Improved Method for the Synthesis of New 1,5-Benzothiazepine Derivatives as Analogues of Anticancer Drugs

(±)cis-2-(4-Methoxyphenyl)-3-hydroxy/methoxy-2,3-dihydro-1,5-benzothiazepin-4[5H/5-chloroacetyl/5-(4'-methylpiperazino-1')acetyl]-ones have been synthesized by the condensation of 2-aminobenzene thiols with methyl(±)trans-3-(4-methoxyphenyl)glycidate in xylene. The synthesized compounds have been characterized by elemental analyses and spectral data and screened for their antimicrobial activity.

With this in mind, some new 1,5-benzothiazepine derivatives have been synthesized in search of better therapeutic agents, by a convenient single pot method.The physical data of compounds 1 to 6 is given in Table -1.

Synthesis
In the IR spectra of compounds 3, a broad band in the range 3600-3110 cm -1 was obtained due to the merged N-H and O-H stretching vibrations.Compounds 4 showed a less broad band, in the region 3180-3140 cm -1 due to the presence of only the N-H group.This band was absent in compounds 5 and 6.
The N-H bending vibrations were observed as a sharp medium to strong band at 1540-1500 cm -1 in compounds 3 and 4. The C-S-C linkage of the seven membered ring caused a weak and sharp absorption band at 800-760 cm -1 in all the compounds.The C=O group was observed as a strong and sharp band at 1660-1600 cm -1 in these compounds.The C-O-C linkage showed two sharp and strong bands at 1360-1340 cm -1 and 1070-1020 cm -1 due to asymmetric and symmetric vibrations respectively.The C-H (aliphatic and aromatic), C=C, C-Cl, stretching vibrations were observed at their usual positions.(Table 2).
In the 1 H NMR spectra of compounds 3 the -OH proton was found to be at δ 8.17-10.00ppm.The proton of the -NH group was observed at δ 8.10-8.25 ppm, as a broad singlet.Two characteristic doublets at δ 2.35-2.92ppm (J=8 Hz) and δ 3.05-3.44ppm (J=8 Hz) were assigned to cis-protons at C-2 and C-3.All the compounds showed a complex multiplet of aromatic protons in the range δ 6.00-7.90ppm.Protons of the methoxy group were observed at δ 3.32-3.54ppm.The piperazine protons were observed at d 4.10-4.60ppm in compounds 6.The methyl protons, whenever present, were observed at their usual position (δ 1.65-2.30ppm) as a singlet (Table -3

Antimicrobial activity
All the synthesized compounds were screened for their in vivo antimicrobial activity against the bacteria S. aureus, E. coli and fungi Aspergillus niger, Aspergillus flavus, Curvularia lunata and Fusarium moniliformae at a concentration of 100 µg/disc in agar media.A single disc method of Bauer et al [8] was employed using Streptomycin and Mycostatin as the reference compounds in antibacterial and antifungal activity respectively.The data are given in Table-4

General
All the melting points were determined in open capillary tubes and are uncorrected.The IR spectra were recorded on a Perkin Elmer-833 grating infrared spectrophotometer in KBr pallets.
The 1 H NMR spectra were scanned on a FX 90Q Jeol spectrometer (90 MHz) in CDCl 3 /DMSO-d 6 using TMS as the internal standard.The puritiy of the compounds synthesized was checked by TLC using silica gel-G as adsorbent.
*Activity index=Inhibition area of the sample/Inhibition area of the standard.