2009) 3( 22مجلة ابن الھیثم للعلوم الصرفة والتطبیقیة المجلد التخلیق والتقییم الفارماكولوجي األولي لبعض مشتقات الترایزول سلسل كمال عبد الرحمن باب المعظم –بغداد للصیدله ةكلی ةصالالخ ــائج المعلومــات الســابقة التـــي تــم الحصــول ـى نتـ ــا مــن الدراســة النظریـــة لألدویــة التــياعتمــادا علـ ـا علیهـ ا فعالیــة بیتــ –لهـــ 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 college of pharmacy —Baghdad-bab almoadam Abstract On the basis of the results which was previously obtained from the structural and the theoretical studies on ~-adrenergic drugs, a series of 2-propanolamine derivatives containing triazole moiety have been prepared and evaluated for their cardiovascular activity . These derivatives were tested by using spontaneously-beating right atria of albino rats. Introduction 1,2,4 —Triazole is one of a class of organic heterocyclic compounds containing a five member di-unsaturated ring structure composed of three nitrogen atoms and two ton odjacent carbon atoms. The 1,2,4- Triazole derivatives are known in the specific literature for their wide pharmacological activity (5,7). Main types of their activity are antibacterial and antifungal activities (4, 8 & 11). Which led to an intensive research on their synthesis The incentive for the present work was thus devoted to the synthesis of certain arylthiopropanolamine series. 4,5-Diaryls-1,2,4-triazole [II] was synthesized by the oxidative cyclization of appropriate 1- substituted-4-arylthiosemicarbozide [1] ,, scheme (1) . A series of 2-propanolamine derivatives containing triazole moiety [III – IX ] have been prepared ,, table (1), investigated and evaluated for their cardiovascular activity in rats, table (2 )inorder to study their effect on blood pressure and heart rate . The basic requirement to have cardiovascular and β -adrenergic blocking effect in the propanolamine moiety besides the aromatic moiety is attached by the ethereal linkage as it has previously shown in literature (1-5 & 8,9). Experimental Chemical part Synthesis of 4, 5-diaryls-1. 2. 4-triazole-3yl-thiol [ II ] N—N N—NH SH Tout 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-substituted-4-arylthiosemicarbazide [I], 8% sodium hydroxide in ethanol was heated under reflex for 5hr. After concentration and cooling the solution was filtered and neutralized with 10% acetic acid solution (8) The solid.product that formed was filtered and recrystallized from ethanol. Synthesis 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], potassium hydroxide (1mM) in 80% ethanol (10 ml) andN-3 (chloro-2-hydroxypropyl ) substituted amine (1mM) with a continuous stirring and was left for 24hr at room temperature. The residual solution was concentrated in vacuo and the product was precipitated by agradual addition of water. The precipitate was filtered, washed with water, dried and recrystallized from methanol/water .Table (1) showed the physical properties of the products. Pharmacological part: (a) Animals being used In these experiments 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 oC temperature, with lighting on from 6 a.m. to 5p.m. They were fed adlibitum , a local pelleted diet containing by dry weight 56% carbohydrate , 20% protein , 5% fat & 10% of salt, vitamins & cellulose . (b) Spontaneously-beating right atria. Rats were stunned & hearts were quickly removed . Right atria were dissected out & were suspended in a 20 ml, double jacketed organ bath containing krebs physiological solution of the following composition [gm/I]: NaC1 5.5, KCI 0.35 , MgSO4 , 7 H20 0.11 ,CaCL2 0.14, KH2P04 0.16 ,NaHCO3 2.10 , glucose 2.0 , PH 7.4 maintained at 370C±1 0C & continuously bubbled with a stream of 5% CO2-95% O2 mixture. Initial tension [ Resting tension] of 1.0gm was applied, the tissue was allowed to equilibrate for a period of 45-60 min .and during this time, the bathing fluid was changed every 15 min(9), spontaneous contractions of the right atria were isometrically recorded by using a force transducer [UFI], , coupled to lectromed recorder physiographe. The results were registered at least 3 in 6 different experiments & in different preparations. Results and Discussion Triazoles play an important role among the heterocyclic compounds. By keeping this in view, it was considered desirable to synthesis the title compound with the hope that the inner in corporation of l,2,4-triazole ring might enhance the biological activity of the original synthesized compound . 4,5-diaryls-l,2,4-triazole [II] was obtained by the oxidative cyclization appropriate l-substitited-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 spectra 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 appearance of avery weak band of (2400-2700)cm -1 due to the (SH) group and (3 l00-3060)cm-1 due to (C-H aromatic)which also showed an appearance band at (1980-2853 )cm -1 due to (C-H) aliphatic. The new 1.2. 4-triazole derivative [ III – IX ] N—N — S— CH2CHCH2R′ N OH [III—IX] R They were synthesized by stirring aqueous methanolic solution 80% (10m1) with 4,5-diaryle- 1,2,4-triazole[ II] and N-(3-chloro-2-hydroxypropyl ) substituted amine ( 1 mM) for 24hr at room temperature .The product was recrystallized from methanol/water. The compound [III-IX] was identified by IR spectrum which showed the disappearance of absorption band at (2400-2700) cm -1 due to ( S-H ) group and appearance of band at (3500-3440) cm-1 due to (O-H) group .This is astrong evidence to present this reaction .Also an appearance band at (3400-3200)cm -1 due to stretching 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: Experiments were carried .Several & different concentrations of compounds [III—IX] were tested on the spontaneous contractions of the right atria of albino rats to detect their behavior & to determine the median effective dose of each compound . Compounds with concentration 1 mg/ml showed anegative inotropic effect on the right atria except compounds [IV & VIII] which needed more concentration to produce asimilar activity. The increasing of the concentrate in organ bath of these experiments showed calcium antagonistic activity. The median effective dose of compounds[III-- IX] on the spontaneous contractions of the right atria of albino rats,is shown in table (2) These results are promising and more work should be continued before landing at the precise mechanisms for cardiovascular effects inorder to have the correct decision for the usage of these compounds for medicinal purposes . Reference 1. Hazzaa,A.A.B.; Ashour ,F. and Shafik, R.M. (1980). Synthesis of 1,2,4-Triazolylthio- propanolamines as potential Cardiovascular Agents” Pharmazia 34 (5-6): 324-5 2. A1-shiabany, Ikbal S.; Alwan ,S.M. and Ahdul-Rahman, S. K. (1994) “Synthesis & Pharmacological Evaluation of some new Thiadiazol Derivative Mu’tah J. for research & studies 9(2): 3. Gaertner, V.R. (1967)”Alkyl-2, 3-Epoxypropylamines.’ Tetrahedron (London), 23:2123-2136 4. Bartroli ,J. et al(1998) “ new azole antifungals Synthesis & antifungal activity of 3-substituted “ J M ed Chem. 11: 1869-1882 May . Table 2 Compound Median effective dose ED50 III IV V VI VII VIII IX 2mg / ml (5.4x10 -3 M) 1mg / ml (2.7x10-3M) 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 patients with invasive mycoses” Eur J M ed Res 5: 242-56 May 6. Marie —Christiana Cair, et al, (1984) “Synthesis of a Novel series of(Aryloxy) propanolamine: New selective β2- Blocking Agents ‘J. M ed. Chem, 27: 7. Morzycki, J.W.; Maj, J.; Nikitivuk, A. and Kwolek, G. M alinnowska(1984) “Three new derivative of 3-amino 1,2- Propanediol; their spectral properties & biological evaluation” Acta Pol. Pharm., Jul-Aug; 58 (4):249-56, (2001). 8. Al-Joboury ,N . R. (1987) Thesis of Synthesis of new Acety lenic compound: & other derivatives 1, 2, 4-Triazole of possible , Biological Activity; June 9. Perry,W .L.W. (1970) Pharmacological experimentation on isolated preparations, by the staff of Dept. of pharmacology, University of Edinburgh, Churchill Livingston, London & New York, 10. Abdul-Rahman, S.K. ; Alwan ,S. M. (1989)” Synthesis of new thiadiazolylthiopropanolamine derivatives of potential cardiovascular potency”.The fifth scientific conference, 5 (I 7- 11)Oct. 11. Kolin,Y. and Hitchcock ,C. A. (1997)” The search for new triazole antifungal agents “ Curr Opin Chem. Biol. 1(2):176-82 Aug. 12. Youichi Hara, et al(1978) “Synthesis & β-Adrenergic Blocking Action of a new Thiazolylthiopropanolamine Derivatives” J. Pharmaceutical Sciences 67:9 September 2009) 3( 22مجلة ابن الھیثم للعلوم الصرفة والتطبیقیة المجلد التخلیق والتقییم الفارماكولوجي األولي لبعض مشتقات الترایزول سلسل كمال عبد الرحمن باب المعظم –بغداد للصیدله ةكلی ةصالالخ ــائج المعلومــات الســابقة التـــي تــم ـى نتـ ــا مــن الدراســة النظریـــة لألدویــة التــياعتمــادا علـ ـا الحصــول علیهـ ا فعالیــة بیتــ –لهـــ 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 college of pharmacy —Baghdad-bab almoadam Abstract On the basis of the results which was previously obtained from the structural and the theoretical studies on ~-adrenergic drugs, a series of 2-propanolamine derivatives containing triazole moiety have been prepared and evaluated for their cardiovascular activity . These derivatives were tested by using spontaneously-beating right atria of albino rats. Introduction 1,2,4 —Triazole is one of a class of organic heterocyclic compounds containing a five member di-unsaturated ring structure composed of three nitrogen atoms and two ton odjacent carbon atoms. The 1,2,4- Triazole derivatives are known in the specific literature for their wide pharmacological activity (5,7). Main types of their activity are antibacterial and antifungal activities (4, 8 & 11). Which led to an intensive research on their synthesis The incentive for the present work was thus devoted to the synthesis of certain arylthiopropanolamine series. 4,5-Diaryls-1,2,4-triazole [II] was synthesized by the oxidative cyclization of appropriate 1- substituted-4-arylthiosemicarbozide [1] ,, scheme (1) . A series of 2-propanolamine derivatives containing triazole moiety [III – IX ] have been prepared ,, table (1), investigated and evaluated for their cardiovascular activity in rats, table (2 )inorder to study their effect on blood pressure and heart rate . The basic requirement to have cardiovascular and β -adrenergic blocking effect in the propanolamine moiety besides the aromatic moiety is attached by the ethereal linkage as it has previously shown in literature (1-5 & 8,9). Experimental Chemical part Synthesis of 4, 5-diaryls-1. 2. 4-triazole-3yl-thiol [ II ] N—N N—NH SH Tout 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-substituted-4-arylthiosemicarbazide [I], 8% sodium hydroxide in ethanol was heated under reflex for 5hr. After concentration and cooling the solution was filtered and neutralized with 10% acetic acid solution (8) The solid.product that formed was filtered and recrystallized from ethanol. Synthesis 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], potassium hydroxide (1mM) in 80% ethanol (10 ml) andN-3 (chloro-2-hydroxypropyl ) substituted amine (1mM) with a continuous stirring and was left for 24hr at room temperature. The residual solution was concentrated in vacuo and the product was precipitated by agradual addition of water. The precipitate was filtered, washed with water, dried and recrystallized from methanol/water .Table (1) showed the physical properties of the products. Pharmacological part: (a) Animals being used In these experiments 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 oC temperature, with lighting on from 6 a.m. to 5p.m. They were fed adlibitum , a local pelleted diet containing by dry weight 56% carbohydrate , 20% protein , 5% fat & 10% of salt, vitamins & cellulose . (b) Spontaneously-beating right atria. Rats were stunned & hearts were quickly removed . Right atria were dissected out & were suspended in a 20 ml, double jacketed organ bath containing krebs physiological solution of the following composition [gm/I]: NaC1 5.5, KCI 0.35 , MgSO4 , 7 H20 0.11 ,CaCL2 0.14, KH2P04 0.16 ,NaHCO3 2.10 , glucose 2.0 , PH 7.4 maintained at 370C±1 0C & continuously bubbled with a stream of 5% CO2-95% O2 mixture. Initial tension [ Resting tension] of 1.0gm was applied, the tissue was allowed to equilibrate for a period of 45-60 min .and during this time, the bathing fluid was changed every 15 min(9), spontaneous contractions of the right atria were isometrically recorded by using a force transducer [UFI], , coupled to lectromed recorder physiographe. The results were registered at least 3 in 6 different experiments & in different preparations. Results and Discussion Triazoles play an important role among the heterocyclic compounds. By keeping this in view, it was considered desirable to synthesis the title compound with the hope that the inner in corporation of l,2,4-triazole ring might enhance the biological activity of the original synthesized compound . 4,5-diaryls-l,2,4-triazole [II] was obtained by the oxidative cyclization appropriate l-substitited-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 spectra which showed the following characteristic absorption band (Nujol ). The IR showed an appearance band at (1640)cm -1due to stretching vibration of ( C=N), also an appearance of avery weak band of (2400-2700)cm-1 due to the (SH) group and (3 l00-3060)cm -1 due to (C-H aromatic)which also showed an appearance band at (1980-2853 )cm-1 due to (C-H) aliphatic. The new 1.2. 4-triazole derivative [ III – IX ] N—N — S— CH2CHCH2R′ N OH [III—IX] R They were synthesized by stirring aqueous methanolic solution 80% (10m1) with 4,5-diaryle- 1,2,4-triazole[ II] and N-(3-chloro-2-hydroxypropyl ) substituted amine ( 1 mM) for 24hr at room temperature .The product was recrystallized from methanol/water. The compound [III-IX] was identified by IR spectrum which showed the disappearance of absorption band at (2400-2700) cm -1 due to ( S-H ) group and appearance of band at (3500-3440) cm -1 due to (O-H) group .This is astrong evidence to present this reaction .Also an appearance band at (3400-3200)cm-1 due to stretching 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: Experiments were carried .Several & different concentrations of compounds [III—IX] were tested on the spontaneous contractions of the right atria of albino rats to detect their behavior & to determine the median effective dose of each compound . Compounds with concentration 1 mg/ml showed anegative inotropic effect on the right atria except compounds [IV & VIII] which needed more concentration to produce asimilar activity. The increasing of the concentrate in organ bath of these experiments showed calcium antagonistic activity. The median effective dose of compounds[III-- IX] on the spontaneous contractions of the right atria of albino rats,is shown in table (2) These results are promising and more work should be continued before landing at the precise mechanisms for cardiovascular effects inorder to have the correct decision for the usage of these compounds for medicinal purposes . Reference 1. Hazzaa,A.A.B.; Ashour ,F. and Shafik, R.M. (1980). Synthesis of 1,2,4-Triazolylthio- propanolamines as potential Cardiovascular Agents” Pharmazia 34 (5-6): 324-5 2. A1-shiabany, Ikbal S.; Alwan ,S.M. and Ahdul-Rahman, S. K. (1994) “Synthesis & Pharmacological Evaluation of some new Thiadiazol Derivative Mu’tah J. for research & studies 9(2): 3. Gaertner, V.R. (1967)”Alkyl-2, 3-Epoxypropylamines.’ Tetrahedron (London), 23:2123-2136 4. Bartroli ,J. et al(1998) “ new azole antifungals Synthesis & antifungal activity of 3-substituted “ J M ed Chem. 11: 1869-1882 May . Table 2 Compound Median effective dose ED50 III IV V VI VII VIII IX 2mg / ml (5.4x10 -3 M) 1mg / ml (2.7x10-3M) 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 patients with invasive mycoses” Eur J M ed Res 5: 242-56 May 6. Marie —Christiana Cair, et al, (1984) “Synthesis of a Novel series of(Aryloxy) propanolamine: New selective β2- Blocking Agents ‘J. M ed. Chem, 27: 8. Morzycki, J.W.; Maj, J.; Nikitivuk, A. and Kwolek, G. M alinnowska(1984) “Three new derivative of 3-amino 1,2- Propanediol; their spectral properties & biological evaluation” Acta Pol. Pharm., Jul-Aug; 58 (4):249-56, (2001). 8. Al-Joboury ,N . R. (1987) Thesis of Synthesis of new Acety lenic compound: & other derivatives 1, 2, 4-Triazole of possible , Biological Activity; June 9. Perry,W .L.W. (1970) Pharmacological experimentation on isolated preparations, by the staff of Dept. of pharmacology, University of Edinburgh, Churchill Livingston, London & New York, 10. Abdul-Rahman, S.K. ; Alwan ,S. M. (1989)” Synthesis of new thiadiazolylthiopropanolamine derivatives of potential cardiovascular potency”.The fifth scientific conference, 5 (I 7- 11)Oct. 11. Kolin,Y. and Hitchcock ,C. A. (1997)” The search for new triazole antifungal agents “ Curr Opin Chem. Biol. 1(2):176-82 Aug. 12. Youichi Hara, et al(1978) “Synthesis & β-Adrenergic Blocking Action of a new Thiazolylthiopropanolamine Derivatives” J. Pharmaceutical Sciences 67:9 September