2009) 3( 22مجلة ابن الھیثم للعلوم الصرفة والتطبیقیة المجلد التخلیق والتقییم الفارماكولوجي األولي لبعض مشتقات الترایزول ن سلسل كمال عبد الرحم باب المعظم –بغداد للصیدله ةكلی ةصالالخ –لهـــا فعالیــة بیتـــا علیهـــا مــن الدراســة النظریـــة لألدویــة التــياعتمــادا علــى نتـــائج المعلومــات الســابقة التـــي تــم الحصــول فـيه المشـتقات ذوتـأثیر هـ ةترایازول وتـم تقیـیم فعالیـة بروبانول امین تحتوي على حلق-2سلسله من مشتقات تادرینیرجیه حضر . ان البیضاءذه من الجر ذه المركبات اختبرت على ادینات القلب النابضة المأخو ذوه. أوعیة القلب IBN AL- HAITHAM J. FO R PURE & APPL. SC I VO L.22 (3) 2009 Synthesis and Preliminary Pharmacological Evaluation of Some New Triazole Derivatives S . K Abdul-Rahmann Baghdad colle ge of pharmacy —Baghdad- bab almoadam Abstract On t he basis of t he results which was p reviously obtained from the structural and the theoretical st udies on ~-adrenergic dru gs, a series of 2-p rop anolamine d erivatives containing triazole moiety have been p repared and evaluated for their cardiovascular activity . These derivatives were test ed by using sp ontaneously -beating right atria of albino rats. Introduction 1,2,4 —Triazole is one of a class of organic heterocyclic comp ounds containing a five member di-unsaturated ring st ructure comp osed of three nitrogen atoms and two t on odjacent carbon atoms. The 1,2,4- Triazole derivatives are known in the sp ecific literature for their wide p harmacological activity (5,7). M ain ty p es of their activity are antibacterial and antifungal activities (4, 8 & 11). Which led to an intensive research on their sy nthesis The incentive for the p resent work was thus devoted to the sy nthesis of certain arylthiop rop anolamine series. 4,5-Diaryls-1,2,4-triazole [II] was sy nthesized by the oxidative cyclization of app rop riate 1- substitut ed-4-ary lthiosemicarbozide [1] ,, scheme (1) . A series of 2-p rop anolamine derivatives containing triazole moiety [III – IX ] have been p repared ,, table (1), invest igated and evaluated for their cardiovascular activity in rats, table (2 )inorder to st udy their effect on blood p ressure and heart rate . The basic requirement to have cardiovascular and β -adrenergic blocking effect in the p rop anolamine moiety besides the aromatic moiety is att ached by the ethereal linkage as it has p reviously shown in literature (1-5 & 8,9). Experime ntal Chemical part S ynthesis of 4, 5-diaryls-1. 2. 4-triazole-3yl-thiol [ II ] N—N N—NH SH T out S N N [ II ] R R IBN AL- HAITHAM J. FO R PURE & APPL. SC I VO L.22 (3) 2009 A mixture of 1-subst itut ed-4-ary lthiosemicarbazide [I], 8% sodium hy droxide in ethanol was heated under refle x for 5hr. Aft er concentration and cooling the solution was filtered and neutralized with 10% acetic acid solution (8) The solid.product that formed was filtered and recry st allized from ethanol. S ynthesis of 1,2,4-triazole derivatives [ III – IX ] N—N S— CH2CHCH2R′ N OH [III—IX ] R General procedure A mixture of 4,5-diaryls-1,2,4-triazol-3y1-thiol [II], p otassium hydroxide (1mM ) in 80% ethanol (10 ml) andN-3 (chloro-2-hydroxy p rop y l ) subst itut ed amine (1mM ) with a continuous stirring and was left for 24hr at room temp erature. The residual solution was concentrated in vacuo and the p roduct was p recipitated by agradual addition of water. The p recipitate was filtered, washed with water, dried and recryst allized from methanol/water .Table (1) showed the p hy sical prop erties of the products. Pharmacological part: (a) Ani mals bei ng use d In these exp eriments adult albino rats of either sex [300—400 gm ] were used. The animals were housed as apair in a cage in an environmentally controlled room at 21-23 o C temp erature, with lighting on from 6 a.m. to 5p .m. They were fed adlibitum , a local p elleted diet containing by dry weight 56% carbohy drate , 20% p rotein , 5% fat & 10% of salt, vitamins & cellulose . (b) S pontaneously-beating right atria. Rats were st unned & hearts were quickly removed . Right atria were dissected out & were susp ended in a 20 ml, double jacketed organ bath containing krebs p hy siological solution of the following comp osition [gm/I]: NaC1 5.5, KCI 0.35 , M gSO4 , 7 H20 0.11 ,CaCL2 0.14, KH2P04 0.16 ,NaHCO3 2.10 , glucose 2.0 , PH 7.4 maintained at 37 0 C±1 0 C & continuously bubbled with a stream of 5% CO2-95% O2 mixture. Initial tension [ Rest ing tension] of 1.0gm was ap p lied, the tissue was allowed to equilibrate for a p eriod of 45-60 min .and during this time, the bathing fluid was changed every 15 min(9), sp ontaneous contractions of the right atria were isometrically recorded by using a force transducer [UFI], , coupled to lectromed recorder p hy siographe. The results were registered at least 3 in 6 different exp eriments & in different p reparations. Re sults and Discussion Triazoles p lay an imp ortant role among the heterocyclic comp ounds. By keep ing this in view, it was considered desirable to sy nthesis the title compound with the hop e that the inner in corporation of l,2,4-triazole ring might enhance the biological activity of the original sy nthesized comp ound . 4,5-diary ls-l,2,4-triazole [II] was obt ained by the oxidative cyclization ap p rop riate l-subst itited-4- IBN AL- HAITHAM J. FO R PURE & APPL. SC I VO L.22 (3) 2009 arylyhiosmicarbazide [I]scheme (1). Compound [II] was identified by m.p . and IR sp ectra which showed the following characteristic absorption band (Nujol ). The IR showed an appearance band at (1640)cm -1 due to stretching vibration of ( C=N), also an ap p earance of avery weak band of (2400-2700)cm -1 due to t he (SH) group and (3 l00-3060)cm -1 due to (C-H aromatic)which also showed an app earance band at (1980-2853 )cm -1 due to (C-H) aliphatic. The new 1.2. 4-triaz ole derivative [ III – IX ] N—N — S— CH2CHCH2R′ N OH [III—IX] R They were sy nthesized by st irring aqueous methanolic solution 80% (10m1) with 4,5-diary le- 1,2,4-triazole[ II] and N-(3-chloro-2-hydroxy p rop y l ) substitut ed amine ( 1 mM ) for 24hr at room temp erature .The p roduct was recry st allized from methanol/water. The comp ound [III-IX] was identified by IR sp ectrum which showed the disapp earance of absorp tion band at (2400-2700) cm -1 due to ( S-H ) group and ap p earance of band at (3500-3440) cm -1 due to (O-H) group .This is astrong evidence to p resent t his reaction .Also an app earance band at (3400-3200)cm -1 due to st retching vibration of (N-H) group , (3100-3060)cm -1 is due to (C-H aromatic), (1640 ) cm -1 (C═N) and (1600-l500)cm -1 is due to ( C=C aromatic). Pharmacological results: Exp eriments were carried .Several & different concentrations of comp ounds [III—IX] were tested on the sp ontaneous contractions of the right atria of albino rats to detect t heir behavior & to determine the median effective dose of each comp ound . Compounds with concentration 1 mg/ml showed anegative inotrop ic effect on t he right atria excep t comp ounds [IV & VIII] which needed more concentration to p roduce asimilar activity . The increasing of the concentrate in organ bath of these exp eriments showed calcium antagonistic activity . The median effective dose of comp ounds[III-- IX] on the sp ontaneous contractions of the right atria of albino rats,is shown in table (2) These results are p romising and more work should be continued before landing at the p recise mechanisms for cardiovascular effects inorder to have the correct decision for the usage of these comp ounds for medicinal p urp oses . Re ference 1. Hazzaa,A.A.B.; Ashour ,F. and Shafik, R.M . (1980). Sy nthesis of 1,2,4-Triazolylthio- p rop anolamines as p otential Cardiovascular Agents” Pharmazia 34 (5-6): 324-5 2. A1-shiabany, Ikbal S.; Alwan ,S.M . and Ahdul-Rahman, S. K. (1994) “ Sy nthesis & Pharmacological Evaluation of some new T hiadiazol Derivative M u’tah J. for research & st udies 9(2): 3. Gaertner, V.R. (1967)”Alkyl-2, 3-Ep oxy p rop y lamines.’ Tetrahedron (London), 23:2123-2136 4. Bartroli ,J. et al(1998) “ new azole antifungals Sy nthesis & antifungal activity of 3-substitut ed “ J M ed Chem. 11: 1869-1882 M ay . Table 2 Compound M edian effective dose ED50 III IV V VI VII VIII IX 2mg / ml (5.4x10 -3 M ) 1mg / ml (2.7x10 -3 M ) 1mg / ml (2.6x10 -3 M ) 1mg / ml (2.5xl0 -3 M ) 2mg / ml (5.0x10 -3 M ) 1mg /ml (2.4x10 -3 M ) 1mg / ml (2.3x10 -3 M ) IBN AL- HAITHAM J. FO R PURE & APPL. SC I VO L.22 (3) 2009 5 . Ghannoum, M . A .and Kuhn ,D . M . (2002 )“ Voriconazole-better chances for p atients with invasive my coses” Eur J M ed Res 5: 242-56 M ay 6. M arie —Christ iana Cair, et al, (1984) “Sy nthesis of a Novel series of(Ary loxy ) p rop anolamine: New selective β2- Blocking Agents ‘J. M ed. Chem, 27: 7. M orzy cki, J.W.; M aj, J.; Nikitivuk, A. and Kwolek, G. M alinnowska(1984) “Three new derivative of 3-amino 1,2- Prop anediol; their sp ectral p rop erties & biological evaluation” Acta Pol. Pharm., Jul-Aug; 58 (4):249-56, (2001). 8. Al-Joboury ,N . R. (1987) T hesis of Sy nthesis of new Acety lenic comp ound: & other derivatives 1, 2, 4-Triazole of p ossible , Biological Activity ; June 9. Perry ,W .L.W. (1970) Pharmacological exp erimentation on isolated p reparations, by the st aff of Dep t. of p harmacology , University of Edinburgh, Churchill Livingst on, London & New York, 10. Abdul-Rahman, S.K. ; Alwan ,S. M . (1989)” Sy nthesis of new thiadiazolylthiop rop anolamine derivatives of p otential cardiovascular p otency ”.The fifth scientific conference, 5 (I 7- 11)Oct. 11. Kolin,Y. and Hitchcock ,C. A. (1997)” The search for new t riazole antifungal agents “ Curr Op in Chem. Biol. 1(2):176-82 Aug. 12. Youichi Hara, et al(1978) “Sy nthesis & β-Adrenergic Blocking Action of a new Thiazolylthiop rop anolamine Derivatives” J. Pharmaceutical Sciences 67:9 September 2009) 3( 22مجلة ابن الھیثم للعلوم الصرفة والتطبیقیة المجلد التخلیق والتقییم الفارماكولوجي األولي لبعض مشتقات الترایزول ن سلسل كمال عبد الرحم باب المعظم –بغداد للصیدله ةكلی ةصالالخ –لهـــا فعالیــة بیتـــا الحصــول علیهـــا مــن الدراســة النظریـــة لألدویــة التــياعتمــادا علــى نتـــائج المعلومــات الســابقة التـــي تــم فـيه المشـتقات ذوتـأثیر هـ ةترایازول وتـم تقیـیم فعالیـة بروبانول امین تحتوي على حلق-2سلسله من مشتقات تادرینیرجیه حضر . البیضاء ان ذه من الجر ذه المركبات اختبرت على ادینات القلب النابضة المأخو ذوه. أوعیة القلب IBN AL- HAITHAM J. FO R PURE & APPL. SC I VO L.22 (3) 2009 Synthesis and Preliminary Pharmacological Evaluation of Some New Triazole Derivatives S . K Abdul-Rahmann Baghdad colle ge of pharmacy —Baghdad- bab almoadam Abstract On t he basis of t he results which was p reviously obtained from the structural and the theoretical st udies on ~-adrenergic dru gs, a series of 2-p rop anolamine d erivatives containing triazole moiety have been p repared and evaluated for their cardiovascular activity . These derivatives were test ed by using sp ontaneously -beating right atria of albino rats. Introduction 1,2,4 —Triazole is one of a class of organic heterocyclic comp ounds containing a five member di-unsaturated ring st ructure comp osed of three nitrogen atoms and two t on odjacent carbon atoms. The 1,2,4- Triazole derivatives are known in the sp ecific literature for their wide p harmacological activity (5,7). M ain ty p es of their activity are antibacterial and antifungal activities (4, 8 & 11). Which led to an intensive research on their sy nthesis The incentive for the p resent work was thus devoted to the sy nthesis of certain arylthiop rop anolamine series. 4,5-Diaryls-1,2,4-triazole [II] was sy nthesized by the oxidative cyclization of app rop riate 1- substitut ed-4-ary lthiosemicarbozide [1] ,, scheme (1) . A series of 2-p rop anolamine derivatives containing triazole moiety [III – IX ] have been p repared ,, table (1), invest igated and evaluated for their cardiovascular activity in rats, table (2 )inorder to st udy their effect on blood p ressure and heart rate . The basic requirement to have cardiovascular and β -adrenergic blocking effect in the p rop anolamine moiety besides the aromatic moiety is att ached by the ethereal linkage as it has p reviously shown in literature (1-5 & 8,9). Experime ntal Chemical part S ynthesis of 4, 5-diaryls-1. 2. 4-triazole-3yl-thiol [ II ] N—N N—NH SH T out S N N [ II ] R R IBN AL- HAITHAM J. FO R PURE & APPL. SC I VO L.22 (3) 2009 A mixture of 1-subst itut ed-4-ary lthiosemicarbazide [I], 8% sodium hy droxide in ethanol was heated under refle x for 5hr. Aft er concentration and cooling the solution was filtered and neutralized with 10% acetic acid solution (8) The solid.product that formed was filtered and recry st allized from ethanol. S ynthesis of 1,2,4-triazole derivatives [ III – IX ] N—N S— CH2CHCH2R′ N OH [III—IX ] R General procedure A mixture of 4,5-diaryls-1,2,4-triazol-3y1-thiol [II], p otassium hydroxide (1mM ) in 80% ethanol (10 ml) andN-3 (chloro-2-hydroxy p rop y l ) subst itut ed amine (1mM ) with a continuous stirring and was left for 24hr at room temp erature. The residual solution was concentrated in vacuo and the p roduct was p recipitated by agradual addition of water. The p recipitate was filtered, washed with water, dried and recryst allized from methanol/water .Table (1) showed the p hy sical prop erties of the products. Pharmacological part: (a) Ani mals bei ng use d In these exp eriments adult albino rats of either sex [300—400 gm ] were used. The animals were housed as apair in a cage in an environmentally controlled room at 21-23 o C temp erature, with lighting on from 6 a.m. to 5p .m. They were fed adlibitum , a local p elleted diet containing by dry weight 56% carbohy drate , 20% p rotein , 5% fat & 10% of salt, vitamins & cellulose . (b) S pontaneously-beating right atria. Rats were st unned & hearts were quickly removed . Right atria were dissected out & were susp ended in a 20 ml, double jacketed organ bath containing krebs p hy siological solution of the following comp osition [gm/I]: NaC1 5.5, KCI 0.35 , M gSO4 , 7 H20 0.11 ,CaCL2 0.14, KH2P04 0.16 ,NaHCO3 2.10 , glucose 2.0 , PH 7.4 maintained at 37 0 C±1 0 C & continuously bubbled with a stream of 5% CO2-95% O2 mixture. Initial tension [ Rest ing tension] of 1.0gm was ap p lied, the tissue was allowed to equilibrate for a p eriod of 45-60 min .and during this time, the bathing fluid was changed every 15 min(9), sp ontaneous contractions of the right atria were isometrically recorded by using a force transducer [UFI], , coupled to lectromed recorder p hy siographe. The results were registered at least 3 in 6 different exp eriments & in different p reparations. Re sults and Discussion Triazoles p lay an imp ortant role among the heterocyclic comp ounds. By keep ing this in view, it was considered desirable to sy nthesis the title compound with the hop e that the inner in corporation of l,2,4-triazole ring might enhance the biological activity of the original sy nthesized comp ound . 4,5-diary ls-l,2,4-triazole [II] was obt ained by the oxidative cyclization ap p rop riate l-subst itited-4- IBN AL- HAITHAM J. FO R PURE & APPL. SC I VO L.22 (3) 2009 arylyhiosmicarbazide [I]scheme (1). Compound [II] was identified by m.p . and IR sp ectra which showed the following characteristic absorption band (Nujol ). The IR showed an appearance band at (1640)cm -1 due to stretching vibration of ( C=N), also an ap p earance of avery weak band of (2400-2700)cm -1 due to t he (SH) group and (3 l00-3060)cm -1 due to (C-H aromatic)which also showed an app earance band at (1980-2853 )cm -1 due to (C-H) aliphatic. The new 1.2. 4-triaz ole derivative [ III – IX ] N—N — S— CH2CHCH2R′ N OH [III—IX] R They were sy nthesized by st irring aqueous methanolic solution 80% (10m1) with 4,5-diary le- 1,2,4-triazole[ II] and N-(3-chloro-2-hydroxy p rop y l ) substitut ed amine ( 1 mM ) for 24hr at room temp erature .The p roduct was recry st allized from methanol/water. The comp ound [III-IX] was identified by IR sp ectrum which showed the disapp earance of absorp tion band at (2400-2700) cm -1 due to ( S-H ) group and ap p earance of band at (3500-3440) cm -1 due to (O-H) group .This is astrong evidence to p resent t his reaction .Also an app earance band at (3400-3200)cm -1 due to st retching vibration of (N-H) group , (3100-3060)cm -1 is due to (C-H aromatic), (1640 ) cm -1 (C═N) and (1600-l500)cm -1 is due to ( C=C aromatic). Pharmacological results: Exp eriments were carried .Several & different concentrations of comp ounds [III—IX] were tested on the sp ontaneous contractions of the right atria of albino rats to detect t heir behavior & to determine the median effective dose of each comp ound . Compounds with concentration 1 mg/ml showed anegative inotrop ic effect on t he right atria excep t comp ounds [IV & VIII] which needed more concentration to p roduce asimilar activity . The increasing of the concentrate in organ bath of these exp eriments showed calcium antagonistic activity . The median effective dose of comp ounds[III-- IX] on the sp ontaneous contractions of the right atria of albino rats,is shown in table (2) These results are p romising and more work should be continued before landing at the p recise mechanisms for cardiovascular effects inorder to have the correct decision for the usage of these comp ounds for medicinal p urp oses . Re ference 1. Hazzaa,A.A.B.; Ashour ,F. and Shafik, R.M . (1980). Sy nthesis of 1,2,4-Triazolylthio- p rop anolamines as p otential Cardiovascular Agents” Pharmazia 34 (5-6): 324-5 2. A1-shiabany, Ikbal S.; Alwan ,S.M . and Ahdul-Rahman, S. K. (1994) “ Sy nthesis & Pharmacological Evaluation of some new T hiadiazol Derivative M u’tah J. for research & st udies 9(2): 3. Gaertner, V.R. (1967)”Alkyl-2, 3-Ep oxy p rop y lamines.’ Tetrahedron (London), 23:2123-2136 4. Bartroli ,J. et al(1998) “ new azole antifungals Sy nthesis & antifungal activity of 3-substitut ed “ J M ed Chem. 11: 1869-1882 M ay . Table 2 Compound M edian effective dose ED50 III IV V VI VII VIII IX 2mg / ml (5.4x10 -3 M ) 1mg / ml (2.7x10 -3 M ) 1mg / ml (2.6x10 -3 M ) 1mg / ml (2.5xl0 -3 M ) 2mg / ml (5.0x10 -3 M ) 1mg /ml (2.4x10 -3 M ) 1mg / ml (2.3x10 -3 M ) IBN AL- HAITHAM J. FO R PURE & APPL. SC I VO L.22 (3) 2009 5 . Ghannoum, M . A .and Kuhn ,D . M . (2002 )“ Voriconazole-better chances for p atients with invasive my coses” Eur J M ed Res 5: 242-56 M ay 6. M arie —Christ iana Cair, et al, (1984) “Sy nthesis of a Novel series of(Ary loxy ) p rop anolamine: New selective β2- Blocking Agents ‘J. M ed. Chem, 27: 8. M orzy cki, J.W.; M aj, J.; Nikitivuk, A. and Kwolek, G. M alinnowska(1984) “Three new derivative of 3-amino 1,2- Prop anediol; their sp ectral p rop erties & biological evaluation” Acta Pol. Pharm., Jul-Aug; 58 (4):249-56, (2001). 8. Al-Joboury ,N . R. (1987) T hesis of Sy nthesis of new Acety lenic comp ound: & other derivatives 1, 2, 4-Triazole of p ossible , Biological Activity ; June 9. Perry ,W .L.W. (1970) Pharmacological exp erimentation on isolated p reparations, by the st aff of Dep t. of p harmacology , University of Edinburgh, Churchill Livingst on, London & New York, 10. Abdul-Rahman, S.K. ; Alwan ,S. M . (1989)” Sy nthesis of new thiadiazolylthiop rop anolamine derivatives of p otential cardiovascular p otency ”.The fifth scientific conference, 5 (I 7- 11)Oct. 11. Kolin,Y. and Hitchcock ,C. A. (1997)” The search for new t riazole antifungal agents “ Curr Op in Chem. Biol. 1(2):176-82 Aug. 12. Youichi Hara, et al(1978) “Sy nthesis & β-Adrenergic Blocking Action of a new Thiazolylthiop rop anolamine Derivatives” J. Pharmaceutical Sciences 67:9 September