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. 2021 Apr 7;26(8):2110. doi: 10.3390/molecules26082110

1,3,4-Oxadiazole N-Mannich Bases: Synthesis, Antimicrobial, and Anti-Proliferative Activities

Lamya H Al-Wahaibi 1, Ahmed A B Mohamed 2, Samar S Tawfik 3, Hanan M Hassan 4, Ali A El-Emam 2,*
Editor: Athina Geronikaki
PMCID: PMC8067589  PMID: 33916955

Abstract

The reaction of 5-(3,4-dimethoxyphenyl)-1,3,4-oxadiazole-2(3H)-thione 3 with formaldehyde solution and primary aromatic amines or 1-substituted piperazines, in ethanol at room temperature yielded the corresponding N-Mannich bases 3-arylaminomethyl-5-(3,4-dimethoxyphenyl)-1,3,4-oxadiazole-2(3H)-thiones 4a–l or 3-[(4-substituted piperazin-1-yl)methyl]-5-(3,4-dimethoxyphenyl)-1,3,4-oxadiazole-2(3H)-thiones 5a–d, respectively. The in vitro inhibitory activity of compounds 4a–l and 5a–d was assessed against pathogenic Gram-positive, Gram-negative bacteria, and the yeast-like pathogenic fungus Candida albicans. The piperazinomethyl derivatives 5c and 5d displayed broad-spectrum antibacterial activities the minimal inhibitory concentration (MIC) 0.5–8 μg/mL) and compounds 4j, 4l, 5a, and 5b showed potent activity against the tested Gram-positive bacteria. In addition, the anti-proliferative activity of the compounds was evaluated against prostate cancer (PC3), human colorectal cancer (HCT-116), human hepatocellular carcinoma (HePG-2), human epithelioid carcinoma (HeLa), and human breast cancer (MCF7) cell lines. The optimum anti-proliferative activity was attained by compounds 4l, 5a, 5c, and 5d.

Keywords: 1,3,4-oxadiazoles; N-Mannich bases; antimicrobial activity; anti-proliferative activity

1. Introduction

The 1,3,4-Oxadiazoles are an important class of heterocyclic compounds with diverse pharmacological properties [1,2,3]. The 1,3,4-Oxadiazole nucleus represents an essential building unit in several drugs including the broad spectrum antibacterial drug furamizole [4], the antiretroviral drug raltegravir [5], the anticancer agent zibotentan [6], the anti-obesity/antidiabetic agent AZD 3988 [7], and the antihypertensive drugs tiodazosin [8], and nesadipil [9].

In addition, there is a growing interest in the chemotherapeutic activities of 2,5-disubstituted-1,3,4-oxadiazoles as antibacterial [10,11,12], antifungal [13,14,15], antitubercular [16,17], and antiviral [18,19,20,21] agents. Moreover, 1,3,4-Oxadiazole-2(3H)-thiones, their thioether derivatives and 3-aminomethyl analogues (N-Mannich bases) are the most interesting for their anticancer activities [21,22]. The 1,3,4-Oxadiazole derivatives exert their anticancer activities via different mechanisms, such as targeting epidermal growth factor receptors (EGFR) [23], vascular endothelial growth factor receptors (VEGF) [24], focal-adhesion kinase (FAK) [25,26], histone deacetylases (HDAC) [27,28], methionine aminopeptidase (MetAP) [29], NF-κB (nuclear factor κB) [30], poly(ADP-ribose) polymerase (PARP-1) [31], thymidine phosphorylase (TP) [32], telomerase [33], thymidylate synthase (TS) [34], zinc-finger protein 143 (ZNF143) [35], and tubulin polymerase [36].

Furthermore, 1,3,4-oxadiazoles were proved to exhibit potent anti-inflammatory [37,38,39], antioxidant [40], antidiabetic [41,42], and monoamine oxidase (MAO) inhibitory activities [43,44]. Besides, 1,3,4-oxadiazole derivatives are highly attractive compounds in the development of organic light-emitting diodes (OLEDs) [45,46].

Furthermore, 3,4-dimethoxyphenyl moiety represents an essential motif in various chemotherapeutic agents with anticancer [47,48,49,50,51,52], antibacterial [53,54], and antiviral [55] activities.

Motivated by the above-mentioned findings and following an ongoing interest in the pharmacological [56] and structural properties [57,58,59] of 1,3,4-oxadiazole-2(3H)-thione N-Mannich bases, we report herein the synthesis, characterization, antibacterial, antifungal, and anti-proliferative activities of related series of 5-(3,4-dimethoxyphenyl)-1,3,4-oxadiazole-2(3H)-thione N-Mannich bases.

2. Results and Discussion

2.1. Chemical Synthesis

The 3,4-Dimethoxybenzohydrazide 2 was prepared from the commercially-available methyl 3,4-dimethoxybenzoate 1 via treatment with hydrazine in ethanol [60]. 1,3,4-Oxadiazole-2(3H)-thione 3 was obtained via reaction of the carbohydrazide 2 with carbon disulfide in ethanolic potassium hydroxide as previously described [61]. Furthermore, 1,3,4-Oxadiazole-2(3H)-thiones were reported to undergo aminomethylation through reaction with primary aromatic amines and formaldehyde to yield the corresponding N-Mannich bases [62]. Consequently, treatment of 3 with formaldehyde solution and various primary aromatic amines or 1-substituted piperazines, in ethanol at room temperature yielded their corresponding 3-arylaminomethyl 4a–l or 3-piperazinomethyl 5a–d N-Mannich bases, respectively, in good yields (Scheme 1, Table 1).

Scheme 1.

Scheme 1

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Synthesis of compounds 4a–l and 5a–d.

Table 1.

Crystallization solvents, melting points (M.P.), yield percentages, molecular (Mol.) formulae, and molecular weights (Wt.) of compounds 4a–l and 5a–d.

Compound No. X/R Crystallization Solvents M.P. (°C) Yield (%) Mol. Formula (Mol. Wt.)
4a H EtOH/H2O 147–149 82 C17H17N3O3S (343.40)
4b 4-F EtOH/H2O 135–137 84 C17H16FN3O3S (361.39)
4c 3-Cl EtOH 143–145 77 C17H16ClN3O3S (377.85)
4d 4-Cl EtOH 166–168 79 C17H16ClN3O3S (377.85)
4e 2-NO2 EtOH/CHCl3 211–213 88 C17H16N4O5S (388.40)
4f 3-NO2 EtOH/CHCl3 181–183 85 C17H16N4O5S (388.40)
4g 4-NO2 EtOH/CHCl3 222–224 92 C17H16N4O5S (388.40)
4h 2-CF3 EtOH/H2O 220–222 90 C18H16F3N3O3S (411.40)
4i 3-CF3 EtOH/H2O 206–208 86 C18H16F3N3O3S (411.40)
4j 2,4-F2 EtOH 169–171 92 C17H15F2N3O3S (379.38)
4k 2,5-F2 EtOH 212–214 90 C17H15F2N3O3S (379.38)
4l 2,4-Cl2 EtOH 227–229 94 C17H15Cl2N3O3S (412.29)
5a C6H5 EtOH 151–153 85 C21H24N4O3S (412.51)
5b 4-FC6H4 EtOH 118–120 78 C21H23FN4O3S (430.50)
5c C6H5CH2 EtOH/H2O 121–123 75 C22H26N4O3S (426.53)
5d 2-CF3C6H4CH2 EtOH 141–143 89 C23H25F3N4O3S (494.53)
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The structures of compounds 4a–l and 5a–d were confirmed by elemental analyses, 1H NMR and 13C NMR spectral data.

2.2. In Vitro Antibacterial and Antifungal Activities

The in vitro growth inhibitory activity of compounds 4a–l and 5a–d was evaluated towards the standard Gram-positive bacterial strains Staphylococcus aureus American type culture collection (ATCC) 6571, Bacillus subtilis ATCC 5256 and Micrococcus luteus ATCC 27141, Gram-negative bacterial strains Escherichia coli ATCC 8726, and Pseudomonas aeruginosa ATCC 27853, and the yeast-like pathogenic fungus Candida albicans MTCC 227. The initial screening was performed by the semi-quantitative agar-disc diffusion method using Müller-Hinton agar medium [63]. The results of the preliminary screening of compounds 4a–l and 5a–d (200 μg/disc); the antibacterial antibiotics Gentamicin sulfate, Ampicillin trihydrate, and the antifungal drug Clotrimazole (100 μg/disc); and the calculated log P values (Clog P) are depicted in Table 2.

Table 2.

In vitro activity of compounds 4a–l and 5a–d (200 μg/8 mm disc); the broad-spectrum antibacterial drugs Gentamicin sulfate, Ampicillin trihydrate, and the antifungal drug Clotrimazole (100 μg/8 mm disc) against Staphylococcus aureus American type culture collection (ATCC) 6571 (SA), Bacillus subtilis ATCC 5256 (BS), Micrococcus luteus ATCC 27,141 (ML), Escherichia coli ATCC 8726 (EC), Pseudomonas aeruginosa ATCC 27,853 (PA), and the yeast-like pathogenic fungus Candida albicans MTCC 227 (CA).

Comp.
No.		 C log Pc Diameter of Growth Inhibition Zone (mm) a
SA BS ML EC PA CA
4a 3.701 14 13 15 - - 10
4b 4.146 15 16 17 - - 12
4c 4.716 14 17 13 - - -
4d 4.716 15 13 14 - - -
4e 4.242 12 11 10 - - 13
4f 4.092 11 12 - - - 12
4g 4.092 13 12 11 - - 16
4h 5.113 15 12 - - - -
4i 5.113 16 12 - - - -
4j 4.395 19 (4) b 12 16 12 13 11
4k 4.395 17 14 15 14 - 12
4l 5.535 19 (4) b 21 (2) b 18 (16) b 15 12 11
5a 3.789 23 (1) b 26 (1) b 21 (1) b 14 13 -
5b 4.103 20 (8) b 23 (1) b 20 (1) b 16 17 -
5c 4.712 26 (1) b 30 (0.5) b 22 (1) b 19 (4) b 18 (4) b -
5d 5.595 28 (1) b 29 (1) b 26 (1) b 22 (1) b 20 (2) b -
Gentamicin sulfate 27 (1) b 26 (2) b 20 (2) b 22 (0.5) b 21 (0.5) b NT
Ampicillin trihydrate 22 (2) b 23 (1) b 20 (2) b 16 (8) b 16 (8) b NT
Clotrimazole NT NT NT NT NT 21 (4) b
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a (-): inactive (inhibition zone < 10 mm), b Figures shown in parentheses represent the minimal inhibitory concentration (MIC) values (μg/mL), c Calculated using the CS ChemOffice Ultra version 8.0, CambridgeSoft, Cambridge, MA, USA), NT: not tested. SA, Staphylococcus aureus; BS, Bacillus subtilis; ML, Micrococcus luteus; EC, Escherichia coli; PA, Pseudomonas aeruginosa; CA, Candida albicans. High activity (>18 mm) values have been bolded for emphasis.

The results revealed that potent antibacterial activity was displayed by the compounds 4j, 4l, 5a, 5b, 5c, and 5d, which displayed growth inhibition zones ≥ 18 mm against one or more of the tested microorganisms. In addition, compounds 4a, 4b, 4c, 4d, 4h, 4i, and 4k showed medium activity (growth inhibition zones 14–17 mm) and compounds 4e, 4f, and 4g showed poor antibacterial activity (growth inhibition zones 10–13 mm) against the tested microorganisms. In general, the activity against the tested Gram-positive bacteria is higher than the activity against the tested Gram-negative bacteria. The optimal antibacterial activity was attained by compounds 5c and 5d, which showed potent and broad-spectrum antibacterial activity against all the tested bacterial strains. The inhibitory activity of the compounds against Candida albicans was generally lower than their antibacterial activity, compounds 4g displayed medium activity, and all other compounds were either poorly active or inactive compared with Clotrimazole.

The minimal inhibitory concentrations (MICs) of the most active compounds 4j, 4l, 5a, 5b, 5c, and 5d, and the antibacterial antibiotics Gentamicin sulfate, Ampicillin trihydrate, and the antifungal drug Clotrimazole were determined by the microdilution susceptibility method in Müller–Hinton broth and Sabouraud liquid medium [64]. The MIC values were highly consistent with their growth inhibition zones.

Based on the results of the antibacterial activity, it could be concluded that the activity of the piperazinomethyl N-Mannich bases 5a–d is superior to their arylaminomethyl analogues 4a–l. Considering the anilinomethyl analogue 4a as the basic structure of the arylaminomethyl analogues 4a–l, the antibacterial activity of the monohalo derivatives 4b–d was slightly improved against the tested Gram-positive bacteria. Meanwhile, the antibacterial activity of the nitro derivatives 4e–g was greatly declined with general improvement of the antifungal activity. Despite the high lipophilicity of the trifluoromethyl derivatives 4h and 4i, the compounds only retained moderate activity against Staphylococcus aureus and lacked activity against the tested Gram-positive bacteria and Candida albicans. Introduction a difluoro- or dichlorophenyl moieties (compounds 4j–l) greatly enhanced the Gram-positive antibacterial activity and these derivatives endowed moderate or marginal activity against the tested Gram-negative bacteria and Candida albicans.

The replacement of the arylaminomethyl moiety with a piperazinomethyl moiety greatly enhanced the antibacterial activity and the piperazinomethyl derivatives 5a–d exhibited higher potency and broader antibacterial spectrum compared to their arylaminomethyl analogues 4a–l, with no antifungal activity. In addition, the antibacterial activity of the piperazinomethyl derivatives seems correlated to their lipophilicity as the optimum antibacterial activity against the tested Gram-negative bacteria was displayed by compounds 5c and 5d.

2.3. In Vitro Anti-proliferative Activity

The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) colorimetric assay [65,66] was adopted to evaluate the in vitro anti-proliferative activity of compounds 4a–l and 5a–d against five human cancer cell lines namely; prostate cancer (PC3), human colorectal cancer (HCT-116), human hepatocellular carcinoma (HePG-2), human epithelioid carcinoma (HeLa) and human breast cancer (MCF7) cell lines. The results of the anti-proliferative activity of compounds 4a–l, 5a–d, and the anticancer drug Doxorubicin [67] are displayed in Table 3.

Table 3.

In vitro anti-proliferative activity of the tested compounds 4a–l, 5a–d, and Doxorubicin expressed as IC50 values against prostate cancer (PC3), human colorectal cancer (HCT-116), human hepatocellular carcinoma (HePG-2), human epithelioid carcinoma (HeLa), and MCF7 human cancer cell line.

Comp.
No.		 IC50 (µM) a
PC3 HCT-116 HePG-2 HeLa MCF7
4a 63.94 ± 3.8 53.17 ± 3.3 47.23 ± 3.1 28.31 ± 2.0 55.34 ± 2.8
4b 71.80 ± 4.0 77.52 ± 4.1 56.34 ± 3.3 49.47 ± 3.0 68.26 ± 3.4
4c 84.52 ± 4.8 39.44 ± 2.6 78.86 ± 4.1 44.69 ± 2.8 33.86 ± 2.3
4d 78.35 ± 4.5 48.30 ± 3.0 73.80 ± 3.9 54.02 ± 3.2 40.52 ± 2.5
4e >100 92.11 ± 4.9 >100 75.61 ± 3.9 88.33 ± 3.9
4f 74.67 ± 4.4 69.38 ± 3.8 58.41 ± 3.5 57.26 ± 2.5 65.35 ± 3.2
4g >100 92.11 ± 4.9 >100 75.61 ± 3.9 88.33 ± 3.9
4h 59.48 ± 3.5 35.01 ± 2.7 42.74 ± 2.9 31.72 ± 2.2 29.10 ± 2.1
4i 59.48 ± 3.5 35.01 ± 2.7 42.74 ± 2.9 31.72 ± 2.2 29.10 ± 2.1
4j 95.61 ± 5.1 64.07 ± 3.5 86.45 ± 4.5 61.98 ± 3.5 59.87 ± 2.7
4k 75.22 ± 4.1 61.07 ± 3.4 77.40 ± 3.6 49.55 ± 3.2 29.56 ± 3.6
4l 34.60 ± 2.3 19.95 ± 1.8 17.42 ± 1.4 10.96 ± 1.1 12.97 ± 1.0
5a 52.53 ± 3.3 27.49 ± 2.3 36.08 ± 2.5 24.09 ± 1.8 17.80 ± 1.3
5b >100 89.26 ± 4.6 91.78 ± 4.9 67.53 ± 3.7 79.16 ± 3.6
5c 23.92 ± 1.9 14.69 ± 1.2 11.93 ± 1.0 9.50 ± 0.8 6.49 ± 0.4
5d 38.02 ± 2.5 32.81 ± 2.6 22.91 ± 1.6 18.37 ± 1.4 24.33 ± 1.9
Doxorubicin 8.87 ± 0.6 5.23 ± 0.3 4.50 ± 0.2 5.57 ± 0.4 4.17 ± 0.2
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a IC50 values presented as the mean ± SD of three separate determinations. Significant values (<25 µm) have been bolded for emphasis.

According to the anti-proliferative activity results, the tested compounds exhibited variable degrees of activity against the tested cancer cell lines. In general, the activity against MCF-7 and HeLa seems higher than PC-3, HCT-116, and HePG-2. In addition, the activity of the piperazinomethyl analogues is higher than their arylaminomethyl analogues. The optimal activity was attained by compounds 4l, 5a, 5c, and 5d with IC50 < 25 μM against the tested cell lines.

Within the arylaminomethyl analogues 4a–l, the compounds were inactive against PC3 cell lines (IC50 > 100 μM) or weakly active (IC50 = 51–100 μM) except compounds 4l, which retained moderate activity (IC50 34.60 μM). The anti-proliferative activity of the arylaminomethyl analogues 4a–l seems dependent on the aryl substituents, the 2,4-dichlorophenyl is the optimal substituents while the nitrophenyl substitution at 2- or 4- position (compounds 4e,g) greatly deteriorated the anti-proliferative activity. The anilinomethyl analogue 4a, monohalophenylaminomethyl analogues 4b–d, the trifluoromethylphenyl aminomethyl analogues 4h,i and the difluorophenylaminomethyl analogues 4j,k analogues only retained moderate anti-proliferative activity (IC50 = 26–50 μM) or poor activity (IC50 = 51–100 μM).

Concerning the anti-proliferative activity of the piperazinomethyl derivatives 5a–d, the 4-phenylpiperazinomethyl derivative 5a exhibited potent activity against HeLa and MFC7 cell lines, moderate activity against HCT-116 cell lines and weak activity against PC3 cell lines. Substitution of the phenyl group of compound 5a with 4-fluorophenyl group (compound 5b) dramatically deteriorated the anti-proliferative activity. The optimum antiproliferative activity was attained by the 4-benzylpiperazinomethyl derivative 5c, which showed potent activity against all the tested cell lines. Replacement of the benzyl group of compound 5c with 2-trifluoromethylbenzyl group (compound 5d) reduced the anti-proliferative activity against the tested cancer cell lines.

3. Materials and Methods

3.1. General Information

Melting points (°C, uncorrected) were determined in open glass capillaries using a Barnstead 9100 electro-thermal melting point apparatus. Nuclear magnetic resonance (NMR) spectra were determined in DMSO-d6 on a JEOL ECA 500 III at 500.16 MHz for 1H and 125.77 MHz for 13C. Elemental analyses (C, H, N, and S) were in agreement with the proposed structures within ± 0.4% of the theoretical values (Table S1). Monitoring of the reactions and checking of the purity of the final products were carried out by thin layer chromatography (TLC) using silica gel pre-coated aluminum sheets (60 F254; Merck) and visualization with ultraviolet light (UV) at 365 and 254 nm and/or stained with an anisaldehyde solution and a phosphomolybdic acid solution. All chemicals and solvents were purchased from Alfa Aesar (Germany), and used without additional purification. The reference drugs Gentamicin sulfate (CAS 1405-41-0), Ampicillin trihydrate (CAS 7177-48-2), Clotrimazole (CAS 23593-75-1) and Doxorubicin (CAS 23214-92-8) were purchased from Sigma-Aldrich Chemie GmbH (Germany). Compound 3 was prepared according to the previously reported procedure [61].

3.2. Synthesis of 3-(Arylaminomethyl)-5-(3,4-Dimethoxyphenyl)-1,3,4-Oxadiazole-2(3H)-Thiones 4a–l and 3-[(4-Substituted Piperazin-1-yl)Methyl]-5-(3,4-Dimethoxyphenyl}-1,3,4-Oxadiazole- 2(3H)-Thiones 5a–d

The appropriate primary aromatic amine or 1-substituted piperazine (0.01 mole) and 37% formaldehyde solution (1.0 mL) were added to a hot solution of 5-(3,4-dimethoxyphenyl)-1,3,4-oxadiazole-2(3H)-thione 3 (1.19 g, 5.0 mmole), in ethanol (10 mL), and the mixture was stirred at room temperature for 5 h and allowed to stand overnight. Water (5 mL) was then added drop-wisely to the reaction mixture with continuous stirring for one hour. The separated precipitate was filtered, washed with water, dried, and crystallized.

3-Anilinomethyl-5-(3,4-dimethoxyphenyl)-1,3,4-oxadiazole-2(3H)-thione4a. Fine colorless needle crystals. 1H NMR: δ 3.84–3.90 (m, 7H, OCH3 & NH), 6.01–6.09 (m, 2H, CH2), 6.69 (t, 1H, Ar-H, J = 7.0 Hz), 6.91 (d, 2H, Ar-H, J = 8.5 Hz), 7.08–7.33 (m, 5H, Ar-H). 13C NMR: δ 55.6, 55.8 (OCH3), 57.9 (CH2), 108.4, 112.1, 112.9, 114.0, 117.9, 120.0, 129.1, 145.3, 149.1, 152.4 (Ar-C), 159.0 (Oxadiazole C5), 175.3 (C=S).

3-[(4-Fluorophenylamino)methyl]-5-(3,4-dimethoxyphenyl)-1,3,4-oxadiazole-2(3H)-thione4b. Fine colorless needle crystals. 1H NMR: δ 3.86–3.90 (m, 7H, OCH3 & NH), 5.49 (d, 2H, CH2, J = 7.0 Hz), 6.89–6.94 (m, 2H, Ar-H), 6.99–7.06 (m, 2H, Ar-H), 7.21–7.25 (m, 1H, Ar-H), 7.32 (d, 1H, Ar-H, J = 1.5 Hz), 7.51 (d, 1H, Ar-H, J = 1.5 Hz). 13C NMR: δ 55.7, 55.8 (OCH3), 58.3 (CH2), 108.4, 112.1, 114.0 (d, JC-F = 5.0 Hz), 115.6 (d, JC-F = 23.0 Hz), 119.1 (d, JC-F = 7.0 Hz), 120.1, 141.9, 149.1, 152.4, 155.4 (d, JC-F = 232.5 Hz) (Ar-C), 159.0 (Oxadiazole C5), 175.4 (C=S).

3-[(3-Chlorophenylamino)methyl]-5-(3,4-dimethoxyphenyl)-1,3,4-oxadiazole-2(3H)-thione4c. Fine colorless needle crystals. 1H NMR: δ 3.87–3.88 (m, 7H, OCH3 & NH), 5.50 (d, 2H, CH2, J = 7.0 Hz), 6.73 (d, 1H, Ar-H, J = 1.5 Hz), 6.87 (d, 1H, Ar-H, J = 1.5 Hz), 7.02–7.05 (m, 1H, Ar-H), 7.17–7.19 (m, 1H, Ar-H), 7.33 (d, 1H, Ar-H, J = 1.5 Hz), 7.51 (d, 1H, Ar-H, J = 1.5 Hz), 7.55 (t, 1 H, Ar-H, J = 7.0 Hz). 13C NMR: δ 55.6, 55.8 (OCH3), 57.5 (CH2), 108.4, 111.8, 112.1, 112.5, 113.9, 117.5, 120.1, 130.7, 133.8, 147.1, 149.1, 152.4 (Ar-C), 159.1 (Oxadiazole C5), 175.4 (C=S).

3-[(4-Chlorophenylamino)methyl]-5-(3,4-dimethoxyphenyl)-1,3,4-oxadiazole-2(3H)-thione4d. Fine colorless needle crystals. 1H NMR: δ 3.87–3.88 (s, 7H, OCH3 & NH), 5.49 (d, 2H, CH2, J = 7.0 Hz), 6.93 (d, 2H, Ar-H, J = 9.0 Hz), 7.20–7.22 (m, 2H, Ar-H), 7.32 (d, 1 H, Ar-H, J = 1.5 Hz), 7.42 (d, 1 H, Ar-H, J = 8.0 Hz), 7.50 (d, 1 H, Ar-H, J = 1.5, 8.0 Hz). 13C NMR: δ 55.7, 55.8 (OCH3), 57.8 (CH2), 108.4, 112.1, 113.9, 114.5, 120.1, 121.5, 128.8, 144.4, 149.1, 152.4, 159.1 (Oxadiazole C5), 175.4 (C=S).

3-[(2-Nitrophenylamino)methyl]-5-(3,4-dimethoxyphenyl)-1,3,4-oxadiazole-2(3H)-thione4e. Pale yellow block crystals. 1H NMR: δ 3.85–3.89 (m, 7H, OCH3 & NH), 5.77 (d, 2H, CH2, J = 7.0 Hz), 6.89–6.95 (m, 1H, Ar-H), 7.16–7.21 (m, 1H, Ar-H), 7.44–7.48 (m, 1H, Ar-H), 7.49–7.54 (m, 1H, Ar-H), 7.65–7.70 (m, 1H, Ar-H), 8.16 (d, 1H, Ar-H, J = 1.5 Hz), 8.85–8.91 (m, 1H, Ar-H). 13C NMR: δ 55.7, 55.8 (OCH3), 56.6 (CH2), 108.5, 112.1, 115.4, 117.9, 119.8, 120.0, 125.4, 126.5, 136.6, 142.2, 149.2, 152.5 (Ar-C), 159.3 (Oxadiazole C5), 175.5 (C=S).

3-[(3-Nitrophenylamino)methyl]-5-(3,4-dimethoxyphenyl)-1,3,4-oxadiazole-2(3H)-thione4f. Pale yellow block crystals. 1H NMR: δ 3.86–3.90 (m, 7H, OCH3 & NH), 5.59 (d, 2H, CH2, J = 7.0 Hz), 7.19 (d, 1H, Ar-H, J = 9.0 Hz), 7.32–7.36 (m, 1H, Ar-H), 7.45 (t, 1 H, Ar-H, J = 8.0 Hz), 7.51 (d, 1H, Ar-H, J = 1.5 Hz), 7.55 (d, 1H, Ar-H, J = 1.5 Hz), 7.87–7.94 (m, 2H, Ar-H). 13C NMR: δ 55.6, 55.8 (OCH3), 57.4 (CH2), 106.9, 108.4, 112.0, 112.4, 113.9, 119.6, 120.1, 130.2, 146.9, 148.8, 149.1, 152.4 (Ar-C), 159.0 (Oxadiazole C5), 175.5 (C=S).

3-[(4-Nitrophenylamino)methyl]-5-(3,4-dimethoxyphenyl)-1,3,4-oxadiazole-2(3H)-thione4g. Pale yellow block crystals. 1H NMR: δ 3.86–3.90 (m, 7H, OCH3 & NH), 5.61 (d, 2H, CH2, J = 7.0 Hz), 7.07 (d, 2H, Ar-H, J = 9.0 Hz), 7.19 (d, 1H, Ar-H, J = 8.5 Hz), 7.33 (d, 1H, Ar-H, J = 2.0 Hz), 7.52 (d, 1H, Ar-H, J = 2.0 Hz), 8.12 (d, 2H, Ar-H, J = 9.0 Hz). 13C NMR: δ 55.7, 55.8 (OCH3), 56.7 (CH2), 108.5, 112.1, 112.5, 113.9, 120.2, 126.0, 138.1, 149.1, 152.1, 152.5 (Ar-C), 159.2 (Oxadiazole C5), 175.5 (C=S).

3-[(2-Trifluoromethylphenylamino)methyl]-5-(3,4-dimethoxyphenyl)-1,3,4-oxadiazole-2(3H)-thione4h. Colorless prism crystals. 1H NMR: δ 3.86–3.90 (m, 7H, OCH3 & NH), 5.61 (d, 2H, CH2, J = 6.5 Hz), 6.89 (t, 2H, Ar-H, J = 8.0 Hz), 7.24 (d, 2H, Ar-H, J = 9.0 Hz), 7.31–7.37 (m, 2H, Ar-H), 7.50–7.52 (m, 2H, Ar-H). 13C NMR: δ 55.7, 55.8 (OCH3), 57.3 (CH2), 108.5, 112.0, 114.6, 115.0, 116.7, 117.8, 119.8, 120.1, 126.6, 133.0, 133.7, 149.1, 152.1 (Ar-C & CF3), 160.6 (Oxadiazole C5), 177.2 (C=S).

3-[(3-Trifluoromethylphenylamino)methyl]-5-(3,4-dimethoxyphenyl)-1,3,4-oxadiazole-2(3H)-thione4i. White amorphous powder. 1H NMR: δ 3.86–3.90 (m, 7H, OCH3 & NH), 5.56 (d, 2H, CH2, J = 7.5 Hz), 7.02 (d, 1H, Ar-H, J = 7.5 Hz), 7.17–7.21 (m, 1H, Ar-H), 7.31–7.34 (m, 2H, Ar-H), 7.37–7.42 (m, 1H, Ar-H), 7.51 (d, 1H, Ar-H, J = 1.5 Hz), 7.71 (t, 1 H, Ar-H, J = 7.5 Hz). 13C NMR: δ 55.6, 55.8 (OCH3), 57.4 (CH2), 108.3, 109.0, 112.0, 113.9, 115.4, 117.0, 120.1, 123.3, 125.5, 130.1, 146.2, 149.1, 152.4 (Ar-C & CF3), 159.0 (Oxadiazole C5), 175.5 (C=S).

3-[(2,4-Difluorophenylamino)methyl]-5-(3,4-dimethoxyphenyl)-1,3,4-oxadiazole-2(3H)-thione4j. Colorless needle crystals. 1H NMR: δ 3.86-3.90 (m, 7H, OCH3 & NH), 5.52 (d, 2H, CH2, J = 7.0 Hz), 6.95–7.04 (m, 2H, Ar-H), 7.17–7.21 (m, 2H, Ar-H), 7.32 (d, 1H, Ar-H, J = 1.5 Hz), 7.49–7.52 (m, 1H, Ar-H). 13C NMR: δ 55.6, 55.8 (OCH3), 57.9 (CH2), 104.0 (d, JC-F = 23.05 Hz), 108.4, 111.0 (d, JC-F = 19.0 Hz), 112.0, 113.8 (d, JC-F = 8.5 Hz), 113.9, 120.1, 130.2 (d, JC-F = 13.0 Hz), 149.1, 152.4, 154.3 (d, JC-F = 225.5 Hz), 159.7 d, JC-F = 237.5 Hz) (Ar-C), 159.2 (Oxadiazole C5), 175.4 (C=S).

3-[(2,5-Difluorophenylamino)methyl]-5-(3,4-dimethoxyphenyl)-1,3,4-oxadiazole-2(3H)-thione4k. Colorless needle crystals. 1H NMR: δ 3.86–3.90 (m, 7H, OCH3 & NH), 5.51 (d, 2H, CH2, J = 6.5 Hz), 7.02–7.07 (m, 1H, Ar-H), 7.12–7.16 (m, 1H, Ar-H), 7.18–7.21 (m, 1H, Ar-H), 7.33 (d, 1H, Ar-H, J = 1.5 Hz), 7.39–7.44 (m, 1H, Ar-H), 7.49–7.53 (m, 1H, Ar-H). 13C NMR: δ 55.7, 55.8 (OCH3), 57.1 (CH2), 100.5 (d, JC-F = 27.5 Hz), 103.2 (d, JC-F = 7.0 Hz), 108.4, 111.9, 112.0, 114.6, 115.6 (d, JC-F = 11.0 Hz), 119.8, 120.1, 149.1, 152.1, 159.0 (d, JC-F = 241.0 Hz) (Ar-C), 159.7 (Oxadiazole C5), 175.5 (C=S).

3-[(2,4-Dichlorophenylamino)methyl]-5-(3,4-dimethoxyphenyl)-1,3,4-oxadiazole-2(3H)-thione4l. Fine colorless needle crystals. 1H NMR: δ 3.86–3.90 (m, 7H, OCH3 & NH), 5.58 (d, 2H, CH2, J = 7.0 Hz), 7.04–7.08 (m, 1H, Ar-H), 7.16–7.20 (m, 1H, Ar-H), 7.28–7.33 (m, 2H, Ar-H), 7.47–7.52 (m, 2H, Ar-H). 13C NMR: δ 55.7, 55.8 (OCH3), 57.4 (CH2), 108.5, 112.0, 113.8, 113.9, 119.1, 120.1, 121.7, 127.9, 128.8, 140.5, 149.1, 152.4 (Ar-C), 159.2 (Oxadiazole C5), 175.4 (C=S).

5-(3,4-Dimethoxyphenyl)-3-[(4-phenylpiperazin-1-yl)methyl]-1,3,4-oxadiazole-2(3H)-thione5a. Fine colorless needle crystals. 1H NMR: δ 2.89-2.99 (m, 4H, Piperazine-H), 3.13–3.23 (m, 4H, Piperazine-H), 3.89 (s, 6H, OCH3), 5.13 (s, 2H, CH2), 6.80 (t, 1H, Ar-H, J = 7.0 Hz), 6.96 (d, 2H, Ar-H, J = 8.0 Hz), 7.18–7.26 (m, 3H, Ar-H), 7.36–7.39 (m, 1H, Ar-H), 7.55 (d, 1H, Ar-H, J = 8.0 Hz). 13C NMR: δ 48.3, 49.6 (Piperazine-C), 55.7, 55.8 (OCH3), 69.7 (CH2), 108.5, 112.0, 114.1, 115.7, 119.0, 120.1, 128.9, 149.1, 151.0, 152.3 (Ar-C), 158.7 (Oxadiazole C5), 177.2 (C=S).

5-(3,4-Dimethoxyphenyl)-3-{4-[(4-fluorophenyl)piperazin-1-yl]methyl}-1,3,4-oxadiazole-2(3H)-thione5b. Colorless needle crystals. 1H NMR: δ 2.92–2.95 (m, 4H, Piperazine-H), 3.09–3.16 (m, 4H, Piperazine-H), 3.89 (s, 6H, OCH3), 5.12 (s, 2H, CH2), 6.96–6.98 (m, 2H, Ar-H), 7.05-7.07 (m, 1H, Ar-H), 7.08-7.19 (m, 1H, Ar-H), 7.21 (d, 1H, Ar-H, J = 1.5 Hz), 7.37 (d, 2H, Ar-H, J = 8.0 Hz). 13C NMR: δ 49.1, 49.6 (Piperazine-C), 55.7, 55.8 (OCH3), 69.7 (CH2), 108.5, 112.0, 114.2, 115.3 (d, JC-F = 21.5 Hz), 117.4 (d, JC-F = 7.0 Hz), 120.1, 147.0, 149.1, 152.3, 156.1 (d, JC-F = 236.5 Hz) (Ar-C),158.6 (Oxadiazole C5), 177.2 (C=S).

5-(3,4-Dimethoxyphenyl)-3-[(4-benzylpiperazin-1-yl)methyl]-1,3,4-oxadiazole-2(3H)-thione5c. White amorphous powder. 1H NMR: δ 2.30–2.50 (m, 4H, Piperazine-H), 2.74–2.88 (m, 4H, Piperazine-H), 3.50 (s, 2H, Benzylic CH2), 3.89 (s, 6H, OCH3), 5.05 (s, 2H, CH2), 7.19 (d, 1H, Ar-H, J = 9.0 Hz), 7.24–7.41 (m, 6H, Ar-H), 7.53 (d, 1H, Ar-H, J = 8.0 Hz). 13C NMR: δ 49.5, 52.3 (Piperazine-C), 55.7, 55.8 (OCH3), 61.9 (Benzylic CH2), 69.7 (CH2), 108.5, 112.0, 114.3, 120.0, 127.0, 128.1, 128.8, 137.8, 149.1, 152.2 (Ar-C), 158.6 (Oxadiazole C5), 177.2 (C=S).

5-(3,4-Dimethoxyphenyl)-3-{4-[(2-trifluorobenzyl)piperazin-1-yl]methyl}-1,3,4-oxadiazole-2(3H)-thione5d. Colorless needle crystals. 1H NMR: δ 2.38–2.52 (m, 4H, Piperazine-H), 2.78-2.90 (m, 4H, Piperazine-H), 3.64 (s, 2H, Benzylic CH2), 3.89 (s, 6H, OCH3), 5.06 (s, 2H, CH2), 7.20 (d, 1H, Ar-H, J = 8.0 Hz), 7.37 (d, 1H, Ar-H, J = 1.5 Hz), 7.47 (t, 1H, Ar-H, J = 7.0 Hz), 7.55 (d, 1H, Ar-H, J = 8.0 Hz), 7.64 (t, 1H, Ar-H, J = 8.0 Hz), 7.71 (d, 1H, Ar-H, J = 8.0 Hz), 7.76 (d, 1H, Ar-H, J = 8.0 Hz). 13C NMR: δ 49.7, 52.6 (Piperazine-C), 55.7, 55.8 (OCH3), 57.5 (Benzylic CH2), 69.8 (CH2), 108.5, 112.0, 114.2, 118.5, 120.1, 123.4, 125.7, 127.3, 130.3, 132.4, 137.2, 149.1, 152.3 (Ar-C & CF3), 158.6 (Oxadiazole C5), 177.2 (C=S).

4. Conclusions

Sixteen 1,3,4-oxadiazole-linked N-Mannich bases namely; 3-arylaminomethyl-5-(3,4- dimethoxyphenyl)-1,3,4-oxadiazole-2(3H)-thiones 4a–l and 3-[(4-substituted piperazin-1- yl)-methyl]-5-(3,4-dimethoxyphenyl)-1,3,4-oxadiazole-2(3H)-thiones 5a–d were synthesized and their structures were confirmed by 1H NMR, 13C NMR and elemental analysis. The in vitro inhibitory activity of compounds 4a–l and 5a–d was assessed against a panel of standard pathogenic Gram-positive bacteria, Gram-negative bacteria, and the yeast-like pathogenic fungus Candida albicans. Compounds 5c and 5d displayed potent broad spectrum antibacterial activities and compounds 4j, 4l, 5a, and 5b showed potent activity against the tested Gram-positive bacteria. The anti-proliferative activity of the compounds was evaluated against prostate cancer (PC3), human colorectal cancer (HCT-116), human hepatocellular carcinoma (HePG-2), human epithelioid carcinoma (HeLa), and human breast cancer (MCF7) cell lines. Compounds 4l, 5a, 5c, and 5d showed potent inhibition of cell proliferation in almost all the tested cancer cell lines. The prepared 1,3,4-oxadiazole-linked N-Mannich bases could be considered good antibacterial and anticancer drug candidates. The biological testing results are considered as preliminary and further investigations, including experimental and theoretical investigations for the exploration of their targets, are required for optimization of their chemotherapeutic activities.

Supplementary Materials

The micro-analytical data (C, H, N, and S), the experimental details of the determination of in vitro antimicrobial activity, in vitro anti-proliferative activity, and the NMR spectra can be found online.

Click here for additional data file. (3.5MB, pdf)

Author Contributions

Conceptualization, A.A.E.-E. and A.A.B.M.; methodology, L.H.A.-W., S.S.T., and H.M.H.; validation, H.M.H..; formal analysis, L.H.A.-W., A.A.B.M., and S.S.T.; investigation, L.H.A.-W. and H.M.H.; data curation, H.M.H. and S.S.T.; writing—original draft preparation, A.A.E.-E.; writing—review and editing, A.A.E.-E. and A.A.B.M.; supervision, L.H.A.-W., A.A.E.-E.; project administration, A.A.E.-E.; funding acquisition, L.H.A.-W. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by the Deanship of Scientific Research at Princess Nourah bint Abdulrahman University through the Research Groups Program (Grant No. RGP-1442-0010-4).

Conflicts of Interest

The authors declare no conflict of interest.

Sample Availability

Samples of the compounds 4a–l and 5a–d are available from the corresponding author.

Footnotes

Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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