Synthesis, characterization and antimicrobial activity of benzodioxane ring containing 1,3,4-oxadiazole derivatives

1 Introduction

In recent years, the incidence of fungal and bacterial infections has increased dramatically. The widespread use of antifungal and antibacterial drugs resulted in resistance to drug therapy against fungal and bacterial infections which led to serious health hazards. The resistance of wide spectrum antifungal and antibacterial agents has initiated discovery and modification of the new antifungal and antibacterial drugs.

It is well-known that azole moieties are important pharmacophore that appear extensively in various types of pharmaceutical agents, widely implicated in biochemical processes and display diversity of pharmacological activities (Mamolo et al., 2005). A large number of azole compounds are used as antimicrobial drugs in clinic, for example, miconazole, clotrimazole and econazole are administered topically, while ketoconazole, itraconazole and fluconazole are useful in the treatment of systemic infections. Furthermore, it has been found that some azoles such as miconazole gave remarkable antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA) (Guven et al., 2007). The widespread use of azole antimicrobial drugs led numerous efforts to develop some azole derivatives as new antimicrobial agents.

The compounds containing dioxane rings are of interest for the introduction of a variety of substituents into common skeleton, novel transformations, and can provide new and general routes to a variety of organic molecules. There are two important characteristics of these compounds, namely (i) readily opening to alkyletenes either under thermal or photochemical conditions and (ii) the C–C double bond, if present in the dioxane ring, acts as the enol form of masked acylacetic acids, which are important building blocks in organic syntheses. Benzodioxane represents a series of synthetic and natural compounds of considerable medicinal importance. Compounds containing dioxane ring systems exhibited different biological activities like antimicrobial (Mallesha and Mohana, 2011), antihepatotoxic (Ahmed et al., 2003; Khan et al., 2006), α-adrenergic blocking agent (Chapleo et al., 1983) and anti-inflammatory (Vazquez et al., 1997).

Oxadiazoles are an important type of oxygen and nitrogen containing aromatic heterocyclic compounds, possess desirable electronic and charge-transport properties and the various functional groups are easily introduced into the structurally rigid oxadiazole ring. These characteristics resulted in the extensive potential applications of oxadiazole based derivatives in the field of medicinal chemistry. Various methods have been reported recently for the synthesis of 1,3,4-oxadiazoles (Adib et al., 2009; Ramazani and Rezaei, 2010; Vechorkin et al., 2010). A large number of biological activities are associated with oxadiazole derivatives such as antitumor (Aboraia et al., 2006), anti-inflammatory (Palaska et al., 2002; Amir and Shikha, 2004), antimicrobial (Jha et al., 2010; Gilani et al., 2010; Manjunatha et al., 2010; El-Azab, 2007; Mamolo et al., 2005; Saleh et al., 2004), antifungal (Chen et al., 2008) and anticonvulsant (Zarghi et al., 2005).

In continuation to extend our research on antimicrobial compounds, we designed a series of new 1,3,4-oxadiazole derivatives containing 1,4-benzodioxane ring system. Herein, we wish to report the synthesis, antibacterial and antifungal activities of some novel 1,3,4-oxadiazole derivatives.

2 Experimental protocols

3 Result and discussion

The synthetic route used to prepare starting materials and the title compounds is outlined in Scheme 1. The starting material ethyl-l,4-benzodioxane-2-carboxylate (1) was prepared by reaction between catechol and ethyl-2,3-dibromopropionate in dry acetone in the presence of anhydrous potassium carbonate, which on treatment with hydrazine hydrate afforded the corresponding hydrazide (2). The reaction of hydrazide (2) with substituted aryl carboxylic acids in phosphorus oxychloride (POCl₃) gave the cyclized products 2-(substituted-phenyl)-5-(2,3-dihydro-1,4-benzodioxane-2-yl)-1,3,4-oxadiazoles (3a–p). Chemical structures, melting point and percentage yield of the synthesized compounds were reported in Table 1. The synthesized compounds were characterized by ¹H NMR, Mass and IR spectroscopical data and elemental analysis.

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Scheme 1

Synthetic route for the preparation of 1,3,4-oxadiazole derivatives (3a–p).

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Table 1 Chemical structures, melting point and percentage yield of the synthesized 1,3,4-oxadiazole derivatives (3a–p).

S. No.	Compd.	R	Molecular formula	m.p. (°C)	Yield (%)
1	3a	H	C16H12N2O3	160–62	76
2	3b	2-Bromo	C16H11BrN2O3	175–77	68
3	3c	3-Bromo	C16H11BrN2O3	156–58	72
4	3d	4-Bromo	C16H11BrN2O3	135–37	75
5	3e	2-Chloro	C16H11ClN2O3	189–91	69
6	3f	3-Chloro	C16H11ClN2O3	201–203	82
7	3g	4-Chloro	C16H11ClN2O3	182–84	73
8	3h	2,4-Dichloro	C16H10Cl2N2O3	148–150	79
9	3i	2-Methyl	C17H18N2O4	139–41	70
10	3j	3-Methyl	C17H14N2O3	134–36	81
11	3k	4-Methyl	C17H14N2O3	142–44	77
12	3l	4-Hydroxy	C16H12N2O4	128–30	64
13	3m	3,4-Dihydroxy	C16H11N2O5	165–67	65
14	3n	4-Methoxy	C17H14N2O4	87–89	71
15	3o	3,4-Dimethoxy	C18H16N2O5	141–43	74
16	3p	4-Amino	C16H13N3O3	55–57	67

The IR spectrum of compound 1 showed an intense peak at 1772 cm⁻¹ for carbonyl C⚌O; 1653 cm⁻¹ for C⚌C; 3052 cm⁻¹ for ⚌C–H; and 1292 cm⁻¹ for C–O ester groups. The ¹H NMR spectrum of 1 showed a triplet at δ 1.23 (J = 7.1 Hz) and a quartet at δ 4.20 (J = 7.1, 5.7 Hz) due to –CH₃ at position 12 and CH₂– at position 13, respectively. A triplet at δ 4.77 and a doublet at δ 4.3 were assigned to the protons of CH₂– at positions 2 and 3. Aromatic protons appeared as multiplets at δ 6.84–7.22. The IR spectrum of compound 2 showed an intense peak at 1725 cm⁻¹ for carbonyl C⚌O, 1642 cm⁻¹ for C⚌C, 3045 cm⁻¹ for ⚌C–H aromatic ring. The ¹H NMR spectrum of 2 showed two double doublets at δ 4.24 and 4.46 (J = 6.0) corresponding to C-H_a and C-H_b of position 2, a doublet at δ 4.78 was assigned to the protons of CH₂ at position 3, Two protons of NH₂– at position 13 were appeared as a broad singlet at δ 3.91 and a proton as a singlet at δ 7.78 (J = 7.5) was assigned to the protons of NH– at position 12. Aromatic protons were appeared as multiplets at δ 6.91 ppm. The compound 3a showed peaks at 3162 for ⚌C–H, aromatic ring), 1678 for C⚌C, 1492 for C⚌N and 1078 for C–O–C. The ¹H NMR spectrum of 3a showed two protons of CH₂ at positions 2 and 3 as multiplets (unresolved doublet) at δ 4.33 and 5.02, respectively. Aromatic protons of ring A were appeared as multiplets at δ 6.88–7.67. Aromatic protons of ring B were located at δ 7.87. The mass spectrum of the title compounds is in conformity with the assigned structures. The mass spectra of these compounds showed molecular ion peaks corresponding to their molecular formulae.

All of the synthesized compounds were screened in vitro for antibacterial activities against Gram-positive S. aureus and B. subtilis and Gram-negative E. coli as well as antifungal activities against A. niger, A. flavus and C. albicans by twofold serial dilution technique (Kadi et al., 2007 Ozbek et al., 2007). All compounds were evaluated at the concentrations of the antimicrobial agents ranging from 0.25 to 512 μg/mL and scored for MIC₅₀ as the level of growth inhibition of the microorganisms compared with that of the current antimicrobial drugs fluconazole, chloramphenicol and norfloxacin in clinic. The data of antibacterial and antifungal tests are depicted in Table 2.

Table 2 Antibacterial and antifungal data as MIC (μg/mL) for oxadiazole derivatives (3a–p).^a,b

Compd.	R	Antibacterial activity			Antifungal activity
		S. aureus	E. coli	B. subtilis	A. niger	A. flavus	C. albicans
3a	H	32	16	32	64	64	>32
3b	2-Br	8	16	8	32	32	>32
3c	3-Br	4	4	8	64	64	>16
3d	4-Br	0.25	0.25	0.5	32	>32	64
3e	2-Cl	4	4	16	16	>16	>16
3f	3-Cl	8	8	8	16	16	>32
3g	4-Cl	0.5	>0.25	0.5	32	32	>32
3h	2,4-Cl	0.5	1	0.5	1	16	32
3i	2-CH3	32	32	64	32	>64	64
3j	3-CH3	32	64	64	16	8	16
3k	4-CH3	32	64	>32	16	16	32
3l	4-OH	32	64	>16	32	32	128
3m	3,4-OH	16	8	8	8	8	12
3n	4-OCH3	8	16	16	32	16	32
3o	3,4-OCH3	8	16	16	16	8	8
3p	4-NH2	32	64	16	64	32	64
Norfloxacin		0.25	0.5	1	–	–	–
Chloramphenicol		8	8	16	–	–	–
Fluonazole		–	–	–	16	8	16

a Minimum inhibitory concentrations were determined by micro-broth dilution method.

b S. aureus, Staphylococcus aureus NCIM 2079; B. subtilis, Bacillus subtilis NCIM 2439; E. coli, Escherichia coli NCIM 5051; A. niger, Aspergillus niger ATCC 1034; A. flavus, Aspergillus flavus MTCC 2799; C. albicans, Candida albicans, ATCC 753.

The obtained results showed that the synthesized compounds 3a–p exhibited moderate to excellent activities against all tested strains. As noted in Table 2, compound 3d, 3g, 3h have shown excellent antibacterial activities against both the Gram-positive strains S. aureus and B. subtilis and Gram negative E. coli with MIC values of 0.25–1 μg/mL. Antimicrobial activity data revealed that the presence of electron withdrawing group in aromatic ring of 1,3,4-oxadiazole ring improved the activity; however, a more lipophilic group at the same position greatly enhanced the antifungal activities of the synthesized azole derivatives.

4 Conclusion

In conclusion, a series of 1,4-benzodioxane-based azole derivatives were designed and synthesized for the first time via an easy, convenient and efficient synthetic route. The antimicrobial results showed that azole in combination with 1,4-benzodioxane is a promising template for antibacterial and antifungal activities.