Synthesis, anticonvulsant and toxicity evaluation of 2-(1H-indol-3-yl)acetyl-N-(substituted phenyl)hydrazine carbothioamides and their related heterocyclic derivatives (original) (raw)

Abstract

In recent years, indole derivatives have acquired conspicuous significance due to their wide spectrum of biological activities. The anticonvulsant drug design is based on the presumption (1) that for the activity in maximal electroshock seizure (MES) evaluation, at least one phenyl or similar aromatic group in close proximity to a two electron donor atom is required. For activity in pentylenetetrazole (PTZ) evaluation, an alkyl group close to a two electron donor atom is needed.

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References (26)

  1. 61 (s, 3H, OCH 3 ), 1.23 (s, 2H, CH 2 ) 4e 3580 (NH str.), 3417 (Ar-CH), 2349 (CH 3 ), 1643 (C=N), 1550 (C=C), 1449 (C=S), 1024 (N-N) 10.53 (s, 1H, NH triazole), 7.53 (s, 1H, NH indole), 6.81-7.33 (m, 8H, Ar-H), 6.35 (s, 1H, CH indole), 4.14 (s, 2H, CH 2 ), 3.71 (s, 3H, CH 3 ) 4f 3556 (NH str.), 3401 (Ar-CH), 2398 (CH 3 ), 1601 (C=N), 1567 (C=C), 1487 (C=S), 1032 (N-N) 10.51 (s, 1H, NH triazole), 7.48 (s, 1H, NH indole), 6.78-7.41 (m, 8H, Ar-H), 6.41 (s, 1H, CH indole), 4.23 (s, 2H, CH 2 ), 3.75 (s, 3H, CH 3 )
  2. 4g 3573 (NH str.), 3415 (Ar-CH), 2382 (CH 3 ), 1634 (C=N), 1543 (C=C), 1476 (C=S), 1056 (N-N) 10.49 (s, 1H, NH triazole), 7.50 (s, 1H, NH indole), 6.84-7.65 (m, 8H, Ar-H), 6.29 (s, 1H, CH indole), 4.27 (s, 2H, CH 2 ), 3.63 (s, 3H, CH 3 )
  3. 5a 3556 (NH str.), 3261 (Ar-CH), 2356 (CH 2 ), 1642 (C=N), 1568 (C=C), 1093 (N-N), 1009 (C-O-C) 10.83 (s,1H, NH), 8.70 (s, 1H, NH indole), 6.54-7.46 (m, 9H, Ar-H), 5.66 (s, 1H, CH indole), 4.13 (s, 2H, CH 2 ) 5b 3660 (NH str.), 3426 (Ar-CH), 2348 (CH 2 ), 1665 (C=N), 1638 (C=C), 1386 (N-N), 1089 (C-O-C), 746 (C-Cl)
  4. 93 (s,1H, NH), 8.24 (s, 1H, NH indole), 6.96-8.22 (m, 8H, Ar-H), 6.96 (s, 1H, CH indole), 2.72 (s, 2H, CH 2 ) 5c 3745 (NH str.), 3447 (Ar-CH), 2366 (CH 2 ), 1646 (C=N), 1517 (COCH 3 ), 1096 (C-O-C), 793 (N-N) 10.70 (s, 1H, NH), 8.36 (s, 1H, NH indole), 6.83-7.52 (m, 8H, Ar-H), 6.54 (s, 1H, CH indole), 3.85 (s, 3H, OCH 3 ), 3.77 (s, 2H, CH 2 )
  5. The anticonvulsant activity and neurotoxicity of all compounds were examined us- ing reported procedures (7-10). The anticonvulsant evaluation of compounds 4a-g, 5a-g and 6a-g in mice at 30, 100 and 300 mg kg -1 by i.p. MES (maximal electroshock seizure) and NT (neurotoxicity screening) are summarized in Table III together with the litera- ture data on the drugs used as standards, phenytoin and carbamazepine. Compounds 4b, 4e, 4f, 5b, 5d, 5g, 6b, 6d and 6e exhibited fifty percent or more pro- tection at a dose of 30 mg kg -1 after 0.5 h and have shown activity comparable to pheny- toin and carbamazepine. Among these compounds, 4b, 4e, 4f, 5d, 5g, 6d and 6e were also active after 4 h at a dose of 100 mg kg -1 body mass. This shows the rapid onset and long duration of action of these compounds at a comparatively low dose. Compound 5b
  6. N. Siddiqui et al.: Synthesis, anticonvulsant and toxicity evaluation of 2-(1H-indol-3-yl)acetyl-N-(substituted phenyl)hydrazine carbothioamides and their related heterocyclic derivatives, Acta Pharm. 58 (2008) 445-454. 5d 3751 (NH str.), 3456 (Ar-CH), 2398 (CH 2 ), 1676 (C=N), 1534 (COCH 3 ), 1112 (C-O-C), 780 (N-N) 10.74 (s, 1H, NH), 8.41 (s, 1H, NH indole), 6.78-7.76 (m, 8H, Ar-H), 6.49 (s, 1H, CH indole), 3.81 (s, 3H, OCH 3 ), 3.60 (s, 2H, CH 2 )
  7. 5e 3671 (NH str.), 3423 (Ar-CH), 2367 (CH 2 ), 1640 (C=N), 1563 (C=C), 1230 (N-N), 1014 (C-O-C) 10.69 (s, 1H, NH), 8.31 (s, 1H, NH indole), 6.82-7.75 (m, 8H, Ar-H), 6.35 (s, 1H, CH indole), 3.02 (s, 3H, CH 3 ), 2.72 (s, 2H, CH 2 ) 5f 3676 (NH str.), 3414 (Ar-CH), 2356 (CH 2 ), 1667 (C=N), 1565 (C=C), 1245 (N-N), 1023 (C-O-C) 10.74 (s, 1H, NH), 8.46 (s, 1H, NH indole), 6.76-7.87 (m, 8H, Ar-H), 6.23 (s, 1H, CH indole), 3.15 (s, 3H, CH 3 ), 2.63 (s, 2H, CH 2 )
  8. 5g 3692 (NH str.), 3456 (Ar-CH), 2360 (CH 2 ), 1630 (C=N), 1565 (C=C), 1243 (N-N), 1002 (C-O-C) 10.54 (s, 1H, NH), 8.27 (s, 1H, NH indole), 6.78-7.62 (m, 8H, Ar-H), 6.20 (s, 1H, CH indole), 3.23 (s, 3H, CH 3 ), 2.69 (s, 2H, CH 2 )
  9. 6a 3568 (NH str.), 3211 (Ar-CH), 2340 (CH 2 ), 1630 (C=N), 1594 (C=C), 1032 (N-N), 604 (C-S-C) 10.22 (s, 1H, NH), 9.52 (s, 1H, NH indole), 6.66-8.70 (m, 9H, Ar-H), 6.66 (s, 1H, CH indole), 4.25 (s, 2H, CH 2 ) 6b 3694 (NH str.), 2921 (Ar-CH), 2283 (CH 2 ), 1585 (C=N), 1503 (C=C), 943 (N-N), 743 (C-S-C), 699 (C-Cl) 10.22 (s, 1H, NH), 8.31 (s, 1H, NH indole), 6.50-8.91 (m, 8H, Ar-H), 6.50 (s, 1H, CH indole), 4.03 (s, 2H, CH 2 ) 6c 3519 (NH str.), 3296 (Ar-CH), 2365 (CH 2 ), 1649 (C=N), 1598 (C=C), 1149 (COCH 3 ), 1030 (N-N), 605 (C-S-C) 11.07 (s, 1H, NH), 8.41 (s, 1H, NH indole), 7.08-7.52 (m, 8H, Ar-H), 5.34 (s, 1H, CH indole), 4.39 (s, 2H, CH 2 ), 3.81 (s, 3H, OCH 3 )
  10. 6d 3523 (NH str.), 3287 (Ar-CH), 2350 (CH 2 ), 1640 (C=N), 1587 (C=C), 1154 (COCH 3 ), 1046 (N-N), 615 (C-S-C) 11.13 (s, 1H, NH), 8.23 (s, 1H, NH indole), 7.16-7.67 (m, 8H, Ar-H), 5.12 (s, 1H, CH indole), 4.43 (s, 2H, CH 2 ), 3.78 (s, 3H, OCH 3 )
  11. 6e 3633 (NH str.), 3263 (Ar-CH), 2921 (CH 3 ), 2386 (CH 2 ), 1614 (C=N), 1585 (C=C), 1030 (N-N), 616 (C-S-C) 11.02 (s, 1H, NH), 9.23 (s, 1H, NH indole), 7.84 (s, 1H, CH indole), 6.98-7.81 (m, 8H, Ar-H), 4.33 (s, 2H, CH 2 ), 1.51 (s, 3H, CH 3 ) 6f 3627 (NH str.), 3255 (Ar-CH), 2943 (CH 3 ), 2378 (CH 2 ), 1623 (C=N), 1598 (C=C), 1043 (N-N), 632 (C-S-C) 11.15 (s, 1H, NH), 9.29 (s, 1H, NH indole), 7.81 (s, 1H, CH indole), 6.82-7.98 (m, 8H, Ar-H), 4.45 (s, 2H, CH 2 ), 1.43 (s, 3H, CH 3 )
  12. 6g 3643 (NH str.), 3271 (Ar-CH), 2934 (CH 3 ), 2390 (CH 2 ), 1623 (C=N), 1590 (C=C), 1043 (N-N), 665 (C-S-C) 11.23 (s, 1H, NH), 9.34 (s, 1H, NH indole), 7.98 (s, 1H, CH indole), 6.78-7.89 (m, 8H, Ar-H), 4.25 (s, 2H, CH 2 ), 1.65 (s, 3H, CH 3 )
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  26. S A @ E T A K Sinteza 2-(1H-indol-3-il)acetil-N-(supstituiranih fenil)hidrazinkarbotioamida i srodnih heterocikli~kih spojeva te procjena njihovog antikonvulzivnog djelovanja i toksi~nosti NADEEM SIDDIQUI, M. SHAMSHER ALAM i WAQUAR AHSAN Reakcijom 2-(1H-indol-3-il)acetil-N-(supstituiranih fenil)hidrazinkarbotioamida (3a-g) s odgovaraju}im reaktantom sintetizirana je serija novih 5-(1H-indol-3-il)metil-4-(supsti- tuiranih aril)-2,4-dihidro-3H-1,2,4-triazol-3-tiona (4a-g), 5-(1H-indol-3-yl)metil-N-(sup- stituiranih aril)-1,3,4-oksadiazol-2-amina (5a-g) i 5-(1H-indol-3-il)metil-N-(supstituiranih aril)-1,3,4-tiadiazol-2-amina (6a-g). Ispitano je antikonvulzivno djelovanje sintetizi-ra- nih spojeva na MES modelu i uspore|eno s djelovanjem fenitoin natrija i karbamaze- pina. Spojevi 4b, 4e, 4f, 5b, 5d, 5g, 6b, 6d i 6e pokazali su MES djelovanje usporedivo s djelovanjem fenitoina i karbamazepina nakon 0,5 h, dok je spoj 5b nakon 4 sata imao sna`nije djelovanje od karbamazepina. Osim toga, spojevi 4a, 4c, 4d, 5a, 5c, 5e, 5f, 6f i 6g su manje neurotoksi~ni od fenitoina. Klju~ne rije~i: indoli, triazoli, tiadiazoli, oksadiazoli, antikonvulzivi, neurotoksi~nost Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Jamia Hamdard (Hamdard University) New Delhi-110062, India