Synthesis of some alkoxy based bisthiadiazolines

1 Introduction

The synthesis of macrocyclic compounds have been studied in the past decades on the compounds containing heterocyclic subunits, because of their unique chemical and biological properties. Several five-membered systems having three hetero atoms have been investigated because of their interesting physiological properties (Montegomery, 1981; Hetzhein and Mockel, 1996; Sandstorm, 1968). It is well established that various derivatives of trizole, thiadiazole and oxadiazole exhibit broad spectrum of pharmacological properties such as anti-inflammatory, (Boschelli et al., 1993; Unangst et al., 1992) antiviral (Shrivastava et al., 1984) and antibacterial (Hosam, 1996; Hui et al., 2002). Thiadiazoline and their derivatives (Gursoy et al., 1997; Joshi et al., 2000; Yamamoto et al., 1989; Brousse et al., 2002; Abdelhamid et al., 2004; H-Zaki et al., 2006; Wolkoff and Hammerum, 1976; Hu et al., 2005; Nagao et al., 1998; Araki et al., 1988; Gupta et al., 2008; Kumar et al., 2009; Gannon et al., 1980; Hagiwara et al., 1992; Eroglu, 2008; Hagiwara et al., 1993; Polvonov et al., 2003; Abbas and Rateb, 2005; Alho et al., 2000; Er et al., 2008; Aridoss et al., 2009) represent a group of compounds possessing a wide spectrum of biological activities. They exhibit hypoglycemic, antitubercular, antifungal and antibacterial properties (Leafe, 1966; Bhat et al., 1967; Zsolnai, 1962a,b; Thakar and Bhawal, 1977; Holmberg, 1954). In view of the above mentioned facts and in continuation of our work on the synthesis of biologically important heterocyclic compounds (Khan and Yusuf, 2009), the present investigations focus upon the synthesis of some bisthiadiazolines 3a–3h built around the carbon chains of varying lengths. The major interest behind this study was to investigate the effect of internal spacer length upon the stereochemical features and biological activity of the resultant bisthiadiazolines.

2 Results and discussion

The bisthiadiazolines 3a–3h required for the present study were obtained starting from 4-hydroxybenzaldehyde which was reacted with suitable 1,ω-dibromoalkane in the presence of KOH in dry EtOH and DMF to yield bisaldehydes 1a–1h (Abdelhamid and El-Shaity, 1988; Ibrahim et al., 1994). The latter were treated with thiosemicarbazide in dry EtOH and catalytic amounts of HCl to furnish bisthiosemicarbazones 2a–2h which were further refluxed in Ac₂O to furnish bisthiadiazolines 3a–3h in good yields (Scheme 1).

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Scheme 1

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The structures of compounds 2a–2h and 3a–3h were based upon their spectroscopic data (IR, ¹H and ¹³C NMR and Mass) and elemental analysis.

In compounds 2a–2h, 5-NH₂ and 3-NH protons appeared as two broad singlets at δ 7.74–7.30 and a sharp singlet at δ 11.33–11.20, respectively, which were exchangeable with D₂O and their IR spectra also exhibited the NH stretching at 3364–3160 cm⁻¹ and did not reveal any absorption in the carbonyl group region. Other major features of their ¹H NMR spectra were the appearance of sharp singlet at δ 8.03–7.99 which could be very well ascribed to azomethyne proton (H-1) and the two doublets in the aromatic region at δ 7.63–7.58 (J_o = 8.8 Hz) and δ 6.92–6.88 (J_o = 8.8 Hz) integrating for four hydrogens each that could be denoted by H-2′, 6′ and H-3′, 5′, respectively. In the ¹³C NMR spectra of 2a–2h, C-4 and C-1 were found placed at δ 176–173 and 149–147, respectively, and the resonances present at δ 133–130 and 118–115 could be resulted by aromatic carbons C-6′, 2′ and 5′, 3′, respectively.

IR spectra of bisthiadiazolines 3a–3h displayed intense absorptions at 3220–3180, 1690–1638 and 1610–1600 cm⁻¹ due to NH, C⚌O and C⚌N stretchings, respectively. ¹H NMR (400 MHz, DMSO) spectra of 3a–3h had D₂O exchangeable singlet at δ 11.46–11.24 generated by the 1′-NH proton. The hydrogen (H-2) belonging to thiadiazoline ring appeared as a singlet at δ 6.75–6.70; the downfield resonance of this hydrogen could be ascribed to its benzylic nature and its placement between two heteroatoms (N and S). The singlets present at δ 2.26–2.22 and 2.15–2.11 could be very well represented by 2″ and 3′ methyl groups, respectively, and these groups have also been confirmed by the two resonances at δ 28–22 in ¹³C NMR spectra. Additionally, the internal methylene protons were resonating at δ 4.11–3.90 (OCH₂) and 2.21–1.20 {(CH₂)_n}. The downfield resonance of the former could be attributed to their direct linkage to the electronegative oxygen atom. These methylene groups also furnished suitable signals in the ¹³C NMR (DMSO) spectra at δ 68–66 (OCH₂) and 28–22{(CH₂)_n}. The presence of two carbonyl groups in 3a–3h were confirmed by the appearance of two resonances at δ 169–164 and the signals resonating at δ 158–154 and 146–143 could be allotted to C-4″′ and C-5, respectively.

3 Biological activity

All the synthesized compounds were evaluated for antibacterial activity by disc-diffusion method. The compounds 2a–2h and 3a–3h were examined for their antibacterial activity against bacteria strains, namely, Escherichia coli (MTCC 390), Staphylococcus aureus (MTCC 435), Klebsiella pneumoniae (MTCC 3384) and Pseudomonas (MTCC 130). Norfloxin (MIC-2 μg/ml) and Amoxicillin (MIC-20 μg/ml) were taken as the standard drugs and DMSO was used as a blank.

The bisthiosemicarbazones 2c (MIC-100 μg/ml), 2d (MIC-250 μg/ml) and 2f (MIC-250 μg/ml) showed low activity against gram-positive bacteria, Staphylococcus aureus and 2c (MIC-100 μg/ml) also exhibited low activity against gram-negative bacteria, Escherichia coli as compared to the reference drugs. Unfortunately, bisthiadiazolines 3a–3h did not exhibit any significant activity against the above said bacteria.

4 Conclusion

It may be concluded that the present study describes the general and efficient method for the synthesis of some bisthiadiazolines built around the alkyl chains of varying length under the normal conditions. The length of the intermediate spacer did not have any significant effect upon the stereochemistry and biological behaviour of bisthiadiazolines.

5 Experimental

Melting points reported are uncorrected. IR spectra were scanned in KBr pellets on a Perkin Elmer RXIFT Infrared spectrophotometer. ¹H NMR spectra were recorded on a 400 MHz Bruker spectrometer using TMS as the internal standard. The mass spectra have been scanned on the Waters Micromass Q-T of Micro (ESI) spectrometer. TLC plates were coated with silica gel suspended in MeOH–CHCl₃ and iodine vapors were used as visualizing agent. Bisaldehydes 1a–1h were synthesized according to the reported methods (Abdelhamid and El-Shaity, 1988; Ibrahim et al., 1994).