K. Waisser et al. / Il Farmaco 56 (2001) 803–807
805
3.1.5. 3-(4-Chloropheny)l-6,8-dichloro-2H-1,3-
benzoxazine-2,4(3H)-dithione (4)
(m, 2H (H2%, H6%)), 7.32 (dt, 1H, J=8.24, J=1.37,
(H6)), 7.25–7.22 (m, 1H (H5%)), 7.17–7.11 (m, 2H (H8,
H4%)). 13C NMR (75 MHz, CDCl3) l=189.5, 172.9,
144.3, 135.6, 135.2, 133.9, 132.9, 130.6, 129.1, 128.8,
126.7, 126.0, 124.4, 114.9. Anal. (C, H, N, S).
Red crystals 36% yield, m.p. 192–194 °C; IR (KBr,
1
cm−1) 1453 (CꢀS). H NMR (300 MHz, CDCl3) l 8.19
(d, 1H, J=2.47 (H5)), 7.76 (d, 1H, J=2.47 (H7)),
7.56–7.50 (m, 2H, AA%, BB% (H2%, H6%)), 7.16–7.10 (m,
2H, AA%, BB% (H3%, H5%)). 13C NMR (75 MHz, CDCl3)
l=184.7, 175.5, 144.8, 141.3, 135.8, 135.3, 131.9,
130.6, 129.9, 129.1, 123.6, 122.5. Anal. (C, H, N, S).
3.1.11. 3-(3,4-Dichlorophenyl)quinazoline-2,4(1H,3H)-
dithione (10)
Orange crystals 31% yield, m.p. 291–294 °C; IR
1
(KBr, cm−1) 1442 (CꢀS). H NMR (300 MHz, CDCl3)
3.1.6. 3-(3-Chloropheny)l-6,8-dichloro-2H-1,3-
benzoxazine-2,4(3H)-dithione (5)
l 11.00 (bs, 1H (NH)), 8.47 (dd, 1H, J=8.24, J=1.1
(H5)), 7.68 (dt, 1H, J=8.24, J=1.1, (H7)), 7.63 (d,
1H, J=8.52 (H5%)), 7.33 (dt, overlapped 1H, J=8.24,
J=1.1, (H6)), 7.33 (d, overlapped 1H, J=2.47 (H2%)),
7.15 (ddd, 1H, J=8.24, J=1.1, J=0.55 (H8)), 7.09
(dd, 1H, J=8.52, J=2.47 (H6%)). 13C NMR (75 MHz,
CDCl3) l=189.4, 172.8, 142.3, 135.8, 133.8, 133.7,
133.2, 132.9, 131.4, 130.5, 127.9, 126.2, 124.3, 114.9.
Anal. (C, H, N, S).
Red crystals 35% yield, m.p. 192–194 °C; IR (KBr,
1
cm−1) 1453 (CꢀS). H NMR (300 MHz, CDCl3) l 8.20
(d, 1H, J=2.47 (H5)), 7.76 (d, 1H, J=2.47 (H7)),
7.52–7.45 (m, 2H (H2%, H6%)), 7.23–7.19 (m, 1H (H5%)),
7.13–7.07 (m, 1H (H4%)). 13C NMR (75 MHz, CDCl3)
l=184.6, 175.3, 144.8, 143.7, 135.7, 135.6, 131.9,
131.1, 129.8, 129.6, 128.2, 126.1, 123.6, 122.5. Anal. (C,
H, N, S).
3.1.7. 3-Phenylquinazoline-2,4(1H,3H)-dithione (6)
Orange crystals 39% yield, m.p. 258–261 °C; lit. [10]
m.p. 252–254 °C. IR (KBr, cm−1) 1442 (CꢀS). 1H
NMR (300 MHz, CDCl3) l 11.56 (bs, 1H (NH)), 8.49
(dd, 1H, J=8.24, J=1.1 (H5)), 7.67–7.48 (m, 4H (H7,
H3%, H4%, H5%)), 7.30 (dt, 1H, J=8.24, J=1.1, (H6)),
7.27–7.17 (m, 3H (H8, H2%, H6%)). 13C NMR (75 MHz,
CDCl3) l=190.1, 173.4, 144.0, 135.7, 134.3, 133.1,
130.0, 129.1, 128.5, 126.3, 124.9, 115.4. Anal. (C, H, N,
S).
3.2. Microbiology
For the evaluation of the antimycobacterial activity
of the substances in vitro, the following strains were
used: M. tuberculosis CNCTC My 331/ 88, M. kansasii
CNCTC My 235/ 80, M. a6ium CNCTC My 330/ 88,
obtained from the Czech National Collection of Type
Cultures (CNCTC), National Institute of Public
Health, Prague, and a clinical isolate of M. kansasii 6
509/ 96. The antimycobacterial activities of the com-
pounds against these strains were determined in the
&
3.1.8. 3-(4-Bromophenyl)quinazoline-2,4(1H,3H)-
dithione (7)
Sula semisynthetic medium (SEVAC, Prague). The
compounds were added to the medium in dimethyl
sulfoxide solutions. The following concentrations were
used: 125, 64, 32, 16, 8, and 4 mmol/l. The minimum
inhibitory concentrations were determined after incuba-
tion at 37 °C for 14 and 21 days. MIC was the lowest
concentration of a substance, at which the inhibition of
the growth of mycobacteria occurred.
Orange crystals 32% yield, m.p. 287–289 °C; IR
1
(KBr, cm−1) 1442 (CꢀS). H NMR (300 MHz, CDCl3)
l 10.86 (bs, 1H (NH)), 8.48 (dd, 1H, J=8.24, J=1.1
(H5)), 7.71–7.74 (m, 3H (H7, H3%, H5%)), 7.32 (dt, 1H,
J=8.24, J=1.1, (H6)), 7.14 (dm, 1H (H8)), 7.12–7.07
(m, 2H, AA%,BB%(H2%, H6%). 13C NMR (75 MHz,
CDCl3) l=189.6 172.9, 142.5, 135.6, 133.9, 133.1,
133.0, 129.9, 126.0, 124.4, 122.8, 114.8. Anal. (C, H, N,
S).
4. Results and discussion
3.1.9. 3-(4-Methylphenyl)quinazoline-2,4(1H,3H)-
dithione (8)
Orange crystals 38% yield, m.p. 296–303 °C; lit. [10]
m.p. 286–287 °C. IR (KBr, cm−1) 1441 (CꢀS). Anal.
(C, H, N, S).
The antimycobacterial activities of the compounds
together with that of isoniazide (INH) are shown in
Tables 1 and 3. It can be concluded that the condition-
ally pathogenic strains of M. kansasii CNCTC My 235/
80 and M. a6ium CNCTC My 330/ 88 are not suscepti-
ble against INH. The clinical isolate of M. kansasii 6
509/ 96 is susceptible against INH, but the most active
of the new substances match the activity of the drug.
They are, however, more efficient than this standard
against the other two strains. In general, the replace-
ment of the oxo function with the thioxo moiety gives
rise to an increase of antimycobacterial activity. In the
3.1.10. 3-(4-Chlorophenyl)quinazoline-
2,4(1H,3H)-dithione (9) (T2299)
Orange crystals 29% yield, m.p.273–278 °C; IR
1
(KBr, cm−1) 1442 (CꢀS). H NMR (300 MHz, CDCl3)
l 10.82 (bs, 1H (NH)), 8.48 (dd, 1H, J=8.24, J=1.37
(H5)), 7.67 (dt, 1H, J=8.24, J=1.37 (H7)), 7.54–7.45