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Synthetic CommunicationsAn International Journal for Rapid Communication of Synthetic OrganicChemistry

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6-Iodo-2-isopropyl-4H-3,1-benzoxazin-4-one asbuilding block in heterocyclic synthesis

Maher A. El-Hashash, Abeer M. El-Naggar, Eman A. El-Bordany, Magda I.Marzouk & Tarek M. S. Nawar

To cite this article: Maher A. El-Hashash, Abeer M. El-Naggar, Eman A. El-Bordany, MagdaI. Marzouk & Tarek M. S. Nawar (2016) 6-Iodo-2-isopropyl-4H-3,1-benzoxazin-4-one asbuilding block in heterocyclic synthesis, Synthetic Communications, 46:24, 2009-2021, DOI:10.1080/00397911.2016.1244272

To link to this article: http://dx.doi.org/10.1080/00397911.2016.1244272

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2016, VOL. 46, NO. 24, 2009–2021 http://dx.doi.org/10.1080/00397911.2016.1244272

6-Iodo-2-isopropyl-4H-3,1-benzoxazin-4-one as building block in heterocyclic synthesis Maher A. El-Hashash, Abeer M. El-Naggar, Eman A. El-Bordany, Magda I. Marzouk, and Tarek M. S. Nawar

Chemistry Department, Faculty of Science, Ain Shams University, Cairo, Egypt

ABSTRACT As a part of ongoing studies in the synthesis of a variety of heterocycles of biological importance, we report here an efficient and convenient method for the synthesis of novel compounds from 6- iodo-2-isopropyl-4H-3,1-benzoxazin-4-one 1 as building block. The reaction of benzoxazinone 1 with various reagents such as diethylmalonate, sodium azide, and phosphorus pentasulfide yielded the compounds 2–5. The behavior of benzothiazin-4-thione 5 toward formamide and hydrazine hydrate was investigated, forming the compounds 6 and 7. The reaction of quinazolinone derivative 8 with β-D-glucose pentaacetate, ethyl 2-methyl-5-((1S,2R,3R)-1,2,3,4-tetrahy-droxybutyl)furan-3-carboxylate, epichlorohydrin and benzenesulpho-nyl chloride afforded quinazolinone derivatives 9, 10, 12, and 13 respectively. The reaction of quinazolinone derivative 10 with acetic anhydride resulted in formation of the acylated compound 11. The behavior of quinazolinylacetohydrazide derivative 14 toward carbon electrophiles[16] has been investigated by its reaction with ethyl benzoylacetate, potassium thiocyanate, and phenyl isothiocyanate, affording the quinazolinone derivatives 15, 16, and 18, respectively. Treatment of compound 16 with sodium hydroxide followed by hydrochloric acid yielded the mercapto-triazole derivative 17. The structures of the newly synthesized compounds were confirmed by elemental analysis, infrared (IR), 1H NMR, 13C NMR, and mass spectra. The antimicrobial activities of some of the synthesized compounds were preliminarily evaluated.

ARTICLE HISTORY Received 1 August 2016

KEYWORDS Antibacterial; antifungal; benzoxazinone; quinazolinone

CONTACT Abeer M. El-Naggar elsayedam@sci.asu.edu.eg Chemistry Department, Faculty of Science, Ain Shams University, Abassia 11566, Cairo, Egypt.

Supplemental data for this article can be accessed on the publisher’s website. © 2016 Taylor & Francis

GRAPHICAL ABSTRACT

Introduction

Benzoxazinone derivatives are considered to be important chemical synthons of physio-logical significance and pharmaceutical utility. They possess a variety of biological effects including antitubercular,[1] antifungal, antimalarial, anticancer, antiviral, and antibacterial activities.[2,3] Quinazolinones are compounds with wide spectra of biological activities, including anticancer, anticonvulsant, anti-inflammatory, antitubercular, and antibacterial effects.[4–11]

Iodine was selected because it has received considerable attention in organic synthesis,[11] due to its high tolerance to air and moisture, low cost, nontoxic nature, and ready availability. The presence of iodine increases the lipophilicity of the molecules. Iodine increases the lipophilicity of the compound more than fluorine, chlorine, and bromine as iodine is bigger and possesses higher polarizability.[18] Iodine atoms can change considerably the pharmacology of the original molecule because of (i) a change of the torsion angle, (ii) a change of the electronic density, and (iii) the increase of lipophilicity.

Anthranilic acid (2-aminobenzoic acid) has two different functional groups (-CO2H and -NH2) and therefore it is often used in the synthesis of heterocyclic compounds as it can readily undergo condensation and nucleophilic reactions. Considering the special structure of benzoxazinone derivatives, two sites are available for nucleophilic attack, that is, two dif-ferent sites with partial positive charges that can lead to the opening of heterocyclic part of benzoxazinone derivatives by different attacking nucleophiles. In most of cases, reclosure of the heterocyclic part of the molecule provides a new compound with interesting chemi-cal properties.[12] From all these factors, we aim to synthesize novel benzoxazinone

2010 M. A. EL-HASHASH ET AL.

derivatives containing iodine atoms, and the present investigation is a continuation of our earlier study on benzoxazinone[13] and quinazolinone derivatives.[14,15] We report herein the synthesis of new biological active compounds based on benzoxazinone nucleus.

Results and discussion

The quinazolinone derivatives 1, 8, and 14 are used as key starting materials in the present study. They were prepared according to the literature.[16]

Benzoxazinone derivative 1 reacted with diethylmalonate and yielded the β-ketoester 2 via ring opening of benzoxazinone derivative at C(4) followed by hydrolysis and decarboxylation (Scheme 1). The structure of 2 was confirmed by IR spectra, which showed 1734 (C=O) of ester and 1673 cm� 1. Moreover, 1H NMR spectrum showed signals at 4.17, 1.39, and 4.58 ppm attributable to (OCH2CH3) and CH2 protons. Benzoxazinone derivative 1 reacted with sodium azide in boiling acetic acid to give a mixture of the corresponding 5-iodo-1- isobutyryl-1,3-dihydro-2H-benzo[d]imidazol-2-one 3 and tetrazolylbenzoic acid 4. The reac-tion of the benzoxazinone derivative 1 with sodium azide[19] and the rearrangement via nitrene and isocyanate intermediates afforded the imidazole carboxamide derivative 3 (Scheme 2). The mechanism of formation of the imidazolecarboxamide derivative 3 consists

Scheme 1. Synthesis of compounds 1–7.

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of attack of azide ion at C(4), then the release of nitrogen gas followed by an aryl shift of the aryl group from the carbonyl carbon to the closest nitrogen. The release of gas drives the reaction forward and results in the formation of the isocyanate product via nitrene intermedi-ate, which can potentially react further with the nitrogen nucleophile (Curtius rearrange-ment). While the benzoic acid derivative 4 was formed through nucleophilic attack at C(2) followed by ring opening and ring closure (Scheme 2).

Reflux of benzoxazinone derivative 1 with P2S5 afforded 6-iodo-2-isopropyl-4H-benzo [d][1, 3] thiazine-4-thione 5, which was considered the key starting material of compounds 6 and 7 by reaction with formamide and hydrazine hydrate respectively. This was con-firmed by spectroscopic data. The IR and the 1H NMR spectra of 3-acetylquinazolinone derivative 6 showed the presence of NH at ν: 3321, 3165 cm� 1 and δ: 11.48 ppm, and for compound 7 showed the presence of NH2 at ν: 3324 cm� 1 and δ: 5.28 ppm.

Quinazolinone derivatives with halogen at the 6- or 8-position are known to act against bacteria and inflammation.[18,19] In view of the previous rationale, we aim to synthesize quinazolin-4(3H)-one derivatives containing iodine in the 6-position and study their effect on bacteria and fungi activity. Iodine was selected because of its high tolerance to moisture, low cost, nontoxic nature, and ready availability.

Quinazolinone derivative 8 was prepared through the reaction of the benzoxazinone derivative 1 with formamide.[16] Reaction of 8 with (2R,3S,4R,5R,6S)-6-(acetoxymethyl) tetrahydro-2H-pyran-2,3,4,5-tetrayl tetraacetate, ethyl 2-methyl-5-((1R,2S,3S)-1,2,3,4- tetrahydroxybutyl) furan-3-carboxylate, epichlorohydrin, and benzenesulphonyl chloride afforded (2S,3R,4R,5S,6R)-2-(acetoxymethyl)-6-(6-iodo-2-isopropyl-4-oxoquinazolin-3 (4H)-yl)tetrahydro-2H-pyran-3,4,5-triyl triacetate 9, 6-iodo-2-isopropyl-3-(2-methyl- 5-((1S,2R,3R)-1,2,3,4-tetrahydroxybutyl)furan-3-carbonyl) quinazolin-4(3H)-one 10, 6-iodo- 2-isopropyl-3-(oxiran-2-ylmethyl)quinazolin-4(3H)-one 12 and 6-iodo-2-isopropyl-3- (phenylsulfonyl)quinazolin-4(3H)-one 13 (Scheme 3). The IR spectra of 9, 10, 12, and

Scheme 2. Mechanism of formation of compounds 3 and 4.

2012 M. A. EL-HASHASH ET AL.

13 are devoid of any signal for NH and showed signals for C=O at 1679, 1674, 1678, and 1675 cm� 1 respectively. Treatment of 10 with acetic anhydride afforded the acylated com-pound 11. The structure of compound 11 was confirmed by spectral data (IR and 1H NMR). The IR spectrum showed strong absorption bands at 1741, 1679 cm� 1 for the C=O group. The IR and 1H NMR spectra were devoid of any signals for the OH group.

Acid hydrazides have been in the center of attention over many years because of the high practical value of these compounds. In general, acid hydrazides are very important class of compounds, for their high reactivity in heterocyclic synthesis as key starting mate-rials to form various classes of biologically and pharmacologically active compounds.[20–24]

For example, 1,3,4-oxadiazole and 1,3,4-thiadiazole derivatives are as fungicides[25] and antitumor agents.[26] In addition, substituted hydrazides are characterized by low toxicity and possess a broad spectrum of pharmacological activity.[27] In view of these facts and in continuation of our interest in the synthesis of a variety of heterocycles of biological importance,[28–31] we report here an efficient and convenient method for the synthesis of novel compounds 15–20 (Scheme 4).

The behavior of quinazolinylacetohydrazide derivative[16] 14 towards carbon electro-philes has been investigated with a view to obtain some interesting quinazolinone deriva-tives. Interaction of the quinazolinylacetohydrazide derivative 14 with ethyl benzoylacetate,

Scheme 3. Synthesis of compounds 8–13.

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potassium thiocyanate, and phenyl isothiocyanate afforded the quinazolinone derivatives 15, 16, and 18 respectively. These results are depicted in Scheme 4. The IR and 1H NMR spectra of the quinazolinone derivatives 15 and 18 are devoid of any signals for NH2 group. The IR spectrum of 15 revealed bands at 3064, 1677, and 1665 cm� 1

corresponding to CH and C=O groups. The structure of 15 was confirmed by 1H NMR spectrum, which showed signals at 4.17 and 4.71 ppm attributable to CH2 pyrazole ring and CH2 protons. Compound 16 exhibited strong absorption bands in its IR spectrum at 3428, 3327, and 1675 cm� 1 for NH2, NH, and C=O groups. Its 1H NMR spectrum showed signals at 5.67 ppm for NH2 protons and 10.56 ppm for NH protons. Treatment of 16 with sodium hydroxide followed by hydrochloric acid afforded 6-iodo-2-isopropyl- 3-((5-mercapto-4H-1,2,4-triazol-3-yl)methyl)quinazolin-4(3H)-one 17. The IR spectrum of 17 revealed the existence of bands at 3322, 2595, and 1674 cm� 1 corresponding to NH, SH, and C=O groups, respectively. The 1H NMR spectrum showed signals at 4.28, 11.13, and 12.66 ppm corresponding to CH2, NH, and SH protons, respectively. Mixing compound 18 with concentrated sulfuric acid overnight results in cyclization to thiadiazolo quinazoline derivative 19. The structure of 19 was verified by spectral data. The IR spec-trum displayed bands consistent with NH, C=O groups in the range of 3315, 1678 cm� 1.

Scheme 4. Synthesis of compounds 14–20.

2014 M. A. EL-HASHASH ET AL.

The 1H NMR spectrum exhibited signals at 4.43 ppm for CH2 protons and 10.54 ppm for NH proton. The reaction of compound 19 with hydrazine hydrate in refluxing ethanol afforded 3-((4-amino-5-(phenylamino)-4H-1,2,4-triazol-3-yl)methyl)-6-iodo-2- isopropylquinazolin-4(3H)-one 20. The IR spectrum of compound 20 revealed the presence of NH2, NH, C=O groups at ν: 3425, 3166, and 1674 cm� 1, respectively. Also the 1H NMR spectrum showed signals at δ: 4.57, 5.65, 11.38 ppm corresponding to CH2, NH2, and NH protons, respectively. Most of the compounds were confirmed by 13C NMR spectra.

Antimicrobial activity

Antibacterial activity

Antibacterial activities of some of the synthesized compounds have been evaluated by the standard disc-agar diffusion method using ampicillin as standard drug for Gram-positive bacteria (Streptococcus pneumonia and Bacillis subtilis) and gentamicin as standard drug for Gram-negative bacteria (Pseudomonas aeruginosa and Escherichia coli). The results are depicted in Table 1.

The results show that compound 3 exhibits high activity towards Streptococcus pneumonia and Escherichia coli and moderate activity towards Bacillis subtilis and Pseudo-monas aeruginosa. This is due to the presence of the imidazolone moiety. Also compound 4 exhibits the same results due to the presence of tetrazole moiety. Compounds 5 and 6 exhibit moderate activity against all types of bacteria. Compound 7 exhibits the same beha-vior as 3 and 4 due to the presence of the thioquinazolinone moiety bearing amino group. Compounds 9 and 10 are highly active toward Gram-negative bacteria and moderately active toward Gram-positive bacteria due to the presence of a nucleoside moiety. The same results were observed with compound 12 due to the presence of an acyclic nucleoside moiety. Compound 13 is highly active toward all types of bacteria due to the presence of a sulfonyl group. Also, compounds 15, 17, 19, and 20 exhibit high activity toward most types of bacteria due to the presence of another heterocyclic group incorporated with quinazoli-none nucleus (e.g., pyrazolone, 3-mercaptotriazole, sulfadiazole, and 4-aminotriazole).

Table 1. Antibacterial activity of some of the synthesized compounds.

Compound

Inhibition zone diameter � standard deviation (mm)/(Percentage of inhibition relative to the standard (%))

Streptococcus pneumoniae Bacillis subtilis Pseudomonas aeruginosa Escherichia coli

3 18.2 � 0.44/(76.46) 19.3 � 0.38/(59.57) 12.1 � 0.72/(69.94) 15.2 � 0.53/(76.38) 4 16.9 � 0.72/(71) 18.3 � 0.43/(56.48) 11.2 � 0.63/(64.74) 15.5 � 0.25/(77.89) 5 15.4 � 0.25/(64.7) 16.9 � 0.32/(52.16) 10.1 � 0.15/(58.38) 11.6 � 0.58/(58.29) 6 16.2 � 0.36/(68.07) 17.8 � 0.15/(54.94) 10.5 � 0.34/(60.69) 12.3 � 0.44/(61.81) 7 17.6 � 0.63/(73.95) 19.4 � 0.15/(59.88) 11.8 � 0.58/(68.21) 14.7 � 0.38/(73.87) 9 15.5 � 0.42/(65.13) 19.8 � 0.15/(61.11) 14.6 � 0.53/(84.39) 18.4 � 0.25/(92.46) 10 15.2 � 0.43/(63.87) 19.3 � 0.38/(59.57) 13.2 � 0.67/(76.3) 15.7 � 0.44/(78.89) 12 16.2 � 0.25/(68.07) 20.3 � 0.58/(62.65) 13.7 � 0.32/(79.19) 17.1 � 0.15/(85.92) 13 18.9 � 0.53/(79.41) 22.5 � 0.44/(69.44) 15.3 � 0.15/(88.44) 16.2 � 0.32/(81.41) 15 16.5 � 0.32/(69.33) 21.4 � 0.67/(66.05) 14.6 � 0.43/(84.39) 15.9 � 0.15/(79.9) 17 20.1 � 0.72/(84.45) 25.3 � 0.46/(78.09) 13.4 � 0.43/(77.46) 18.2 � 0.32/(91.46) 19 17.2 � 0.53/(72.27) 18.4 � 0.34/(56.79) 11.6 � 0.25/(67.05) 14.3 � 0.72/(71.86) 20 19.4 � 0.15/(81.51) 21.7 � 0.53/(66.98) 12.3 � 0.44/(71.1) 15.6 � 0.38/(78.39) St. 23.8 � 0.2 32.4 � 0.3 17.3 � 0.1 19.9 � 0.3

Note. Standard drug (St.): Ampicillin for Gram-positive bacteria, gentamicin for Gram-negative bacteria.

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Antifungal activity

Antifungal activities of some of the synthesized compounds have been evaluated by the standard disc-agar diffusion method using amphotericin B as standard drug. The results are depicted in Table 2.

The results show that compound 3 exhibits high activity toward Aspergillus fumigatus and Syncephalastrum racemosum and moderate activity towards Geotricum candidum and Candida albicans due to the presence of an imidazolone moiety. Compound 4 shows moderate activity with Aspergillus fumigatus, Geotricum candidum, and Candida albicans and shows high activity with Syncephalastrum racemosum due to the presence of a tetrazole moiety. Compound 5 exhibits moderate activity toward all types of fungi in the absence of another heterocyclic moiety. Also, compound 6 exhibits moderate activity toward Aspergil-lus fumigatus, Geotricum candidum, and Candida albicans and shows high activity with Syncephalastrum racemosum. Compound 7 exhibits high activity toward Syncephalastrum racemosum and Geotricum candidum and shows moderate activity toward Aspergillus fumigatus and Candida albicans. Compounds 9 and 10 exhibit moderate activity toward Aspergillus fumigatus, Geotricum candidum, and Candida albicans and show high activity toward Syncephalastrum racemosum due to the presence of nucleoside moieties. The same behavior was observed with compound 12. Compounds 13, 15, 17, and 20 exhibit high activity towards all types of fungi due to the presence of another heterocyclic ring. Compound 19 is similar to compound 4. The lower activity towards fungi compared by bacteria in certain types is probably attributed to the complex structure of the fungal cell wall, as it is typically composed of chitin, β-(1,3)-glucan, β-(1,6)-glucan, mannan, and protein,[32] which may have inhibited or completely prevented tested compounds from diffusing into the cell.

Experimental

All melting points were measured on a Gallenkamp melting-point apparatus and were uncorrected. The infrared spectra were recorded using potassium bromide disks on a

Table 2. Antifungal activity of some of the synthesized compounds.

Compound

Inhibition zone diameter � standard deviation (mm)/(Percentage of inhibition relative to the standard (%))

Aspergillus fumigatus Syncephalastrum racemosum Geotricum candidum Candida albicans

3 16.7 � 0.36/(70.46) 15.4 � 0.25/(78.17) 18.5 � 0.58/(64.46) 13.8 � 0.67/(54.33) 4 14.6 � 0.58/(61.6) 14.8 � 0.46/(75.13) 19.5 � 0.32/(67.94) 16.2 � 0.15/(63.78) 5 13.2 � 0.72/(55.7) 12.5 � 0.36/(63.45) 17.3 � 0.43/(60.28) 12.9 � 0.63/(50.79) 6 13.7 � 0.38/(57.81) 14.4 � 0.46/(73.1) 18.6 � 0.53/(64.81) 13.5 � 0.72/(53.15) 7 15.3 � 0.25/(64.56) 16.1 � 0.34/(81.73) 21.5 � 0.53/(74.91) 15.9 � 0.43/(62.6) 9 16.2 � 0.58/(68.35) 15.6 � 0.32/(79.19) 19.3 � 0.67/(67.25) 13.7 � 0.33/(53.94) 10 15.1 � 0.63/(63.71) 14.8 � 0.15/(75.13) 17.5 � 0.37 (60.98) 14.2 � 0.25/(55.91) 12 14.4 � 0.53/(60.76) 13.8 � 0.67/(70.05) 16.9 � 0.42/(58.89) 13.5 � 0.36/(53.15) 13 18.7 � 0.37/(78.9) 16.4 � 0.25/(83.25) 20.6 � 0.38/(71.78) 18.3 � 0.42/(72.05) 15 18.3 � 0.42/(77.22) 17.4 � 0.36/(88.32) 21.8 � 0.15/(75.96) 17.6 � 0.58/(69.29) 17 21.4 � 0.63/(90.3) 19.3 � 0.15/(97.97) 24.7 � 0.58/(86.06) 16.8 � 0.25/(66.14) 19 15.5 � 0.46/(65.4) 14.9 � 0.58/(75.63) 19.1 � 0.44/(66.55) 14.3 � 0.36/(56.3) 20 17.8 � 0.34/(75.11) 16.3 � 0.25/(82.74) 20.2 � 0.32/(70.38) 15.7 � 0.63/(61.81) St. 23.7 � 0.1 19.7 � 0.2 28.7 � 0.2 25.4 � 0.1

Note. Standard drug (St.): Amphotericin B for fungi.

2016 M. A. EL-HASHASH ET AL.

Pye Unicam SP-3-300 infrared spectrophotometer. 1H NMR spectra were run at 300 MHz on a Varian Mercury VX-300 NMR spectrometer. The mass spectra were recorded on Shimadzu GCMS-QP-1000EX mass spectrometers at 70e.V. All the spectral measurements were carried out at the Microanalytical Center of Cairo University, Egypt. The elemental analyses were carried out at the Microanalytical Center of Cairo University, Egypt. The antimicrobial activities were carried out at Al-Azhar University, Faculty of Agriculture, Egypt. All the chemical reactions were monitored by thin-layer chromatography (TLC). All the newly synthesized compounds gave satisfactory elemental analyses.

Starting materials

6-Iodo-2-isopropyl-4H-benzo[d][1,3]oxazin-4-one 1, 6-iodo-2-isopropylquinazolin-4(3H)- one 8, and 2-(6-iodo-2-isopropyl-4-oxoquinazolin-3(4H)-yl)acetohydrazide 14 were synthesized according to literature.[16] Ethyl 2-methyl-5-((1S,2R,3R)-1,2,3,4-tetrahydroxy-butyl)furan-3-carboxylate was synthesized according to literature.[33] Other chemicals used in this study were commercially available.

Synthesis of ethyl 3-(5-iodo-2-isobutyramidophenyl)-3-oxopropanoate (2)

A mixture of benzoxazinone 1 (3.15 g, 0.01 mol) and diethylmalonate (1.60 g, 0.01 mol) was heated under reflux in pyridine (30 mL) for 10 h. The reaction mixture was then poured onto ice water with stirring. The separated solid was filtered, dried, and crystallized from ethanol to give 2 (76%), pale yellow crystals, mp 179–181 °C. IR (KBr) ν: 3332 (NH), 3057 (CH-aromatic), 2966, 2872 (CH-aliphatic), 1734, 1673 (2C=O) cm� 1. 1H NMR (300 MHz, DMSO-d6): δ 1.22 (d, J ¼ 7 Hz, 6H, 2CH3), 1.39 (t, J ¼ 7 Hz, 3H, -OCH2CH3), 2.62– 2.71 (m, 1H, CH (CH3)2, 4.17 (q, 2H, -OCH2CH3), 4.58 (s, 2H, CH2), 7.66–8.12 (m, 3H, Ar-H), 11.22 (s, 1H, NH). 13C NMR (75 MHz, DMSO-d6): δ 14.43, 20.16, 33.12, 49.34, 60.48, 92.05, 121.75, 125.93, 134.37, 138.37, 144.05, 165.71, 174.21, 192.50. MS m/z (%): 404 (Mþ þ 1, 5), 403 (Mþ, 13), 358 (51), 261 (36), 233 (100), 162 (28). Anal. calcd. for C15H18INO4 (403.22): C, 44.68; H, 4.50; N, 3.47. Found: C, 44.52; H, 4.31; N, 3.58.

Synthesis of compounds 3 and 4

A mixture of benzoxazinone 1 (3.15 g, 0.01 mol) and sodium azide (0.65 g, 0.01 mol) was heated under reflux in glacial acetic acid (20 mL) for 3 h. The reaction mixture was then poured onto ice water with stirring. The formed solid was filtered, dried, and fractionally crystallized from benzene to give 3, while the residue was crystallized from ethanol to give 4.

5-Iodo-1-isobutyryl-1,3-dihydro-2H-benzo[d]imidazol-2-one (3)

Yield 31%, brown crystals, mp 116–118 °C. IR (KBr) ν: 3320 (NH), 2971, 2926 (CH), 1715, 1664 (2C=O) cm� 1. 1H NMR (300 MHz, DMSO-d6): δ 1.24 (d, J ¼ 7 Hz, 6H, 2CH3), 2.70–2.79 (m, 1H, CH (CH3)2, 7.13–8.11 (m, 3H, Ar-H), 10.25 (s, 1H, NH).13C NMR (75 MHz, DMSO-d6): δ 19.93, 35.61, 90.15, 122.41, 129.36, 131.78, 132.95, 136.50, 152.52, 178.83. MS m/z (%): 331 (Mþ þ 1, 8), 330 (Mþ, 16), 314 (33), 287 (49), 259

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(60), 203 (100), 160 (27). Anal. calcd. for C11H11IN2O2 (330.13): C, 40.02; H, 3.36; N, 8.49. Found: C, 40.21; H, 3.19; N, 8.36.

5-Iodo-2-(5-isopropyl-1H-tetrazol-1-yl)benzoic acid (4)

Yield 37%, yellow crystals, mp 232–234 °C. IR (KBr) ν: 3433 (OH), 3059 (CH-aromatic), 2973, 2873 (CH-aliphatic), 1694 (C=O) cm� 1. 1H NMR (300 MHz, DMSO-d6): δ 1.24 (d, J ¼ 7 Hz, 6H, 2CH3), 2.70–2.79 (m, 1H, CH (CH3)2, 7.28–8.25 (d, 3H, Ar-H), 11.94 (s, 1H, OH). 13C NMR (75 MHz, DMSO-d6): δ 22.11, 29.18, 94.82, 128.97, 130.85, 134.18, 136.03, 143.16, 158.47, 167.32. MS m/z (%): 360 (Mþ þ 2, 3), 359 (Mþ þ 1, 6), 358 (Mþ, 12), 315 (61), 298 (42), 270 (100), 231 (36), 214 (19). Anal. calcd. for C11H11IN4O2 (358.14): C, 36.89; H, 3.10; N, 15.64. Found: C, 36.97; H, 3.25; N, 15.83.

Synthesis of 6-iodo-2-isopropyl-4H-benzo[d][1,3]thiazine-4-thione (5)

A mixture of benzoxazinone 1 (3.15 g, 0.01 mol) and P2S5 (6.66 g, 0.03 mol) in xylene (50 mL) was heated under reflux for half an hour. The reaction mixture was then hot filtered and concentrated. The solid precipitated after cooling was filtered, dried, and crystallized from ethanol to give 5 (68%), brown crystals, mp 147–149 °C. IR (KBr) ν: 3066 (CH-aromatic), 2962, 2867 (CH-aliphatic) cm� 1. 1H NMR (300 MHz, DMSO-d6): δ 1.21 (d, J ¼ 7 Hz, 6H, 2CH3), 2.62–2.71 (m, 1H, CH (CH3)2), 7.05–8.01 (m, 3H, Ar-H).13C NMR (75 MHz, DMSO-d6): δ 21.01, 32.66, 93.27, 124.30, 135.58, 137.50, 142.07, 146.12, 164.57, 215.75. MS m/z (%): 348 (Mþ þ 1, 10), 347 (Mþ, 23), 332 (35), 304 (64), 220 (100), 205 (18). Anal. calcd. for C11H10INS2(347.23): C, 38.05; H, 2.90; N, 4.03. Found: C, 38.17; H, 2.98; N, 4.17.

Synthesis of 6-iodo-2-isopropylquinazoline-4(3H)-thione (6)

A mixture of 6-iodo-2-isopropyl-4H-benzo[d][1,3]thiazine-4-thione 5 (3.47 g, 0.01 mol) was heated under reflux in formamide (20 mL) for 2 h. After cooling, the separated solid was filtered, dried, and crystallized from ethanol to give 6 (74%), pale brown crystals, mp 223–225 °C. IR (KBr) ν: 3321, 3165 (NH), 3038 (CH-aromatic), 2970, 2863 (CH-aliphatic) cm– 1.1H NMR (300 MHz, DMSO-d6): δ 1.22 (d, J ¼ 7 Hz, 6H, 2CH3), 2.65–2.74 (m, 1H, CH (CH3)2), 7.21–8.18 (m, 3H, Ar-H), 11.48 (s, 1H, NH). MS m/z (%): 330 (Mþ, 28), 315 (18), 287 (100), 203 (34), 188 (52), 127 (15). Anal. calcd. for C11H11IN2S (330.19): C, 40.01; H, 3.36; N, 8.48. Found: C, 40.18; H, 3.44; N, 8.57.

Synthesis of 3-amino-6-iodo-2-isopropylquinazoline-4(3H)-thione (7)

A mixture of 6-iodo-2-isopropyl-4H-benzo[d][1,3]thiazine-4-thione 5 (3.47 g, 0.01 mol) was heated under reflux with hydrazine hydrate (1.5 g, 0.03 mol) in ethanol (30 mL) for 2 h. The excess solvent was evaporated and the solid formed was filtered, dried, and crystallized from ethanol to give 7 (79%), pale brown crystals, mp 186–188 °C. IR (KBr) ν: 3324 (NH2), 3056 (CH-aromatic), 2971, 2873 (CH-aliphatic) cm– 1. 1H NMR (300 MHz, DMSO-d6): δ 1.23 (d, J ¼ 7 Hz, 6H, 2CH3), 2.66–2.75 (m, 1H, CH (CH3)2), 5.28 (s, 2H, NH2), 7.22–8.20 (m, 3H, Ar-H). MS m/z (%): 347 (Mþ þ 2, 6), 346 (Mþ þ 1, 8), 345

2018 M. A. EL-HASHASH ET AL.

(Mþ, 13), 329 (36), 314 (70), 302 (100), 286 (50), 175 (21). Anal. calcd. for C11H12IN3S (345.20): C, 38.27; H, 3.50; N, 12.17. Found: C, 38.48; H, 3.63; N, 12.35.

Biological activities

Antimicrobial activity

The standardized disc–agar diffusion method[22,23] was followed to determine the activity of the synthesized compounds against the tested microorganisms.

The tested compounds were dissolved in dimethylformamide (DMF) solvent and prepared in two concentrations, 100 and 50 mg/mL, and then 10 µL of each preparation was dropped on disks of 6 mm in diameter and the concentrations became 1 and 0.5 mg/disk respectively. In the case of insoluble compounds, the compounds were suspended in dimethylformamide (DMF), vortexed, and then processed.

Bacterial cultures were grown in nutrient broth medium at 30 °C. After 16 h of growth, each microorganism, at a concentration of 108 cells/mL, was inoculated on the surface of Mueller–Hinton agar plates using sterile cotton swabs. Subsequently, uniform-size filter paper disks (6 mm in diameter) were impregnated by equal volume (10 µL) from the spe-cific concentration of dissolved compounds and carefully placed on the surface of each inoculated plate. The plates were incubated in the upright position at 36 °C for 24 h. Three replicates were carried out for each extract against each of the test organism. Simul-taneously, addition of the respective solvent instead of dissolved compounds was carried out as negative controls. After incubation, the diameters of the growth inhibition zones formed around the disc were measured with transparent ruler in millimeters and averaged, and the mean values were tabulated.

Antifungal activity

Active inoculum for experiments were prepared by transferring many loopfuls of spores from the stock cultures to test tubes of sterile distilled water (SDW) that were agitated and diluted with sterile distilled water to achieve optical density corresponding to 2.0 � 105

spore/mL. Inoculum of 0.1% suspension was swabbed uniformly and the inoculum was allowed to dry for 5 min, and then the same procedure was followed as described previously.

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