key: cord-0272071-30mmrahj
authors: Kadi, Adnan A.
title: RETRACTED: Synthesis and antimicrobial activity of some new quinazolin-4(3H)-one derivatives
date: 2011-04-30
journal: Journal of Saudi Chemical Society
DOI: 10.1016/j.jscs.2010.06.001
sha: 9d7171c5fcefe70f33f8d20df7940be000c86e29
doc_id: 272071
cord_uid: 30mmrahj

This article has been retracted: please see Elsevier Policy on Article Withdrawal (http://www.elsevier.com/locate/withdrawalpolicy). This article has been retracted at the request of the Editor-in-Chief because the author has plagiarized in its entirety an article that has already been published in 2008 by Ahmed M. Alafeefy [Pharmaceutical Biology, 2008 Vol. 46 Issue 10–11, pp. 751–756, http://dx.doi.org/10.1080/13880200802315907]. The author was contacted through the Scientific Council of the King Saud University and Saudi Chemical Society and it was decided by the council to withdraw the article due to duplication of content. This article represents a severe abuse of the scientific publishing system. The scientific community takes a very strong view on this matter and apologies are offered to readers of the journal that this was not detected during the submission process.

The number of life-threatening infectious diseases caused by multidrug-resistant bacteria has reached an alarming level in many countries around the world. Recently, the Severe Acute Respiratory Syndrome (SARS) caused by the novel coronavirus SARS-CoV (Chang et al., 2007; Yeung and Meanwell, 2007) and bird flu caused by avian influenza (H5N1) virus (Gary and Ting, 2007) have emerged as two important infectious diseases with pandemic potential. Both infections crossed the species barrier to infect humans. Also, the ever growing demand for material protection from microbial contamination is a serious challenge (Berber et al., 2003) . The aforementioned facts are a cause of great concern and create a pressing need for new antibacterial agents.

Despite great effort from the pharmaceutical industry to manage the resistance problem, the discovery and development of new mechanistic classes of antibiotics has found with very little success (Taun et al., 2007) . The difficulty of this task is demonstrated by the fact that only two antibiotics of new classes, linezolid (an oxazolidinone) and daptomycin (a cyclic lipopeptide), have been successfully developed in the past three decades (Carpenter and Champers, 2004; Grunder et al., 2006; Weigelt et al., 2005) .

Quinazoline derivatives represent one of the most active classes of compounds possessing a wide spectrum of biological activity (Apfel et al., 2001) . They are widely used in pharmaceuticals and agrochemicals (Tobe et al., 2003) ; for example, fluquinconazole fungicide for the control of agriculture diseases (Guang-Fang et al., 2007) . Several reports have been published on the biological activity of quinazoline derivatives, including their bactiricidal, herbal and anti-tumor activity (Jiang et al., 1990; Gursoy and Ilhan, 1995; Raffa et al., 1999; Chenard et al., 2001) . Thus, their synthesis has been of great interest in the elaboration of biologically active heterocyclic compounds.

Recently, it was reported that some iodoquinazolines exhibited moderate antibacterial activity (Alafeefy, 2008) . Prompted by these findings, this article reports the design and synthesis of an extension series of 3-substituted 2-phenylquinazolin-4(3H)-one derivatives and tested their antibacterial activities.

All melting points (°C, uncorrected) were determined in open capillaries on a Gallenkamp melting point apparatus (Sanyo Gallenkamp, Southborough, UK). IR spectra (KBr, v max: cm À1 ) were recorded on a Perkin-Elmer spectrophotometer (577 model; Perkin-Elmer, Rotkreuz, Switzerland). NMR spectra were recorded on Bruker AC-300 Ultra Shield NMR spectrometer (Bruker, Flawil, Switzerland; dppm) at 300 MHz for 1 H and 75 MHz for 13 C, using TMS as internal standard, and peak multiplicities are designated as follows: s, singlet; d, doublet; t, triplet; q, quartet; br s, broad singlet; m, multiplet. Mass spectra were recorded on a Jeol D-300 (EI/CI) spectrometer (Jeol, Tokyo, Japan). Elemental analyses were performed on a Carlo Erba 1108 Elemental Analyzer (Heraeus, Hanau, Germany) and were less than 0.4% of theoretical values.

To a vigorously stirred solution of 3-amino-2-phenylquinazolin-4(3H)-one (1, 4.74 g, 0.02 mol) in dimethylsulfoxide (10 mL) at room temperature, carbondisulfide (1.9 g, 0.026 mol) and aqueous sodium hydroxide (1.2 mL, 0.02 mol) were added dropwise. After 30 min, dimethylsulfate (3.15 g, 0.025 mol) was added dropwise while cooling in an ice bath. Stirring was continued for 3 h, and then the reaction mixture was poured into an ice-water mixture. The precipitated solid was filtered, dried, and crystallized from acetic acid.

3: IR (KBr, cm À1 ) 3308 (NH), 2916, 2857 (CH aliph.), 1680 (C‚O). 1 H NMR: 2.30 (s, 3H, CH 3 ), 7.27-8.23 (m, 9H, Ar-H), 9.02 (br s, 1H, NH, D 2 O exchang.). 13 C NMR: 22 (CH 3 ), 120, 125, 127, 129, 131, 133, 139, 145, 153, 155 

A mixture of 2 (3.52 g, 0.01 mol) and the appropriate isothiocyanate (0.01 mol) in absolute ethanol (30 mL) was heated under reflux for 2 h. The reaction mixture was cooled, and the solid separated was filtered, dried, and crystallized from acetic acid. 119, 124, 127, 130, 131, 134, 138, 146, 152, 154, 118, 119, 125, 127, 129, 131, 133, 137, 139, 145, 153, (75), 147 (21), 77 (100).

A mixture of 2 (3.52 g, 0.01 mol), anhydrous potassium carbonate (1.38 g, 0.01 mol) and the appropriate phenacyl halide (0.01 mol) in isopropanol (30 mL) was refluxed for 3 h. The solvent was removed under reduced pressure and the separated solid was filtered, dried, washed with water and crystallized from acetic acid. 9: IR (KBr, cm À1 ) 3287 (2NH), 3072 (CH arom.), 2985 (CH aliph.), 1700, 1683 (2C‚O), 1213 (C‚S). 1 H NMR: 4.50 (s, 2H, CH 2 CO), 7.25-8.31 (m, 14H, Ar-H), 8.65 (br s, 1H, NH, D 2 O exchang.). 13 C NMR: 46 (CH 2 ), 120, 125, 127, 128, 129, 131, 134, 137, 145, 152, 154, 156 119, 120, 124, 127, 128, 130, 132, 135, 137, 138, 147, 154, 168, 180 (2C‚O), 194 (C‚S) . MS, m/z (Rel. Int.): 445 (M + , 17), 362 (33), 119 (100).

quinazolin-4(3H)-one derivatives (14-18) A mixture of the appropriate dithiocarbamate derivative 9-13 (0.01 mol), and sodium ethoxide (0.68 g, 0.01 mol) in absolute ethanol (30 mL) was heated under reflux for 3 h. The solvent was removed under reduced pressure, and the obtained solid was washed with water and crystallized from acetic acid.

14: IR (KBr, cm À1 ) 3065 (CH arom.), 1688 (C‚O), 1220 (C‚S). 1 H NMR: 7.15-8.31 (m, 15H, Ar-H). 13 C NMR: 119, 111, 125, 127, 128, 129, 130, 131, 135, 138, 145, 153, 160, 164 : 119, 111, 125, 127, 129, 130, 131, 133, 135, 136, 139, 145, 153, 160, 164, 167, C‚O and C‚S) . 16: IR (KBr, cm À1 ) 3086 (CH arom.), 1698 (C‚O), 1231 (C‚S). 1 H NMR: 6.95-8.31 (m, 14H, Ar-H). 13 C NMR: 119, 111, 125, 127, 129, 130, 131, 133, 135, 136, 139, 145, 153, 160, , 169 (C‚O), 186 (C‚S). 17: IR (KBr, cm À1 ) 3073 (CH arom.), 1681 (C‚O), 1212 (C‚S). 1 H NMR: 7.0-8.24 (m, 14H, Ar-H). 13 C NMR: 119, 111, 124, 125, 127, 129, 130, 131, 133, 139, 43, 145, 150, 153, 160, 119, 111, 125, 127, 129, 131, 132, 133, 134, 139, 140, 145, 153, 160, , 166 (C‚O), 188 (C‚S).

Solution of 3 (3.26 g, 0.01 mol) in ethanol was treated with hydrazine hydrate (98%; 4.9 g, 0.1 mol) and heated on water bath until methyl mercaptan evolution ceased. After cooling, the solid obtained was filtered, dried, and crystallized from acetic acid. 2.1.6. 1-Acyl-4-[2-phenyl-4-oxo-quinazolin-3(4H)yl]thiosemicarbazide derivatives (20-24) The appropriate acid chloride (0.001 mol), was added slowly to a solution of 19 (0.31 g, 0.001 mol) in pyridine (10 mL) and the reaction mixture was stirred at room temperature for 1 h. The solvent was removed and the residue was treated with dilute hydrochloric acid, washed with water, filtered, and crystallized from acetic acid to afford the target compounds in good yields. 10.13 (br s, 1H, NH, D 2 Oexchang.). 13 C NMR: 28 (CH 3 ), 119, 125, 127, 129, 131, 133, 139, 145, 153, 119, 125, 127, 129, 131, 132, 133, 135, 139, 145, 153, 

All the synthesized compounds were tested for their in vitro antimicrobial activity against a panel of standard strains of the Gram-positive bacteria, Staphylococcus aureus ATCC 19433 (SA) and Bacillus subtilis ATCC 6633 (BS), the Gramnegative bacteria, Escherichia coli ATCC 25922 (EC) and Pseudomonas aeruginosa ATCC 27853 (PA), and the yeast-like pathogenic fungus Candida albicans ATCC 753 (CA). The primary screening was carried out using the agar-disk diffusion method using Muller-Hinton agar medium (Patrick et al., 1995) . Sterile filter paper disks (8 mm diameter) were moistened with the test compound solution in dimethylsulfoxide of specific concentration (200 lg/disk). The disks containing the compounds under test, the antimicrobial antibiotic ampicillin trihydrate (100 lg/disk) and antifungal drug clotrimazole (100 lg/disk), were carefully placed on the agar culture plates that had been previously inoculated separately with the microorganisms suspension at 106 Colony Forming Unit/mL (CFU/mL) concentration. The plates were incubated at 37°C, and the diameter of the growth inhibition zones was measured after 24 h in case of bacteria and 48 h in case of C. albicans. The minimal inhibitory concentration (MIC) for the most active compounds against the same microorganisms used in the primary screening was carried out using the microdilution susceptibility method in Muller-Hinton broth and Sabouraud liquid medium. The compounds, ampicillin trihydrate,

and clotrimazole were dissolved in dimethylsufoxide at concentration 800 lg/mL. The twofold dilutions of the solution were prepared (400, 200, 100, . . . 6.25 lg/mL). The microorganism suspensions at 106 CFU/mL concentrations were inoculated to the corresponding wells. The plates were incubated at 37°C for 24 and 48 h for the bacteria and C. albicans, respectively. The MIC values were determined as the lowest concentration that completely inhibited visible growth of the microorganisms as detected by unaided eye.

The synthetic route designed for the synthesis of the target compounds is summarized in Scheme 1. The key intermediates 3-amino-2-phenylquinazolin-4(3H)-one 1 and the potassium dithiocarbamate derivative 2 were prepared according to a reported procedure (Alafeefy, 2008) . The 3-amino function of 1 was utilized to produce the 3-thioureido analogs 4-8 via its reaction, in absolute ethanol, with some selected isothiocya-nates where two NH absorption bands appeared in the IR spectra around 3300, 3200 cm À1 , in addition to the carbonyl band at around 1680 cm À1 . The dithiocarbamate derivative 3 was obtained by adopting a reported procedure (Prasad et al., 2000) . The potassium salt was converted to the dithioic acid esters 9-13 through reaction with the appropriate a-haloactophenone; generally, the IR spectra of these compounds revealed the presence of two carbonyl bands around 1710, 1680 cm À1 and an NH band around 3260 cm À1 . Cyclization of these esters was accomplished using sodium ethoxide to yield the corresponding 3-[4-substituted-2 thioxothiazol-3(2H)-yl]-quinazolin-4(3H)-one derivatives 14-18. The IR spectra of these cyclic derivatives revealed the absence of the carbonyl band as well as the absence of the NH band. Hydrazinolysis of the intermediate 3 afforded the corresponding thiosemicarbazide derivative 19. The IR spectra of compound 19 revealed the absence of the aliphatic absorption band. The Nacyl derivatives 20-24 were obtained through reacting 19 with some selected acid chlorides (Scheme 1; 

synthesized compounds were further confirmed by elemental analyses in addition to the IR, 1 H NMR, 13 C NMR, and mass spectral data, which were in full agreement with their proposed structures.

The results of the preliminary antimicrobial testing of compounds 1-24 (200 lg/disk) and the broad-spectrum antibacterial antibiotic ampicillin trihydrate (100 lg/disk) are shown in Table 2 . The results revealed that, except compounds 9-18, the majority of the synthesized compounds showed varying degrees of inhibition against the tested microorganisms. In general, the inhibitory activity against the tested Gram-positive bacteria was higher than that of the Gram-negative one, in addition, these derivatives showed weak activity against P. aeruginosa and C. albicans. Compounds 4-6, 19-22 and 24 displayed broad-spectrum antimicrobial activity; they possessed excellent activity against the Gram-positive bacteria, moderate activity against E. coli, and weak activity against C. albicans. The least susceptible organisms were P. aeruginosa and C. albicans. Only compound 4, was moderately active against C. albicans and compounds 20 and 24 showed moderate activity against E. coli. However, compound 21 exhibited moderate activity against E. coli and P. aeruginosa in addition to weak activity against C. albicans. The other compounds were either weakly active or completely inactive against the tested strains. None of the tested compounds were found to be as strong as clotrimazole. However, the dithiocarbamate derivatives 9-13 and the corresponding cyclic, dehydrated, derivatives 14-18 were almost inactive. The structural-antimicrobial activity relationship of the synthesized compounds, based on the structure of the starting compound 1, which possessed very weak antimicrobial activity, revealed that the 

introduction of thioureides enhances the antimicrobial activity according to the nature of the substituent group. The alkyl thioureides had greater influence on the activity than the aryl substituent. The methyl and ethyl derivatives 4, 5 were found to be more active than the allyl derivative 6 and the aryl derivatives 7 and 8. The maximum activity, within this series, was attained with compound 4 (R CH 3 ). Meanwhile, the majority of the carbohydrazide derivatives 19-24 showed good activity although the precursor compound 3 was found to be totally inactive. Also, it was clear that the aliphatic carbohydrazide derivatives 19-21 were more active than the aromatic derivatives 22-24. The most active derivatives in this series were compounds 20 (R CH 3 ) and 21 (R C 2 H 5 ).

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The author expresses his sincere thanks and gratitude to Dr. Hasan A. Samaha, Department of Microbiology, College of Pharmacy, Al-Azhar University, Cairo, Egypt, for carrying out the preliminary antimicrobial screening.