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Molecules 2017, 22(3), 346; https://doi.org/10.3390/molecules22030346

Article
Microwave-Assisted Synthesis of some Novel Azoles and Azolopyrimidines as Antimicrobial Agents
1
Department of Chemistry, Faculty of Science, Cairo University, Giza 12613, Egypt
2
Department of Chemistry, Faculty of Applied Science, Umm Al-Qura University, Makkah-Al-mukkarramah 21514, Saudi Arabia
3
Department of Chemistry, College of Science, King Saud University, P.O. Box 2455, Riyadh-11451, Saudi Arabia
4
Chemistry Department, Faculty of Science, King Abdulaziz University, Jeddah B.O. 208203, Saudi Arabia
*
Correspondence: Tel.: +20-1006-745-618 (T.A.F.); +966-11-467-5898 (Y.N.M.); Fax: +966-11-467-5992 (Y.N.M.)
Received: 1 January 2017 / Accepted: 21 February 2017 / Published: 23 February 2017

Abstract

:
In this study, new derivatives of pyrazole, isoxazole, pyrazolylthiazole, and azolopyrimidine having a thiophene ring were synthesized under microwave irradiation. Their pharmacological activity toward bacteria and fungi inhibition was screened and compared to the references Chloramphenicol and Trimethoprim/sulphamethoxazole. The antimicrobial results of the investigated compounds revealed promising results and some derivatives have activities similar to the references used.
Keywords:
thiophenes; pyrazoles; thiazoles; antimicrobial activity; microwave irradiation

1. Introduction

Five-membered heterocyclic ring systems are very significant class of compounds, not only due to their abundance in nature, but also for their chemical and biological value. Thiophene derivatives have been fully-known for their therapeutic applications. They possess antihypertensive [1], antimicrobial [2], diabetes mellitus [3], antiviral [4], analgesic and anti-inflammatory [5], and antitumor activities [6,7]. Pyrazoles and thiazoles exist in many naturally occurring substances and representing an interesting array of azole compounds. They have a wide range of biological activities as for example, anti-inflammatory [8,9], antimicrobial [10,11,12,13], Akt kinase inhibitive [14], anticonvulsant [15], and antitumor activities [16]. On the other hand, microwave-assisted organic synthesis is a tool by which we can achieve goals in a few minutes with high yield as compared to conventional heating [17,18,19,20,21]. Motivated by these findings, and in continuation of our ongoing research program dealing with the synthesis of bioactive heterocyclic ring systems [22,23,24,25,26], we were encouraged to synthesize heterocyclic having thiophene incorporated pyrazole, thiazole, and/or pyrimidine derivatives under microwave irradiation to investigate their antimicrobial activity.

2. Results and Discussion

2.1. Synthesis

1,3-Di(thiophen-2-yl)prop-2-en-1-one 1 was cyclized with different types of nitrogen nucleophiles, namely, thiosemicarbazide, hydrazine derivatives 3ac, and hydroxylamine hydrochloride which afforded pyrazole derivatives 2, 4ac and isoxazole derivative 5, respectively (Scheme 1). The previous reactions were carried out under conventional heating and under microwave irradiation as shown in Table 1. The heating under microwave was more efficient than thermal heating as it reduced the reaction time and increased the product yields in all cases.
It was reported that pyrazolylthiazole derivatives have a wide range of biological activities such as antimicrobial [27], anti-inflammatory [27], hypotensive [28], and antitumor activities [29]. So we became interested in synthesizing the pyrazolylthiazole derivatives from the reaction of 1-thiocarbamoyl-3,5-di-(2-thienyl)-2-pyrazoline 2 with hydrazonoyl chlorides. Thus, conventional heating or microwave irradiation of mixture of carbothioic acid amide derivative 2 and 2-oxo-N-arylpropanehydrazonoyl chloride 6ae in dioxane in the existence of a base catalyst yielded in each case only one isolated product (Scheme 2). The spectroscopic information confirmed the reaction products 8ae. For example, the mass spectra of the isolated products 8ae displayed the expected molecular ion. Also, all derivatives 8ae showed in their 1H-NMR spectra the characteristic signals for CH3, H-5, and CH2 (see experimental part). The structure of products 8 was further supported by an alternative synthesis. Thus, reaction of compound 1 with 2-hydrazinyl-4-methyl-5-(phenyldiazenyl)thiazole 9 under reflux in ethanol led to the formation of product 8a (Scheme 2).
Azolopyrimidines 11a,b, 13, and 15 were prepared via the reaction of chalcone 1 with heterocyclic amines 10a,b, 12, and 14 in ethanol in the presence of catalytic amount of AcOH using both thermal heating and microwave irradiation for comparison (Scheme 3). Similar to the preparation of compounds 2, 4, 5, and 8ae, the use of microwave irradiation was more effective in the synthesis of azolopyrimidines as illustrated in Table 1. The structure of compounds 11a,b, 13, and 15 was confirmed by different spectroscopic techniques like IR, 1H-NMR, mass, and elemental analysis. The IR spectra of 11a,b, 13, and 15 revealed the absence of any absorption bands for carbonyl group in addition to the presence of absorption band for NH group at 3402–3429 cm−1. The 1H-NMR spectra of 11a, as example, showed three characteristic signals for the two CH-pyrimidine, triazole-H, and NH at δ 5.14 (d, J = 4 Hz, 1Ha, CH-pyrimidine), 6.20 (d, J = 4 Hz, 1Hb, CH-pyrimidine), 8.45 (1H, s, triazole-H), 8.73 (s, br, 1H, NH).

2.2. Antimicrobial Activity

In vitro antimicrobial screening of compounds 2, 4ac, 5, 8ae, 11a,b, 13,and 15 prepared in the study was carried out using cultures of two fungal strains Aspergillus niger (ATCC) (ASP) and Candida albicans (ATCC10231) (CA), as well as three bacteria species, namely, Gram positive bacteria, Staphylococcus aureus (ATCC 29213) (SA), and Bacillus subtilus (ATCC 6051) (BS) and the Gram negative bacteria is Escherichia coli (ATCC 25922) (EC). Chloramphenicol and Trimethoprim/sulphamethoxazole antibacterial agents were used as references to evaluate the potency of the examined compounds under the same conditions. The activity was investigated by measuring the diameter of inhibition zone (IZD) in mm ± standard deviation beyond well diameter (6 mm) generated on a range of environmental and clinically pathogenic microorganisms (gram-positive and gram-negative bacteria and fungi) utilizing (0.1 g/mL) concentration of tested samples and the outcomes are portrayed in Table 2. For the antifungal activity: All tested compounds were inactive against Aspergillus niger (ATCC) (ASP) while, compounds 4c, 8c, and 11b have excellent activity against Candida albicans (ATCC 10231) (CA) with inhibition zones 23, 24, and 25 respectively. For the antibacterial activity: it was found that Gram positive bacteria are more sensitive to the tested compounds especially SA rather than BS as five compounds 2, 4c, 8b, 8d, and 15 have potent activity against SA while for BS only compounds 4a and 4c showed good activity. In the case of Gram negative activity with EC, two derivatives 2 and 8c revealed higher activity. The used solvent DMSO concentration did not exhibit any influence on bacteria or fungi.

3. Materials and Methods

3.1. General Experimental Procedures

Melting points were measured with an IA 9000-series digital melting-point apparatus (Bibby Sci. Lim. Stone, Staffordshire, UK). Solvents were generally distilled and dried by standard literature procedures prior to use. IR spectra were recorded in potassium bromide discs on FTIR 8101 PC infrared spectrophotometers (Shimadzu, Tokyo, Japan). NMR spectra were recorded on a Mercury VX-300 NMR spectrometer (Varian, Inc., Karlsruhe, Germany) operating at 300 MHz (1H-NMR) and run in deuterated dimethylsulfoxide (DMSO-d6). Chemical shifts were related to that of the solvent. Mass spectra were recorded on a Shimadzu GCeMS-QP1000 EX mass spectrometer (Tokyo, Japan) at 70 eV. Microwave reactions were performed with a Millstone Organic Synthesis Unit with a touch control terminal (MicroSYNTH, Giza, Egypt) and a continuous focused microwave power delivery system in a pressure glass vessel (10 mL) sealed with a septum under magnetic stirring. The temperature of the reaction mixture was monitored using a calibrated infrared temperature control under the reaction vessel, and control of the pressure was performed with a pressure sensor connected to the septum of the vessel. Elemental analyses were carried out at the Microanalytical Centre of Cairo University, Giza, Egypt. Compounds 10a,b, 12, and 14 were purchased from Sigma-Aldrich and utilized as it is without previous treatments. Compounds 1, 2, 6ae, and 9 were prepared as previously reported in the respective literature [30,31,32].

3.2. Synthesis of Pyrazoline Derivatives 4ac

Method A: A mixture of chalcone 1 (0.220 g, 1 mmol) and hydrazine derivative (1 mmol) in ethanol (20 mL) in the presence of catalytic drops of acetic acid was refluxed for 3–5 h (monitored by TLC). The reaction mixture was poured into water and the solid product was collected by filtration followed by washing with ethanol. The crude products were then recrystallized from ethanol to give pure pyrazolines 4ac, respectively.
Method B: Repetition of the same reactions of method A with heating in a microwave oven at 500 W and 120 °C for a period of time. The reaction mixture was treated similar to method A to obtain compounds 4ac. Compounds 4ac with their physical constants and spectral data are depicted as shown below:
3-(3,5-Di(thiophen-2-yl)-4,5-dihydro-1H-pyrazol-1-yl)-5,6-diphenyl-1,2,4-triazine (4a). Brown solid, m.p. 187–189 °C; IR: 3083, 2926 (C-H), 1593 (C=N) cm−1; 1H-NMR (300 MHz, DMSO-d6): δ 3.05 (dd, 1H, HA, J = 17.2, 6.1 Hz), 4.13 (dd, 1H, HB, J = 17.2, 12.0 Hz), 6.20 (dd, 1H, HX, J = 12.0, 6.1 Hz), 7.18–8.24 (m, 16H, Ar-H); MS, m/z (%) 465 (M+, 8), 316 (34), 222 (38), 105 (100), 77 (72), 64 (80). Anal. Calcd. For C26H19N5S2 (465.11): C, 67.07; H, 4.11; N, 15.04; found: C, 66.87; H, 4.24; N, 14.90.
3-(3,5-DI(thiophen-2-yl)-4,5-dihydro-1H-pyrazol-1-yl)-3,4-dihydroquinoxalin-2(1H)-one (4b). Brown solid, m.p. 170–172 °C; IR: 3435, 3158 (2NH), 3048, 2966 (C-H), 1596 (C=N) cm−1; 1H-NMR (300 MHz, DMSO-d6): δ 3.05 (dd, 1H, HA, J = 17.2, 6.1 Hz), 4.10 (dd, 1H, HB, J = 17.2, 12.0 Hz), 6.18 (dd, 1H, HX, J = 12.0, 6.1 Hz), 7.04–7.99 (m, 10H, Ar-H), 11.88 (s, br, 1H, NH); MS, m/z (%) 378 (M+, 5), 274 (28), 153 (70), 77 (65), 43 (100). Anal. Calcd. For C19H14N4OS2 (378.47): C, 60.30; H, 3.73; N, 14.80; found: C, 60.03; H, 3.92; N, 14.52.
2-(3,5-Di(thiophen-2-yl)-4,5-dihydro-1H-pyrazol-1-yl)-5,7-di(thiophen-2-yl)pyrido[2,3-d]pyrimidin-4(3H)-one (4c). Brown solid, m.p. 188–190 °C; IR: 3435, 3158 (2NH), 3048, 2966 (C-H), 1596 (C=N) cm−1; 1H-NMR (300 MHz, DMSO-d6): δ 3.07 (dd, 1H, HA, J = 17.2, 6.1 Hz), 4.15 (dd, 1H, HB, J = 17.2, 12.0 Hz), 6.16 (dd, 1H, HX, J = 12.0, 6.1 Hz), 6.92–7.75 (m, 12H, Ar-H), 7.98 (s, 1H, pyridine-H4), 8.63 (s, br, 1H, NH); MS, m/z (%) 543 (M+, 14), 426 (50), 330 (49), 153 (83), 64 (100), 43 (68). Anal. Calcd. For C26H17N5OS4 (543.03): C, 57.44; H, 3.15; N, 12.88; found: C, 57.58; H, 3.10; N, 12.63.

3.3. 3,5-Di(thiophen-2-yl)-4,5-dihydroisoxazole (5)

Method A: A mixture of chalcone 1 (0.220 g, 1 mmol), hydroxylamine. HCl (0.069 g, 1 mmol), and anhydrous sodium acetate (0.3 g) in acetic acid (20 mL) was stirred at room temperature for 6 h. The formed solid was filtered, washed with water, and crystallized from dioxane to give isoxazoline derivative 5.
Method B: The above reaction of chalcone 1 and hydroxylamine with the same quantity in method A were heated under microwave irradiation at 500 W and 150 °C for 10 min. The reaction mixture was treated similarly to method A to obtain compounds 5 as yellow solid; m.p. 212–214°C; IR: 3091, 2922 (C-H), 1593 (C=N) cm−1; 1H-NMR (300 MHz, DMSO-d6): δ3.09 (dd, 1H, HA, J = 17.2, 6.1 Hz), 4.13 (dd, 1H, HB, J = 17.2, 12.0 Hz), 6.08 (dd, 1H, HX, J = 12.0, 6.1 Hz), 7.00–8.23 (m, 6H, Ar-H); MS, m/z (%) 335 (M+, 24), 152 (65), 83 (100), 70 (21). Anal. Calcd. for C11H9NOS2 (235.01): C, 56.14; H, 3.85; N, 5.95; found: C, 56.03; H, 3.72; N, 5.74.

3.4. Synthesis of 2-(3,5-Di(thiophen-2-yl)-4,5-dihydro-1H-pyrazol-1-yl)-4-methyl-5-(aryldiazenyl)thiazoles 8ae

Method A: A mixture of 3,5-di(thiophen-2-yl)-4,5-dihydro-1H-pyrazole-1-carbothioamide 2 (0.293 g, 1 mmol) and the appropriate hydrazonoyl halides 6ae (1 mmol) in dioxane (20 mL) containing TEA (0.5 mL) was refluxed for 6–10 h (monitored by TLC), allowed to cool and the solid formed was filtered off, washed with ethanol, dried, and recrystallized from dimethylformamide to give 8ae.
Method B: Repetition of the same reactions of method A with heating in microwave oven at 500 W and 150 °C for a period of time gave products identical in all respects with those separated from method A.
2-(3,5-Di(thiophen-2-yl)-4,5-dihydro-1H-pyrazol-1-yl)-4-methyl-5-(phenyldiazenyl)-thiazole (8a). Red solid, m.p. 164–166 °C; IR:2919 (C-H), 1603 (C=N) cm−1; 1H-NMR (300 MHz, DMSO-d6): δ 2.58 (s, 3H, CH3), 3.07 (dd, 1H, HA, J = 17.2, 6.1 Hz), 4.17 (dd, 1H, HB, J = 17.2, 12.0 Hz), 6.21 (dd, 1H, HX, J = 12.0, 6.1 Hz), 7.00–7.84 (m, 11H, Ar-H); MS, m/z (%) 435 (M+, 5), 339 (14), 205 (50), 75 (42), 50 (100). Anal. Calcd. for C21H17N5S3 (435.06): C, 57.90; H, 3.93; N, 16.08; found: C, 57.74; H, 3.77; N, 15.82.
2-(3,5-Di(thiophen-2-yl)-4,5-dihydro-1H-pyrazol-1-yl)-4-methyl-5-(o-tolyldiazenyl)-thiazole (8b). Red solid, m.p. 122–124 °C; IR: 2921 (C-H), 1600 (C=N) cm−1; 1H-NMR (300 MHz, DMSO-d6): δ 2.04 (s, 3H, CH3), 2.60 (s, 3H, CH3), 3.09 (dd, 1H, HA, J = 17.2, 6.1 Hz), 4.19 (dd, 1H, HB, J = 17.2, 12.0 Hz), 6.22 (dd, 1H, HX, J = 12.0, 6.1 Hz), 6.93–7.79 (m, 10H, Ar-H); MS, m/z (%) 449 (M+, 18), 218 (12), 110 (48), 91 (100), 65 (52). Anal. Calcd. for C22H19N5S3 (449.08): C, 58.77; H, 4.26; N, 15.58; found: C, 58.52; H, 4.08; N, 15.46.
2-(3,5-Di(thiophen-2-yl)-4,5-dihydro-1H-pyrazol-1-yl)-5-((4-methoxyphenyl)diazenyl)-4-methylthiazole (8c). Red solid, m.p. 143–145 °C; IR: 2923 (C-H), 1602 (C=N) cm−1; 1H-NMR (300 MHz, DMSO-d6): δ 2.56 (s, 3H, CH3), 3.04 (dd, 1H, HA, J = 17.2, 6.1 Hz), 3.83 (s, 3H, OCH3), 4.12 (dd, 1H, HB, J = 17.2, 12.0 Hz), 6.13 (dd, 1H, HX, J = 12.0, 6.1 Hz), 6.92–7.82 (m, 10H, Ar-H); MS, m/z (%) 465 (M+, 3), 368 (9), 218 (13), 111 (100), 43 (72). Anal. Calcd. for C22H19N5OS3 (465.08): C, 56.75; H, 4.11; N, 15.04; found: C, 56.53; H, 4.04; N, 14.86.
5-((4-Chlorophenyl)diazenyl)-2-(3,5-di(thiophen-2-yl)-4,5-dihydro-1H-pyrazol-1-yl)-4-methylthiazole(8d). Orange solid, m.p. 153–155 °C; IR: 3063, 2922 (C-H), 1605 (C=N) cm−1; 1H-NMR (300 MHz, DMSO-d6): δ 2.56 (s, 3H, CH3), 3.08 (dd, 1H, HA, J = 17.2, 6.1 Hz), 4.08 (dd, 1H, HB, J = 17.2, 12.0 Hz), 6.16 (dd, 1H, HX, J = 12.0, 6.1 Hz), 6.98–7.85 (m, 10H, Ar-H); MS, m/z (%) 471 (M++2, 1), 469 (M+, 4), 368 (6), 264 (15), 111 (59), 77 (57), 43 (100). Anal. Calcd. for C21H16ClN5S3 (469.03): C, 53.66; H, 3.43; N, 14.90; found: C, 53.49; H, 3.40; N, 14.73.
2-(3,5-Di(thiophen-2-yl)-4,5-dihydro-1H-pyrazol-1-yl)-4-methyl-5-((4-nitrophenyl)-diazenyl)thiazole (8e). Brown solid, m.p. 162–164 °C; IR: 3096, 2920 (C-H), 1590 (C=N) cm−1; 1H-NMR (300 MHz, DMSO-d6): δ 2.61 (s, 3H, CH3), 3.09 (dd, 1H, HA, J = 17.2, 6.1 Hz), 4.11 (dd, 1H, HB, J = 17.2, 12.0 Hz), 6.21 (dd, 1H, HX, J = 12.0, 6.1 Hz), 6.58–7.95 (m, 10H, Ar-H); MS, m/z (%) 480 (M+, 7), 427 (16), 232 (31), 111 (100), 77 (59), 43 (86). Anal. Calcd. for C21H16N6O2S3 (480.58): C, 52.48; H, 3.36; N, 17.49; found: C, 52.28; H, 3.19; N, 17.33.

3.5. Alternate Synthesis of 8a

Equimolar amounts of chalcone 1 (0.220 g, l mmol) and 2-hydrazinyl-4-methyl-5-(phenyldiazenyl)thiazole (9) (0.233 g, 1 mmol) in 2-propanol (10 mL), was refluxed for 2 h then cooled to room temperature. The solid precipitated was filtered off, washed with water, dried, and recrystallized from dimethylformamide to give the corresponding product, 8a which were identical in all aspects (m.p., mixed m.p. and IR spectra) with those obtained from reaction of 2 with 6a but in 70% yield.

3.6. General Method for Synthesis of Compounds 11a,b, 13, and 15

Method A: A mixture of chalcone 1 (0.220 g, 1 mmol) and the appropriate heterocyclic amine (10a,b, 12 or 14) (1 mmol) in ethanol (20 mL) in the presence of catalytic drops of acetic acid was refluxed for 10–15 h (monitored through TLC). The reaction mixture was poured into water and the solid product was collected by filtration followed by washing with ethanol. The crude product was then recrystallized from EtOH or DMF to give pure products 11a,b, 13, and 15, respectively.
Method B: Repetition of the same reactions of method A with heating in microwave oven at 500 W and 150 °C for a period of time gave products identical in all respects with those separated from method A. Compounds 11a,b, 13, and 15 with their physical constants and spectral data are depicted as shown below:
5,7-Di(thiophen-2-yl)-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidine (11a). Yellow solid m.p. 241–243 °C (DMF); IR: 3425 (NH), 3091, 2920 (C-H), 1599 (C=N), cm−1; 1H-NMR: δ 5.14 (d, J = 4 Hz, 1Ha, CH-pyrimidine), 6.20 (d, J = 4 Hz, 1Hb, CH-pyrimidine), 6.85–8.04 (m, 6H, Ar-H), 8.45 (1H, s, triazole-H), 8.73 (s, br, 1H, NH); MS m/z (%): 286 (M+, 31), 284 (100), 111 (52), 69 (44). Anal. Calcd. for C13H10N4S2 (286.03): C, 54.52; H, 3.52; N, 19.56; found: C, 54.40; H, 3.64; N, 19.51.
5,7-Di(thiophen-2-yl)-4,7-dihydrotetrazolo[1,5-a]pyrimidine (11b). Yellow solid, m.p. 266–268 °C (DMF); IR: 3402 (NH), 3087, 2924 (C-H), 1636 (C=N), cm−1; 1H-NMR: δ 5.41 (d, J= 4 Hz, 1Ha, CH-pyrimidine), 6.08 (d, J = 4 Hz, 1Hb, CH-pyrimidine), 7.16–8.24 (m, 6H, Ar-H), 8.29 (s,br, 1H, NH); MS m/z (%): 287 (M+, 20), 259 (73), 220 (99), 111 (100), 65 (48). Anal. Calcd. for C12H9N5S2 (287.03): C, 50.16; H, 3.16; N, 24.37; found: C, 50.29; H, 3.07; N, 24.39.
2-Phenyl-5,7-di(thiophen-2-yl)-4,7-dihydropyrazolo[1,5-a]pyrimidine (13). Yellow solid m.p. 218–220 °C (DMF); IR: 3429 (NH), 3095, 3071, 2923 (C-H), 1596 (C=N) cm−1; 1H-NMR: δ 4.86 (d, J= 4 Hz, 1Ha, CH-pyrimidine), 6.14 (d, J = 4 Hz, 1Hb, CH-pyrimidine), 6.59 (s, 1H, pyrazole-H), 6.80–8.25 (m, 11H, Ar-H), 8.72 (s,br, 1H, NH); MS m/z (%): 361 (M+, 27), 359 (100), 228 (16), 111 (49), 77 (63). Anal. Calcd. for C20H15N3S2 (361.07): C, 66.45; H, 4.18; N, 11.62; found: C, 66.61; H, 4.09; N, 11.60.
2,4-Di(thiophen-2-yl)-1,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrimidine (15). Yellow solid, m.p. 230–232 °C (EtOH); IR: 3412 (NH), 3077, 2920 (C-H), 1599 (C=N) cm−1; 1H-NMR: δ 4.79 (d, J = 4 Hz, 1Ha, CH-pyrimidine), 6.12 (d, J = 4 Hz, 1Hb, CH-pyrimidine), 6.69–8.27 (m, 10H, Ar-H), 8.49 (s, br, 1H, NH); MS m/z (%): 335 (M+, 18), 333 (100), 224 (23), 111 (50), 64 (53). Anal. Calcd. for C18H13N3S2 (335.06): C, 64.45; H, 3.91; N, 12.53; found: C, 64.68; H, 3.87; N, 12.49.

3.7. Biological Activity

3.7.1. Antimicrobial Activity

Antimicrobial activity was determined using the agar disc diffusion assay method as described previously by Hossain et al. [33]. The tested organisms were sub-cultured on Trypticase soya agar medium (Oxoid Laboratories, Corporate, UK) for bacteria and Sabouraud dextrose agar (Oxoid Laboratories, Corporate, UK) for fungi. Chloramphenicol and Trimethoprim/sulphamethoxazole were used as a positive control and DMSO solvent as a negative control. The plates were done in duplicate and average zone of inhibition was calculated. Bacterial cultures were incubated at 37 °C for 24 h while the other fungal cultures were incubated at (25–30 °C) for 3–5 days. Antimicrobial activity was determined by measurement zone of inhibition.

3.7.2. Media Used

Sabouraud dextrose agar: The medium used for isolation of pathogenic yeasts has the following composition (g/L): glucose, 20; peptone, 10; agar, 25 and distilled water, 1 L, pH was adjusted at 5.4. The medium was autoclaved at 121 °C for 15 min.
Trypticase soya agar (TSA): The medium was used to cultivate tested bacteria. It contains (g/L) Tryptone (Pancreatic Digest of Casein) 15.0 g, Soytone (Papaic Digest of Soybean Meal) 5.0 g, Sodium Chloride 5.0 g, Agar 15.0 g, and distilled water 1 L. The medium was autoclaved at 121 °C for 15 min.

4. Conclusions

At the end, we have succeeded in the synthesis of new derivatives of pyrazole, isoxazole, pyrazolylthiazole, and azolopyrimidine incorporated with a thiophene ring under microwave irradiation. Different spectroscopic methods and elemental analyses were used to confirm the structures of the newly synthesized compounds. The antimicrobial results of the examined compounds revealed promising results and some derivatives have activities similar to the references used.

Acknowledgments

The authors extend their sincere appreciation to the Deanship of Scientific Research at King Saud University for its funding this Prolific Research group (PRG-1437-29).

Author Contributions

Sobhi M. Gomha, Mohie E.M. Zayed, and Amany M.G. Mohamed conceived and designed the experiments; Mohie E.M. Zayed, and Amany M.G. Mohamed performed the experiments; Sobhi M. Gomha, Yahia Nasser Mabkhot and Thoraya A. Farghaly analyzed the data; Sobhi M. Gomha, Mohie E.M. Zayed, Amany M.G. Mohamed and Yahia Nasser Mabkhot contributed reagents/materials/analysis tools; Thoraya A. Farghaly and Sobhi M. Gomha wrote the paper. All authors have read and approved the final manuscript.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Mongevega, A.; Aldama, I.; Robbani, M.M.; Fernandez, E. The synthesis of 11H-1,2,4-triazolo[4,3-b]pyridazino[4,5-b]indoles,11H-tetrazolo[4,5-b]pyridazino[4,5-b]indoles and 1,2,4-triazolo[3,4-f]-1,2,4-triazino[4,5-a]indoles. J. Heterocycl. Chem. 1980, 17, 77–80. [Google Scholar] [CrossRef]
  2. Russe, L.R.K.; Press, J.B.; Rampulla, R.A. Thiophene systems. 9. Thienopyrimidinedione derivatives as potential antihypertensive agents. J. Med. Chem. 1988, 31, 1786–1793. [Google Scholar] [CrossRef]
  3. Abdelhamid, A.O. Convenient synthesis of some new pyrazolo[1,5-a]pyrimidine, pyridine, thieno[2,3-b]pyridine, and isoxazolo[3,4-d]pyridazine derivatives containing benzofuran moiety. J. Heterocycl. Chem. 2009, 46, 680–686. [Google Scholar] [CrossRef]
  4. Rashad, A.E.; Shamroukh, A.H.; Abdel-Megeid, R.E.; Mostafa, A.; El-Shesheny, R.; Kandeil, A.; Ali, M.A.; Banert, K. Synthesis and screening of some novel fused thiophene and thienopyrimidine derivatives for anti-avian influenza virus (H5N1) activity. Eur. J. Med. Chem. 2010, 45, 5251–5257. [Google Scholar] [CrossRef] [PubMed]
  5. Deka, S.; Mohan, S.; Saravanan, J.; Kakati, M.; Talukdar, A.; Sahariah, B.J.; Dey, B.K.; Sarma, R.K. Syntheses, characterization and in vitro anti-Inflammatory activity of some novel thiophenes. Maced. J. Med. Sci. 2012, 5, 159–163. [Google Scholar]
  6. Ghorab, M.M.; Bashandy, M.S.; Alsaid, M.S. Novel thiophene derivatives with sulfonamide, isoxazole, benzothiazole, quinoline and anthracene moieties as potential anticancer agents. Acta Pharm. 2014, 64, 419–431. [Google Scholar] [CrossRef] [PubMed]
  7. Saad, H.A.; Youssef, M.M.; Mosselhi, M.A. Microwave assisted synthesis of some new fused 1,2,4-triazines bearing thiophene moieties with expected pharmacological activity. Molecules 2011, 16, 4937–4957. [Google Scholar] [CrossRef] [PubMed]
  8. Dawood, D.H.; Batran, R.Z.; Farghaly, T.A.; Khedr, M.A.; Abdulla, M.M. New Coumarin Derivatives as Potent Selective COX-2 Inhibitors; Synthesis, Anti-inflammatory, QSAR and Molecular Modeling Studies. Arch. Pharm. Chem. Life Sci. 2015, 348, 875–888. [Google Scholar] [CrossRef] [PubMed]
  9. Tewari, A.K.; Singh, V.P.; Yadav, P.; Gupta, G.; Singh, A.; Goel, R.K.; Shinde, P.; Mohan, G.C. Synthesis, biological evaluation and molecular modeling study of pyrazole derivatives as selective COX-2 inhibitors and anti-inflammatory agents. Bioorg. Chem. 2014, 56, 8–15. [Google Scholar] [CrossRef] [PubMed]
  10. Ningaiah, S.; Bhadraiah, U.K.; Doddaramappa, S.D.; Keshavamurthy, S.; Javarasetty, C. Novel pyrazole integrated 1,3,4-oxadiazoles: Synthesis, characterization and antimicrobial evaluation. Bioorg. Med. Chem. Lett. 2014, 24, 245–248. [Google Scholar] [CrossRef] [PubMed]
  11. Farghaly, T.A.; Gomha, S.M.; Sayed, A.R.; Khedr, M.A. Hydrazonoyl Halides as Precursors for Synthesis of Bioactive Thiazole and Thiadiazole Derivatives: Synthesis, Molecular Docking and Pharmacological Study. Curr. Org. Syn. 2016, 13, 445–455. [Google Scholar] [CrossRef]
  12. Farghaly, T.A.; Abdallah, M.A.; Masaret, G.S.; Muhammad, Z.A. New and efficient approach for synthesis of novel bioactive [1,3,4]thiadiazoles incorporated with 1,3-thiazole moiety. Eur. J. Med. Chem. 2015, 97, 320–333. [Google Scholar] [CrossRef] [PubMed]
  13. Mert, S.; Kasimogullari, R.; Ica, T.; Colak, F.; Altun, A.; Ok, S. Synthesis, structure–activity relationships, and in vitro antibacterial and antifungal activity evaluations of novel pyrazole carboxylic and dicarboxylic acid derivatives. Eur. J. Med. Chem. 2014, 78, 86–96. [Google Scholar] [CrossRef] [PubMed]
  14. Chang, S.; Zhang, Z.; Zhuang, X.; Luo, J.; Cao, X.; Li, H.; Tu, Z.; Lu, X.; Ren, X.; Ding, K. New thiazolecarboxamides as potent inhibitors of Akt kinases. Bioorg. Med. Chem. Lett. 2012, 22, 1208–1212. [Google Scholar] [CrossRef] [PubMed]
  15. Li, M.; Zhao, B. Progress of the synthesis of condensed pyrazole derivatives (from 2010 to mid-2013). Eur. J. Med. Chem. 2014, 85, 311–340. [Google Scholar] [CrossRef] [PubMed]
  16. Gao, M.; Wang, M.; Miller, K.D.; Zheng, Q.H. Synthesis and preliminary in vitro biological evaluation of new carbon-11-labeled celecoxib derivatives as candidate PET tracers for imaging of COX-2 expression in cancer. Eur. J. Med. Chem. 2011, 46, 4760–4767. [Google Scholar] [CrossRef] [PubMed]
  17. Meena, D.R.; Maiti, B.; Chanda, K. Cu(I) catalyzed microwave assisted telescopic synthesis of 3,5-disubstituted isoxazoles in green media. Tetrahedron Lett. 2016, 57, 5514–5517. [Google Scholar] [CrossRef]
  18. Balwe, S.G.; Shinde, V.V.; Jeong, Y.T. Iron-catalyzed microwave-promoted expeditious one-pot synthesis of benzo[b][1,4]thiazine-4-carbonitrile under solvent-free condition. Tetrahedron Lett. 2016, 57, 5074–5078. [Google Scholar] [CrossRef]
  19. Abbas, E.M.H.; Gomha, S.M.; Farghaly, T.A. Multicomponent Reactions for Synthesis of Bioactive Polyheterocyclic Ring Systems under Controlled Microwave Irradiation. Arabian J. Chem. 2014, 7, 623–629. [Google Scholar] [CrossRef]
  20. Gomha, S.M.; Riyadh, S.M. Synthesis of triazolo[4,3-b][1,2,4,5]tetrazines and triazolo[3,4-b][1,3,4]thiadiazines using chitosan as ecofriendly catalyst under microwave irradiation. ARKIVOC 2009, 2009, 58–68. [Google Scholar]
  21. Gomha, S.M.; Eldebss, T.M.A.; Badrey, M.G.; Abdulla, M.M.; Mayhoub, A.S. Novel 4-Heteroaryl-Antipyrines as DPP-IV Inhibitors. Chem. Biol. Drug Des. 2015, 86, 1292–1303. [Google Scholar] [CrossRef] [PubMed]
  22. Awad, H.M.; Fayad, W.; El-Hallouty, S.M.; Farghaly, T.A.; Abdallah, M.M. Anticancer Activity of Some [1,2,4]Triazepino[2,3-a]Quinazoline Derivatives: Monolayer and Multicellular Spheroids In Vitro Models. Med. Chem. Res. 2016, 25, 1952–1957. [Google Scholar] [CrossRef]
  23. Gomha, S.M.; Farghaly, T.A.; Sayed, A.R.; Abdalla, M.M. Synthesis of pyrazolyl-pyrazoles and pyrazolyl-[1,2,4]-triazolo[3,4-d][1,5]benzothiazepines as p53 activators using hydrazonoyl chlorides. J. Heterocycl. Chem. 2016, 53, 1503–1509. [Google Scholar] [CrossRef]
  24. Farghaly, T.A.; Gomha, S.M.; Mousa, E.K.; Elaasser, M. Hydrazonoyl chlorides in synthesis of pyrazolo[5,1-c][1,2,4]triazole derivatives and their biological activities. J. Chem. Res. 2016, 40, 467–470. [Google Scholar] [CrossRef]
  25. Abbas, E.M.H.; Gomha, S.M.; Farghaly, T.A.; Abdalla, M.M. Synthesis of new thiazole derivatives as antitumor agents. Curr. Org. Syn. 2016, 13, 456–465. [Google Scholar] [CrossRef]
  26. Farghaly, T.A.; Gomha, S.M.; Abbas, E.M.H.; Abdalla, M.M. Hydrazonoyl halides as precursors for new fused heterocycles of 5 α-reductase inhibitors. Arch. Pharm. 2012, 345, 117–122. [Google Scholar] [CrossRef] [PubMed]
  27. Khloya, P.; Kumar, S.; Kaushik, P.; Surain, P.; Kaushik, D.; Sharma, P.K. Synthesis and biological evaluation of pyrazolylthiazole carboxylic acids as potent anti-inflammatory-antimicrobial agents. Bioorg. Med. Chem. Lett. 2015, 25, 1177–1181. [Google Scholar] [CrossRef] [PubMed]
  28. Turan, Z.G.; Chevallet, P.; Kilic, T.S.; Erolic, K. Synthesis of some thiazolyl-pyrazoline derivatives and preliminary investigation of their hypotensive acivity. Eur. J. Med. Chem. 2000, 35, 635–641. [Google Scholar] [CrossRef]
  29. Nishida, S.; Maruoka, H.; Yoshimura, Y.; Goto, T.; Tomita, R.; Masumoto, E.; Okabe, F.; Yamagata, K.; Fiyioka, T. Synthesis and biological activities of some new thizolidine derivatives containing pyrazole ring system. J. Heterocycl. Chem. 2012, 49, 303–309. [Google Scholar] [CrossRef]
  30. Ozdemir, Z.; Kandilci, H.B.; Gumusel, B.; Calis, U.; Bilgin, A.A. Synthesis and Studies on Antidepressant and Anticonvulsant Activities of Some 3-(2-Thienyl)pyrazoline Derivatives. Arch. Pharm. 2008, 341, 701–707. [Google Scholar] [CrossRef] [PubMed]
  31. Eweiss, N.F.; Osman, A. Synthesis of heterocycles. Part II new routes to acetylthiadiazolines and alkylazothiazoles. J. Heterocycl. Chem. 1980, 17, 1713–1717. [Google Scholar] [CrossRef]
  32. Abdelhamid, A.O.; Sayed, A.R. Reaction of Hydrazonoyl Halides 52: Synthesis and Antimicrobial Activity of Some New Pyrazolines and 1,3,4-Thiadiazolines. Phosphorus Sulfur Silicon Relat. Elem. 2007, 182, 1767–1777. [Google Scholar] [CrossRef]
  33. Hossain, M.A.; Shah, M.D.; Sang, S.V.; Sakari, M. Chemical composition and antibacterial properties of the essential oils and crude extracts of Merremiaborneensis. J. King Saud Univ. Sci. 2012, 24, 243–249. [Google Scholar] [CrossRef]
  • Sample Availability: Samples of the compounds 2, 4, 5, 6, 8, 11, 13 and 15 are available from the authors.
Scheme 1. Synthesis of pyrazoline derivatives 2, 4ac, and 5.
Scheme 1. Synthesis of pyrazoline derivatives 2, 4ac, and 5.
Molecules 22 00346 sch001
Scheme 2. Synthesis of arylazothiazole derivatives 8ae.
Scheme 2. Synthesis of arylazothiazole derivatives 8ae.
Molecules 22 00346 sch002
Scheme 3. Synthesis of azolopyrimidine derivatives 11a,b, 13 and 15.
Scheme 3. Synthesis of azolopyrimidine derivatives 11a,b, 13 and 15.
Molecules 22 00346 sch003
Table 1. Comparison between conventional heating and microwave irradiation for synthesis of compounds 4ac, 8ae, 11a,b, 13, and 15.
Table 1. Comparison between conventional heating and microwave irradiation for synthesis of compounds 4ac, 8ae, 11a,b, 13, and 15.
Compound No.Reaction TimesReaction Yields (%)
Conventional MethodsMicrowaveConventional MethodsMicrowave
22 h [30]3 min66 [30]84
4a4 h5 min7085
4b5 h8 min7390
4c5h10 min6988
56 h10 min6782
8a6 h8 min7495
8b8 h10 min7690
8c10 h12 min6892
8d8 h9 min7293
8e10 h13 min7590
11a10 h12 min7089
11b15 h15 min6081
1310 h15 min6788
1513 h20 min6085
Table 2. Antimicrobial activity of compounds 2, 4ac, 5, 8ae, 11a,b, 13, and 15 compared to reference drug.
Table 2. Antimicrobial activity of compounds 2, 4ac, 5, 8ae, 11a,b, 13, and 15 compared to reference drug.
Compound NumberFungiGram Positive BacteriaGram Negative Bacteria
ASPCASABSEC
2NA.NA.211923
4aN.A.N.A.182015
4bN.A.20171818
4cN.A.23222017
5N.A.9191217
8aN.A10121811
8bN.A.8211812
8cN.A.24181523
8dN.A.N.A.221217
8eN.A.8181413
11aN.A.9N.A.N.A.10
11bN.A.25191711
13N.A.1214118
15N.A.11211915
Chloramphenicol2925302429
Trimethoprim/sulphamethoxazole2.413202324
DMSON.A.N.A.N.A.N.A.N.A.
High activity Molecules 22 00346 i001 Moderate activity Molecules 22 00346 i002 Low activity Molecules 22 00346 i003 N.A. (No activity) Molecules 22 00346 i004
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