Nilgün Karalı

Synthesis and primary cytotoxicity evaluation of 3-[[(3-phenyl-4(3H)-quinazolinone-2-yl)mercaptoacetyl]hydrazono]-1H-2-indolinones

New esters (2b and 2c) and hydrazides (3b and 3c) were synthesized from 6-methyl/fluoro-3-phenyl-4(1H, 3H)-quinazolinone-2-thiones (1b and 1c). Subsequent treatment of 3-phenyl-4(3H)-quinazolinone-2-yl)mercaptoacetic acid hydrazides (3a-e) with 1H-indole-2,3-diones (4a-e) furnished the corresponding 3-[[(3-phenyl-4(3H)-quinazolinone-2-yl)mercaptoacetyl]hydrazono]-1H-2-indolinones (5a-u). The structures of new compounds were determined by analytical and spectral (IR, 1H-NMR, (13)C-NMR, EIMS) methods. Previously reported 3-[[(3-phenyl-4(3H)-quinazolinone-2-yl)mercaptoacetyl]hydrazono]-5-bromo-1H-2-indolinone 5v and compounds 5b, 5d and 5o chosen as prototypes were evaluated against the full panel of 60 human tumour cell lines at a minimum of five concentrations at tenfold dilutions in the National Cancer Institute in vitro primary cytotoxicity assay. Sulforhodamine B protein assay was used to estimate cell stability or growth. 3-[[(6-Chloro-3-phenyl-4(3H)-quinazolinone-2-yl)mercaptoacetyl]hydrazono]-5-fluoro-1H-2-indolinone 5o showed the most favourable cytotoxicity against a renal cancer cell line UO-31 (log(10)GI(50) value -6.68). Compound 5v was also tested against human immunodeficiency virus 1 (HIV-1). Compound 5v was confirmed moderately active against HIV-1.

Synthesis and antituberculosis activity of 5-methyl/trifluoromethoxy-1H-indole-2,3-dione 3-thiosemicarbazone derivatives

New series of 5-methyl/trifluoromethoxy-1H-indole-2,3-dione 3-thiosemicarbazones 3a-t, 1-methyl-5-methyl/trifluoromethoxy-1H-indole-2,3-dione 3-thiosemicarbazones 4a-y and 5-trifluoromethoxy-1-morpholinomethyl-1H-indole-2,3-dione 3-thiosemicarbazones 5a-m were synthesized. The structures of the synthesized compounds were confirmed by spectral data and elemental analysis. The new 5-methyl/trifluoromethoxy-1H-indole-2,3-dione derivatives, along with previously synthesized 5-methyl-1H-indole-2,3-dione 3-thiosemicarbazones 6a-l, were evaluated for in vitro antituberculosis activity against Mycobacterium tuberculosis H37Rv. 5-Methyl-1H-indole-2,3-dione 3-thiosemicarbazones (3b, 3d, 3f, 6c, 6d, and 6f), 5-trifluoromethoxy-1H-indole-2,3-dione 3-thiosemicarbazones (3q-s) and 5-trifluoromethoxy-1-morpholinomethyl-1H-indole-2,3-dione 3-thiosemicarbazones (5e and 5j-l) were found to be the most potent inhibitors of M. tuberculosis growth described in this study.

Synthesis and antitubercular activity of 4-(3-coumarinyl)-3-cyclohexyl-4-thiazolin-2-one benzylidenehydrazones

In this study, a new series of 4-(3-coumarinyl)-3-cyclohexyl-4-thiazoline-2-one benzylidene hydrazones (3a-p) were synthesized. Structures of the title compounds were determined by analytical and spectral methods. 3a-p were evaluated for antituberculosis activity against Mycobacterium tuberculosis H37Rv.

New cyclohexylidenehydrazide and 4-aza-1-thiaspiro[4.5]decan-3-one derivatives of 3-phenyl-4(3H)-quinazolinones

Abstract In this study, the synthesis of (3-phenyl-4(3 H )-quinazolinon-2-yl)mercaptoacetic acid cyclohexylidenehydrazides and 4-[(3-phenyl-4(3 H )-quinazolinon-2-yl)mercaptoacetylamino]-4-aza-1-thiaspiro[4.5 ]decan-3-ones and the results of the study on their antifungal activity are reported. Most of the tested compounds were found to be active against Microsporum gypseum NCPF-580, Microsporum canis, Tricophyton mentagrophytes NCPF 375 var. erinacei and Tricophyton rubrum at 25 μg/ml.

Synthesis and primary cytotoxicity evaluation of new 5-bromo-3-substituted-hydrazono-1H-2-indolinones.

In this study a new series of 5‐bromo‐3‐[(3‐substituted‐5‐methyl‐4‐thiazolidinone‐2‐ylidene)‐hydrazono]‐1H‐2‐indolinones (3a—i) and 5‐bromo‐3‐[(2‐thioxo‐3‐substituted‐4, 5‐imidazolidinedione‐1‐yl)imino]‐1H‐2‐indolinones (4a—f) was synthesized by the cyclization of 5‐bromo‐3‐(N‐substituted‐thiosemicarbazono)‐1H‐2‐indolinones (2a—i)with ethyl 2‐bromopropionate in anhydrous ethanolic medium and oxalyl cloride in anhydrous diethyl ether, respectively. Six compounds chosen as prototypes were evaluated in the 3‐cell line, one dose in vitro primary cytotoxicity assay. Four of them were evaluated against the full panel of 60 human tumor cell lines at a minimum of five concentrations at 10‐fold dilutions. Among the compounds tested, the 4‐fluoro‐phenylthiosemicarbazone derivative 2f showed the most favorable cytotoxicity. This compound demonstrated the most marked effects on a breast cancer cell line (BT‐549, log10GI50 value —6.40), a non small cell lung cancer cell line (NCI‐H23, log10GI50 value —6.10), and an ovarian cancer cell line (IGROV1, log10GI50 value —6.02).

Synthesis and pharmacology of new dithiocarbamic acid esters derived from phenothiazine and diphenylamine

2‐Methylthio‐10‐[(N,N‐disubstituted‐thiocarbamoylthio)acetyl]‐phenothiazines (4a—g) and N‐(3‐methylthiophenyl)‐N‐[(N,N‐disubstituted‐ thiocarbamoylthio)acetyl]phenylamines (5a—g) were synthesized by subsequent treatment of 2‐methylthio‐10‐chloroacetylphenothiazines (1) and N‐(3‐methylthiophenyl)‐N‐chloroacetylphenylamine (2) with potas sium salts of N,N‐disubstituted dithiocarbamic acid derivatives (3a—i). The structures of the compounds were determined by analytical and spectral (IR, 1H NMR, 13C NMR, EIMS) methods. The antihistaminic and anticholinergic activities of 4a, 4c, 4e g, 5a c, 5e, and 5g were evaluated in comparison with H1‐receptor antagonist mepyramine and nonselective cholinergic antagonist atropine. In the first series of experiments, the cumulative concentration‐response curves to histamine (10‐8‐10‐4M) and acetylcholine (10‐8‐10‐4M) were constructed in seperate fundus strips. The test compounds exhibited marked antihistaminic activity at 10‐6M concentration but compounds did not influence acetylcholine induced contractions. Concentration‐related experiments carried out on 4g and 5g revealed that a moderate antihistaminic activity was present at 10‐7M concentration of the compounds and became strong at higher concentrations. In the second series of experiments, the cumulative concentration‐response curve to histamine (10‐9‐10‐4M) was constructed in guinea‐pig ileum segments. Maximal responses were obtained by 10‐6‐3×10‐6M concentrations of histamine in ileum segments. Similar inhibitions of histamine contractions were also obtained with the test compounds. Their inhibitory effectiveness was evaluated by comparing the pA2 values.

Synthesis and Preliminary CNS Depressant Activity Evaluation of New 3-[(3-Substituted-5-methyl-4-thiazolidinon-2-ylidene)hydrazono]-1H-2-indolinones and 3-[(2-Thioxo-3-substituted-4,5-imidazolidine-dion-1-yl)imino] - 1H-2-indolinones

A series of (+) 3‐[(3‐substituted‐5‐methyl‐4‐thiazolidinon‐2‐ylidene)hydrazono]‐1H‐2‐indolinones (2a–h) and 3‐[(2‐thioxo‐3‐substituted‐4,5‐imidazolidinedion‐1‐yl)imino]‐1H‐2‐indolinones (3a–g) were synthesized by the cyclization of 3‐(4‐substituted‐thiosemicarbazono)‐1H‐2‐indolinones (1a–h) with ethyl 2‐bromopropionate in anhydrous ethanolic medium and oxalyl chloride in anhydrous diethyl ether, respectively. The structures of 2 and 3 were confirmed by analytical and spectral data (IR, 1H NMR, 13C NMR, and EIMS). The configuration of 3 was assigned on the basis of 1H NMR and 13C NMR data. 2c, 2d, 2g, 2h, and 3a–g were evaluated for anticonvulsant activity against maximal electroshock (MES) and subcutaneous pentylenetetrazol (ScMet) induced seizures. Among the compounds tested, only 2d exhibited some activity in anticonvulsant identification (Phase I) trials in mice. 2a, 2b, 2d, 2g, 2h, and 3a–g were additionally tested for potentiating effects on pentobarbital induced hypnosis in mice. All of the test compounds increased the sleeping time of pentobarbital significantly (p < 0.05) and the most potent compound was found to be 3a.

Synthesis and chemotherapeutic activities of 5-chloro-1H-indole-2,3-dione 3-thiosemicarbazones

A series of 5-chloro-1H-indole-2,3-dione 3-thiosemicarbazones 3a-g were syn- thesized to investigate the chemotherapeutic activities. The structures of 3a-g were con- firmed by the spectral data (IR, 1H NMR, 13C NMR-APT, 13C NMR-DEPT, HSQC, HMBC) and elemental analysis. Anticancer activities of the compounds were evaluated using cell kinetic parameters on HeLa cells derived from human cervix carcinoma. The preliminary screening results indicated that alkyl substituted compounds 3a, 3b and 3d were more effective in mi- tosis phase when compared to the synthesis phase. 3a-g were tested against some DNA and RNA viruses in CRFK, HeLa, HEL, MDCK and Vero cells. None of the compounds was active against any of the RNA or DNA viruses at 100 μM. All compounds were also evaluated for antimicrobial activity against selected strains. Methyl substituted 3a and allyl substituted 3c were found to be active against S. aureus and C. albicans.

Simultaneous determination of medazepam and hyoscine butylbromide in tablets by second-derivative ultraviolet spectrometry

Abstract A second-derivative UV spectrophotometric method for the simultaneous determination of medazepam and hyoscine butylbromide in sugar-coated tablets without prior separation is described. In the derivative spectrophotometric determination of these drugs, calibration graphs were obtained by plotting peak-trough amplitudes at 252.6 and 264.8 run versus concentration of medazepam and zero-crossing amplitude at 212.5 nm versus concentration of hyoscine butylbromide. The relative standard deviation of the method was found to be ±0.56% for medazepam and ±0.08% for hyoscine butylbromide. This method has been successfully applied to tablets containing medazepam and hyoscine butylbromide.

Novel sulfonamide-containing 2-indolinones that selectively inhibit tumor-associated alpha carbonic anhydrases

Human carbonic anhydrases IX and XII are upregulated in many tumors and form a novel target for new generation anticancer drugs. Here we report the synthesis of novel 2-indolinone derivatives with the sulfonamide group as a zinc binding moiety. Enzyme inhibition assays confirmed that the compounds showed selectivity against hCA IX and XII over the widely distributed off-targets hCA I and II. Molecular modelling studies were performed to suggest modes of binding for these compounds.