.     

Synthesis, anti-inflammatory and analgesic activity of some new 4(3H)-quinazolinone derivatives

4(3H)-quinazolinone and pyrazole derivatives have been shown to have analgesic and anti-inflammatory properties. In this study, 14 new 3-methyl-4(3H)quinazolinone derivatives bearing 2-[1'-phenyl-3'-(substituted-phenyl)-2'-propenylidene]hydrazino or 2[5'-(substituted phenyl)-3'-phenyl-2'-pyrazolin-1'-yl] groups have been synthesized with the aim of obtaining new analgesic and anti-inflammatory leads. The structures were elucidated by means of UV, IR, 1H-NMR, 13C-NMR, mass spectroscopy, and elemental analysis data. The anti-inflammatory activities of the synthesized compounds were determined by carrageenan-induced hind paw edema test in mice. All the compounds showed statistically significant effects. For analgesic activity assessment, p-benzoquinone-induced writhing test was applied in mice. The results obtained were in accordance with the anti-inflammatory activity tests.     

Synthesis and anticancer activity of new 2-aryl-4h-3,1-benzothiazines

New compounds of 2-aryl-4H-3,1-benzothiazine set were synthesized and tested for their antiproliferative activity as part of our research in the antitumor field. The title compounds were obtained by the reaction of aryl-modified sulfinylbis((2,4-dihydroxyphenyl)methanethione) with 2-aminobenzyl alcohols. The reaction proceeded through thiobenzanilide intermediates, which were converted to the 4H-3,1-benzothiazine fused ring by an endocyclization process. The structures of compounds were identified from elemental, IR, (1) H-NMR, (13) C-NMR, and MS spectra analyses. The cytotoxicity in vitro against four human cancer cell lines was determined. The antiproliferative properties of some compounds were more beneficial than cisplatin studied comparatively.     

Synthesis and cytotoxicity testing of novel 2-(3-substituted-6-chloro-1,1-dioxo-1,4,2-benzodithiazin-7-yl)-3-phenyl-4(3H)-quinazolinones

A new series of thirteen 2-[3-(substituted amino)-6-chloro-1,1-dioxo-1,4,2-benzodithiazin-7-yl]-3-phenyl-4(3H)-quinazolinones 4-16 were prepared in order to evaluate their cytotoxic activity against 12 human cancer cell lines. The bioassay indicated that the quinazolinone derivatives 5, 8-12, 15, and 16 possess cancer-cell growth-inhibitory properties. Compounds 5 and 12 showed a high level of selectivity for certain cell lines. The most active compounds 9, 10, 15, and 16 showed moderate antiproliferative activity and were approximately 4-fold less potent than cisplatin.     

Synthesis and in-vitro antibacterial activity of 5-substituted 1-methyl-4-nitro-1H-imidazoles

A series of 5-substituted 1-methyl-4-nitro-1H-imidazole derivatives were synthesized and evaluated for in-vitro antibacterial activity against a panel of microorganisms including Staphylococcus aureus, Staphylococcus epidermidis, Bacillus subtilis, Escherichia coli, Klebsiella pneumonia, Enterobacter aerogenes, and Helicobacter pylori using conventional agar dilution method. Among the test compounds, 1-methyl-4-nitro-5-(phenylsulfonyl)-1H-imidazole was the most potent against Gram-positive bacteria, with a MIC value of < or =8 microg/mL. All compounds showed no significant activity against Gram-negative bacteria at concentrations < or =64 microg/mL. The MIC values against 15 clinical isolates of H. pylori indicated that compounds 10 and 11 were the most active compounds in this series in terms of inhibiting the growth of H. pylori (MIC = 2 microg/mL). It was also demonstrated that their corresponding activities were four times larger than that of metronidazole.     

Synthesis and Cytotoxicity Screening of Piperazine‐1‐carbodithioate Derivatives of 2‐Substituted Quinazolin‐4(3H)‐ones

A new series of piperazine‐1‐carbodithioate derivatives of 2‐substituted quinazolin‐4(3H)‐ones were synthesized via a five‐steps procedure starting from 2‐amino‐5‐methylbenzoic acid. The cytotoxicity of the resulting compounds against A‐549 (human lung cancer), HCT‐8 (human colon cancer), HepG2 (human liver cancer), and K562 (human myelogenous leukaemia) cell lines was determined by the MTT assay. Preliminary screening results of these compounds are reported.     

Synthesis and evaluation of anticonvulsant and antimicrobial activities of 3-hydroxy-6-methyl-2-substituted 4h-pyran-4-one derivatives

In this study, thirteen 3-hydroxy-6-methyl-2-substituted 4H-pyran-4-one derivatives were synthesized for the evaluation of their potential anticonvulsant activity. Mannich bases were prepared by the reaction of substituted piperazine derivatives with allomaltol and formaline. The structures of the synthesized compounds were confirmed by IR, (1)H-NMR and elemental analysis. Their anticonvulsant activities were determined in vivo by maximal electroshock (MES), sub-cutaneous Metrazol (scMet), and rotorod toxicity tests for neurological deficits. The antimicrobial activities of the synthesized compounds were investigated in vitro against some bacteria and fungi using the microdilution broth method. Ac-cording to the activity studies, 3-hydroxy-6-methyl-2-[4-(2-trifluoromethyl-phenyl)-piperazin-1-ylmethyl]-4H-pyran-4-one (3i) was the compound determined to be most active in the scMet test for all doses at four hours and for the 300 mg/kg dose at half an hour. 2-[4-(4-Chloro-phenyl)-piperazin-1-ylmethyl]-3-hydroxy-6-methyl-4H-pyran-4-one (3f) was found to be protective against MES whereas 2-chlorophenyl derivative (3e) was not. Looking at the antifungal activity results, compounds 3b, 3h, and 3i were determined to have activity against all fungi.     

Synthesis and in vitro-anticancer and antimicrobial evaluation of some novel quinoxalines derived from 3-phenylquinoxaline-2(1H)-thione

Two novel series derived from 3-phenylquinoxaline-2(1H)-thione 2 and 2-(hydrazinocarbonylmethylthio)-3-phenylquinoxaline 6 have been synthesized. Eight out of twenty six new compounds were selected at the National Cancer Institute for evaluation of their in vitro-anticancer activity. Among them, compounds 3b, 3c, 4b, and 4c displayed moderate to strong growth inhibition activity against most of the tested sub-panel tumor cell lines with GI(50) 10(-5) to 10(-6 )molar concentrations. Compound 4b exhibited a significant value of percent tumor growth inhibition against breast cancer at concentration < 10(-8) M. Compound 4c showed moderate selectivity towards leukemia cell lines with GI(50) of 1.8 to 3.8 microM (selectivity ratio = 5.7). Preliminary antimicrobial testing revealed that compounds 7a, 7b, 8a, 11a, and 11b were as active as ampicillin against B. subtilis (MIC = 12.5 microg/mL). Compounds 7b and 8a were also nearly as active as ampicillin against E. coli (MIC = 12.5 microg/mL). In addition, compounds 4a, 7b, 10b, and 11a were as active as ampicillin against P. aerugenosa (MIC = 50 microg/mL). However, compounds 7b, 8a, and 10b showed mild activity against C. albicans (MIC = 50 microg/mL). The values of minimum bactericidal concentrations indicated that compounds 4a and 7b were bactericidal against B. subtilis and P. aerugenosa, respectively, while compound 10b was bactericidal against both organisms. However, compound 11a was bactericidal against E. coli, P. aerugenosa, and S. aureus.     

2-Amino-3-cyano-4-(5-arylisoxazol-3-yl)-4H-chromenes: synthesis and in vitro cytotoxic activity

A new series of 4-aryl-4H-chromenes bearing a 5-arylisoxazol-3-yl moiety at the C-4 position were prepared as potential anticancer agents. The in vitro cytotoxic activity of the synthesized compounds was investigated against a panel of tumor cell lines including MCF-7 (breast cancer), KB (nasopharyngeal epidermoid carcinoma), Hep-G2 (liver carcinoma), MDA-MB-231 (breast cancer), and SKNMC (human neuroblastoma) using the MTT colorimetric assay. Doxorubicin, a well-known anticancer drug, was used as positive standard drug. Among the synthesized compounds, the 5-(3-methylphenyl)isoxazol-3-yl analog (7j) showed the most potent cytotoxic activity against all five human tumor cell lines.     

Synthesis and evaluation of some novel quinazolinone derivatives as diuretic agents

A new series of quinazolin-4(3H)-one derivatives containing either a thiazole or a 1, 3, 4-thiadiazole moiety were prepared in order to study the effect of such a heterocyclic combination on the expected diuretic activity. Synthesis of the target compounds (2, 4, and 6) has been achieved through an interaction of the starting 7-chloro-2-methyl-4H-3, 1-benzoxazin-4-one 1 with different heterocyclic amines. Alkylation of 3-(2-mercapto-1, 3, 4-thiadiazol-5-yl)quinazolin-4(3H)-one derivative 4 with different alkyl halides or chloroacetic acid afforded the corresponding thioethers 5 while interaction of 2-methyl-3-(1, 3, 4-thiadiazol-5-yl or thiazol-5-yl)quinazolin-4(3H)-ones (2 and 6) with various aromatic aldehydes resulted in the formation of the arylvinyl analogs 3 and 7, respectively. On the other hand, 2-morpholinomethyl-3-(2-sulfamoyl or mercapto-1, 3, 4-thiadiazol-5-yl)quinazolin-4(3H)-one derivatives 10 have also been synthesized through an interaction of the sulfonamide or thiol analog 9 with the appropriate amine. Biological evaluation of some of the target compounds as diuretic agents was carried out. The results showed that 2-[2-(4-chlorophenyl)vinyl]-7-chloro-3-(2-sulfamoyl-1, 3, 4-thiadiazol-5-yl)quinazolin-4(3H)-one 7b exhibited significant diuretic activity. The detailed synthesis, spectroscopic and biological data are reported.     

Synthesis of 2-(4-biphenylyl)quinoline-4-carboxylate and carboxamide analogs. New human neurokinin-3 (hNK-3) receptor antagonists

The 2-phenylquinoline-4-carboxamide 1 (Chart[TH]1) has been found to possess moderate affinity for human neurokinin-3 (hNK-3) receptor. In the present work, and in a trial to investigate the effect of the lipophilic moiety at C-2 of the quinoline ring on the antagonistic activity, an enlargement of the aromatic area at this position was suggested. In this respect, two series of 2-(4-biphenylyl)quinoline-4-carboxylates and carboxamides have been synthesized with certain modifications at the quinoline-2 and 4-position in order to study their effect on the anticipated hNK-3 receptor antagonistic activity. Fifteen compounds were screened for such activity using guinea-pig isolated ileum longitudinal muscle preparation and senktide as selective hNK-3 receptor agonist. Some compounds showed considerable antagonistic effect. Compound 7b, 6-bromo-2-(4-biphenylyl)quinoline-4-carboxylic acid, was the most prominent hNK-3 receptor antagonist in this study. Unexpectedly, some compounds were agonists.     

Synthesis of some 2(3H)-benzoxazolone derivatives and their in-vitro effects on human leukocyte myeloperoxidase activity

Myeloperoxidase (MPO), a heme protein expressed by polymorphonuclear leukocytes, generates potent oxidants which are proposed to contribute to tissue damage during inflammation and certain pathogenesis such as neurodegenerative disorders. In this study, twenty omega-[2-oxo-3H-benzoxazol-3-yl]-N-phenylacetamide and propionamide derivatives having substituents of different lipophilic and electronic nature on the N-phenyl ring were synthesized to evaluate the inhibitory effects on in vitro leukocyte MPO chlorinating activity. The most active compounds in the series were the derivatives bearing 2-methyl and 4-nitro substituent on the N-phenyl ring.     

3-硝基-2H-色烯衍生物的合成及抗菌活性研究

目的设计并合成一系列3-硝基-2H-色烯衍生物,研究其抗菌活性与构效关系。方法以水杨醛和2-硝基乙醇为原料合成目标化合物,采用肉汤稀释法测定抗菌活性。结果目标化合物结构均经过1HNMR和HRMS确证,3-硝基-2H-色烯衍生物对金黄色葡萄球菌、耐甲氧西林金黄色葡萄球菌具有很好的抑制活性(MIC=4μg·mL-1)。结论 3-硝基-2H-色烯衍生物具有进一步深入研究的价值。     

Synthesis and antileukemic activity of new 3-(1-phenyl-3-methylpyrazol-5-yl)-2-styrylquinazolin-4(3H)-ones

3-(1-Phenyl-3-methylpyrazol-5-yl)-2-styrylquinazolin-4(3H)-ones 14a-q and 15a-q were synthesized by refluxing in acetic acid the corresponding 2-methylquinazolinones 12 and 13 with the opportune benzoic aldehyde for 12 h. The synthesized styrylquinazolinones 14a-q and 15a-q were tested in vitro for their antileukemic activity against L1210 (murine leukemia), K562 (human chronic myelogenous leukemia) and HL60 (human leukemia) cell lines showing in some cases good activity.     

4-吗啉喹唑啉类PI3K抑制剂的合成及活性研究

目的寻找具有新型骨架结构的磷脂酰肌醇3激酶(PI3K)抑制剂。方法基于活性化合物,利用"杂交"设计原理,设计和合成了系列4-吗啉喹唑啉类衍生物。结果目标化合物经1HNMR、质谱确证结构,并评价了其对Rh30细胞的增殖抑制活性。结论大部分化合物具有较好的抑制活性,化合物8b的活性最强,其IC50达0.8μmol.L-1。4-吗啉喹唑啉是一类新型的PI3K抑制剂骨架,值得进一步进行结构修饰研究。     

Synthesis and antinociceptive activity of (5-chloro-2(3H)-benzothiazolon-3-yl)propanamide derivatives

Ten new (5-chloro-2(3H)-benzothiazolon-3-yl)propanamide derivatives have been synthesized. The compounds were tested for antinociceptive activity by tail clip, tail flick, hot plate and writhing test by using aspirin and dipyrone as standards. Among these compounds, 1-[3-(5-chloro-2(3H)-benzothiazolon-3-yl)-propanoyl]-4-(4-chlorophenyl)piperazine (11e) has been found to be significantly more active than the other compounds synthesized as well as the standards in all tests.     

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.     

Pyrazolo[3,4‐d]pyrimidine Derivatives as COX‐2 Selective Inhibitors: Synthesis and Molecular Modelling Studies

The pyrazolo[3,4‐d]pyrimidine system shows a multitude of interesting pharmacological properties. Owing to the potential anti‐inflammatory activity of 5‐benzamido‐pyrazolo[3,4‐d]pyrimidin‐4‐one derivatives and considering the easy synthesis of this class of compounds, a set of new 5‐benzamido‐1H‐pyrazolo[3,4‐d]pyrimidin‐4‐ones has been prepared in 42‐80% yields by reacting 5‐aminopyrazole‐4(N‐benzoyl)carbohydrazide derivatives and the opportune triethylorthoesters. Compounds 8a , b , 10a – d , and 11a , b revealed a superior inhibitory profile against COX‐2, when compared to that of reference standards NS398 and indomethacin. Molecular modelling studies confirmed the obtained biological results.