Synthesis and antimicrobial evaluation of new 1,3,4 – Thiadiazole Derivatives Iman F. Mustafa Eman M. Hussain Dept. of Chemistry / College of Education for Pure Science (Ibn Al-Haitham) / University of Baghdad Received in : 20 October 2013 , Accepted in : 2 February 2014 Abstract The amino thiadiazole [I] on treatment with aromatic aldehydes yielded Schiff bases [IIa-c] , which cyclized to thiazolidinone [IIIa-c] derivatives by reaction with thioglycolic acid .Reaction of carbon disulfide and methyl iodide with [I] gavedithiomethyl[IV] which on treatment with o-phenylenediamine gave the condensed N-Imidazolythiadiazolylamine [V] , However , reaction of [I] with phenylisocyanate and phenylisothiocyanate afforded the carbamideand carbothiamide derivatives[VI.VII]a-c. The structure of these compounds was characterized from their melting point , FTIR spectroscopy and elementalanalysis . Kew words : antimicrobial 1,3,4–Thiadiazole, thiazolidinone , imidazoly , thiadiazolylamine . 297 | Chemistry @a@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@ÚÓ‘Ój�n€a@Î@Úœäñ€a@‚Ï‹»‹€@·rÓ:a@Âig@Ú‹©@Ü‹127@@ÖÜ»€a@I1@‚b«@H2014 Ibn Al-Haitham Jour. for Pure & Appl. Sci. Vol. 27 (1) 2014 Introduction The recent literature is enriched with progressive findings about the synthesis and pharmacological activity of fused heterocycles. Heterocycles bearing atriazole or 1,3,4 – thiadiazole moiety are reported to show biological properties such as antibacterial [1-2] antiaggregatory agent [3] , antiviral [4] , antiinflammatory activities [5-6] , anticonvulsant [7] , and antihypertensive [8] . 1,3,4 – thiadiazoles exhibit broad spectrum of biological activities , possibly due to the presence of toxophoric N-C-S moiety [9] . They found applications as antibacterial , antitumor , antiinflammatory agents , pesticides , herbicides , dyes , lubricants and analytical reagents [10] . Experimental All melting points, were determined by using " Electro thermal melting point apparatus mettle and are uncorrected . FTIR spectrophotometer ( 8300 ) , by using KBr disc , C.H.N- Elemental Analysis ( Elmer 240 B – perken ) . • Starting material : 2- amino – 5 – mercapto – 1,3,4 – thiadiazole [ I ] was prepared from thiosemicarbazide and carbondisulfide as previously described by [11] . • Schiff Bases [ IIa-c ] : A mixture of [I] (0.01 mol ) and aromatic aldehydes (0.01mol) was dissolved in ethanol containing few drops Et3N, and heated under reflux for 4hr. After cooling the precipitated solid was collected by filtration and crystaillazed [12] from ethanol , see scheme 1 • N – Benzylidene – 5 – mercapto – 1,3,4 – thiadiazole -2- amine [II a] . • N – (4- chlorobenzylidene ) 5 – mercapto -1,3,4 –thiadiazole – 2 – amino [II b] . • N – ( 4- methoxybenzylidene ) -5- mercapto – 1,3,4 – thiadiazole -2- amine [IIc] : see physical properties in table 1. • 3- [ 5- mercapto – 1,3,4 – thiadiazole – 2 – yl ) – 2- aryl thiazolidin – 4 – one [ IIIa-c] [ 13 ] : A mixture of individual derivative [IIa-IIc] (0.01 mol) and thioglycolicacid (0.01mol) was refluxed in absolute ethanol (30 ml) for 4hr .After cooling the reaction mixture , the precipitated solid was filtered off and crystallized from ethanol . • 3 - [ 5- mercapto – 1,3,4 – thiadiazole -2- yl ] -2- phenyl thiazolidin -4- one [ III a] . • 3 - [ 5- mercapto – 1,3,4 – thiadiazole -2- yl ] -2- (4-chlorophenyl ) thiazolidin -5- one [III b] . • 3 - [5- mercapto – 1,3,4 – thiadiazole -2- yl ] -2- ( 4- methoxy phenyl ) thiazolidin -5- one [III c] . see physical properties in (table 1, 2 ) . • N – Di ( methyl thio ) methylene [ 5- thio methyl -1,3,4 – thiadiazole – 2 – yl ] – amino [ IV ] : To stirred cold solution of [I] ( 0.05 mol ) in DMF (25ml), 20 M- NaOH ( 5 ml ) , carbondisulfide ( 8 ml ) , and methyl iodide ( 0.1 mol ) were added and the stirring was continued for additional 4hr . The mixture was poured into cold water and the formed solid was crystallized from benzene . see physical properties in (table 1,2 ) . • N – [ 5- thio methyl – 1,3,4 – thiadiazole -2- yl ] – 1H – benzo [ d ] imidazole – 2 – yl – amine [V] : A mixture of [IV] (0.04 mol) and o- phenylenediamine(0.04 mol ) in DMF ( 30 ml ) was refluxed for 8hr . After cooling the formed solid crystallized from ethanol . see physical properties in (table 1, 2 ) . • 1 - [ 5- mercapto – 1,3,4 – thiadiazole – 2 – yl] – 3 – phenyl urea [VIa] : A mixture of [I] ( 0.01 mol) and phenylisocyanate (0.01mol ) was refluxed in ethanol (30 ml) for 8hr . The separated solid was filtered off and crystallized from benzene , see physical properties in table 1. • 1- [ 5- mercapto -1,3,4 – thiadiazole -2- yl ] -3- phenyl thio urea [ VIb ] [14] : A mixture of [I] ( 0.01mol ) and phenylisothiocyanate (0.01mol) was refluxed in ethanol (30ml) for 8hr. 298 | Chemistry @a@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@ÚÓ‘Ój�n€a@Î@Úœäñ€a@‚Ï‹»‹€@·rÓ:a@Âig@Ú‹©@Ü‹127@@ÖÜ»€a@I1@‚b«@H2014 Ibn Al-Haitham Jour. for Pure & Appl. Sci. Vol. 27 (1) 2014 The separated solid was filtered off and crystallized from benzene , see physical properties in (table 1, 2 ) . • 1 – [ 5-mercapto – 1,3,4 – thiadiazole -2- yl ] -3- phenyl dihydropyrimidne–2,4,6– trione [ VIIa ] . A mixture of [VIa] ( 0.01mol ) and malonic acid ( 0.01mol) was refluxed in acetyl chloride (30 ml ) for 3hr . After cooling the obtained solid was filtered off and crystallized from benzene. see physical properties in (table 1 , 2 ) . • 3- [ 5- mercapto – 1,3,4 – thiadiazole – 2-yl ] -1- phenyl -2- thioxodihydropyrimidine -4 , 6 – dione [ VIIb ] . A mixture of [VIb] ( 0.01mol ) and malonic acide (0.01mol ) was refluxed in acetyl chloride ( 30 ml ) for 3hr . After cooling the obtained solid was filtered off and crystallized from benzene. Discussion The reaction of 2- Amino -5- mercapto – 1,3,4 – thiadiazole [I] with aromatic aldehydes in refluxing ethanol afforded schiffbases [IIa-c] , the IR spectra of Schiff bases showed the stretching bands at ( 1670 – 1675) cm-1 for ( C = N ) groups and disappeared at ( 3450 – 3300 cm-1) , ( 3290 – 3250 cm-1) due to ( NH2 ) . Schiff bases which on condensation with thioglycolic acid yielded 3- [ 5- mercapto – 1,3,4 – thiadiazole -2- yl ] -2- aryl thiazolidin – 4- ones [ III a-c ] ( scheme 1 ) in the first route the thiadiazole [I] reacted with disulfide and methyliodide in the presesnce of concentrated aqueous sodium hydroxide leading to the formation of N- di ( methyl thio ) methylene [ 5- thiomethyl – 1,3,4 – thiadiazole -2- yl ] – amine [IV],the IR spectra showed the stretching bands at ( 1620 ) cm-1for ( C = N ) group and ( 1415cm-1 ) due to ( CH3- S ) then the compound [ IV ] on treatment with nucleophilic reagent such as o-phenylenediamine afforded N- [ 5- thio methyl – 1,3,4 – thiadiazole -2- yl ] -1 H- benzo [ d] imidazole -2- yl –amine [V] the IR spectrum showed the following characteristic absorption bands ( 3340 -3350 cm-1) ( NH ) , ( 1615 – cm-1 ) ( C = N). Finally in the second one [VIa] [VIb] was obtained by direct refluxing of [I] with phenyl isocyanate in ethanolic solution . Similarly [I] was converted to 1- [ 5- mercapto -1,3,4 – thiadiazole -2-yl ] -3- phenyl thiourea [VIb] by the reaction with phenylisothiocyanate . The IR spectra of these compounds revealed the absence of the stretching bands of ( NH2 ) groups and appearance of stretching of ( N –H amide ) at (3200 – 3300cm-1) for compound [VIa] and at (3247-3217 cm-1) for compound [VIb] , and also showed the appearance of two stretching bands at ( 1670 cm-1 ) due to ( C = O ) amide and (1625 cm-1 ) due to ( C = N ) group for compound [ VI a ] and at ( 1240 cm-1 ) due to ( C = S ) and ( 1658 cm-1 ) due to (C = N ) group for compound [ VI b]. The urea derivatives [ VI a ] and thio urea derivatives [ VI b ] on reaction malonic acid in the presence of acetyl chloride under went intermolecular cyclization and yielded 1- [ 5- mercapto – 1,3,4 – thiadiazole -2-yl ] -3- phenyl dihydro pyrimidine – 2,4,6 – trione [ VII a ] and 3- [ 5- mercapto -1,3,4 – thiadiazole -2- yl ] 1- phenyl – 2- thioxodihydropyrimidine – 4,6- dione [ VII b ] . The IR spectra which showed stretching bands at (1670 – 1680 cm-1) of ( C = O amide ) ( 1610 – 1620 cm-1 ) of ( C = N ) and (3116 , 3031 cm -1 ) of ( C – H aromatic ) of the benzene ring for compound [ VII a ] , compound [ VII b ] gave diagnostic IR stretching bands at ( 1255 cm-1 ) of ( C = S ), (1600 -1610) of (C=N) and ( 3110,3025 cm-1) of (C-H) aromatic of the benzene ring . Antimicrobial Activites The antimicrobial activites of the synthesized compounds were determined in vitro using hole plate and filter paper disc method [15] . 299 | Chemistry @a@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@ÚÓ‘Ój�n€a@Î@Úœäñ€a@‚Ï‹»‹€@·rÓ:a@Âig@Ú‹©@Ü‹127@@ÖÜ»€a@I1@‚b«@H2014 Ibn Al-Haitham Jour. for Pure & Appl. Sci. Vol. 27 (1) 2014 Different species of gram-positive and gram-negative bacteria in addition to some fungal plant pathogens were used ( see table 3). The considered compounds were dissolved in 10% acetone , different concentrations have been chosen ( 125 , 250 , 500 Mg cm-3 ) . Agar plates were surface inoculated uniformly from fresh broth culture of microorganisms . The discs were incubated at 28Co to 24hr , the formed inhibition Zones were measured in mm. References 1. ElSayed,R.A.; Shamroukh, A.H.;Hegab,M.I.and Awad, H .M.(2005) Synthesis of some Biologically Active pyrazoles and C-Nucleosides , Acta Chim.Slov. 52: 429-434 2. Vanadma, S. and Sharma , K.V.(2006) " Synthesis and Biological some 3,5 – Diaryl -1- benzothiazolopyrazoline Derivatives : Reaction of chalcones with 2- Hyrazinobenzothiazoles " , E- Journal of chemistry , 6 (2) , 356 – 384 . 3. Czarnocka , J. – A. ; Foks , H.; Nasal , A. ; Petrusewi, CZ , J. ; Damasicwicz , B. ; Radwanska , A. and Kaliszan , R. (1991) Pharmazie 46: 109 . 4. Srivastava , J. ; Swarup , S. ; Saxena , V. K. and Chowdhury , B. L. (1991) Indian chem. , Soc . 68: 103 . 5. Unangst , P. C. ; Shrum , G. P. ; Connor, D. T. and Dyer , R. D. (1992) Novel 1,2,4 – oxiadiazoles and 1,2,4- thiadiazoles as dual 5- lipoxygenaseinhibtars " , J. Med . Chem . 35 : 3691 . 6. Alagrsmay ,V ; Vmuthukumar , N. Paralarani and Revathi, R. (2003) Synthesis , Analagesic and anti – inflammatory Activities of some Novel 2,3 – DisubstitutedQuinazolin -4 (3H) – ones " Biol . Pharma . Bull , 26 (4): 557 – 559 . 7. Akbar Zadeh , T.; Tabatabai , S. A.; Khoshnoud , M.J. ; shafaghi , D. and Shafiee , A. (2003) Bioorg – Med . Chem . 11: 769 . 8. Tyagi , M.and Kumar , A. Orient(2002) J. Chem . 18 : 125 . 9. Heng- Sham , D. and Bin , W. (2005) " Synthesis of some novel 3,6-bis , 1,2,3- triazolyl – triazolo [3,4-b] – 1,3,4- thiadiazole derivatives " , Journal of the Chinese chemical society , 52: 103-108. 10. Kurtzer , F. ; Katritzky , A. R. and Boulton , A. J . (1965) "Advances in Heterocyclic chemistry " , Academic press ; New York , 165. 11. Petrow, V. ; Stephenson, O. and Thomas , A. J. (1958) "preparation and hydrolysis of some derivatives of 1,3,4 – thiadiazole " , J. Chem .Soc . 1508-1513 . 12. I kabl , S. ; Al-shibani , N. K.E. and Al-Dujaili, A. H. (2006) "Synthesis and characterization of some new 1,3,4-thiadiazole Derivatives " National journal of chemistry , 21 : 94-101 . 13. Pratibha , S . and Vikas , K. (2010) "Synthesized some thiadiazole derivatives by in coporating azetidinyl and thiazolidinyl moieties " Asian journal of chemistry , 22(9) : 6829-6839 . 14. Desai , N.C. ; Bhavsar, A.M.; Shah, M.D. and Saxena, A.K . (2008) " Synthesis and QsAR studies of thioemicarbazides , 1,2,4 – triazole , 1,3,4,- thiadiazoles and 1,3,4- oxadiazoles derivatives as potential antibacterial a gents " , lndian journal of chemistry , 47b : 579 – 589 . 15. Leifert , C. ; Chidbouree , S. ; Hampson , S. ; Workman , S. ; Sigee , D. ; Epton , H. A. and Harbour , A. ( 1995 ) J. Appl . Bacteriol . 78: 97. 300 | Chemistry @a@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@ÚÓ‘Ój�n€a@Î@Úœäñ€a@‚Ï‹»‹€@·rÓ:a@Âig@Ú‹©@Ü‹127@@ÖÜ»€a@I1@‚b«@H2014 Ibn Al-Haitham Jour. for Pure & Appl. Sci. Vol. 27 (1) 2014 NN S N=CHArHS + SH O HO NN S NHS Ar SH O OH NN S HS N S Ar O [II] [III] Scheme (2) The mechanism formation of compound [III] -H2O 301 | Chemistry @a@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@ÚÓ‘Ój�n€a@Î@Úœäñ€a@‚Ï‹»‹€@·rÓ:a@Âig@Ú‹©@Ü‹127@@ÖÜ»€a@I1@‚b«@H2014 Ibn Al-Haitham Jour. for Pure & Appl. Sci. Vol. 27 (1) 2014 NN S HS NH-C-NH-Ph X + HO O O OH NN S HS NH-C-N-Ph X H O OHO HO -H2O NN S HS NH N-Ph X HO O NN S HS N N-Ph X O O H O -H2O Scheme (3) The mechanism f ormation of compound [VII] [VI] [VII] Table (1): Physical properties of prepared compounds Com. No . Formula M.W. Elemental Analysis % Calc. % found% C H N C H N IIa C9H7N3S2 221 48.88 3.16 19.00 48.75 3.10 18.85 IIb C9H6CLN3S2 255.5 42.27 2.34 16.43 42.15 2.31 16.33 IIc C10H9N3OS2 251 47.80 3.58 16.73 47.61 3.45 16.66 IIIa C11H10N3OS3 296 44.59 3.37 14.18 44.50 3.30 14.11 IIIb C11H9CLN3O3S 330.5 39.93 2.72 12.70 39.85 2.60 12.55 IIIc C12H12N3O2S3 326 36.80 3.68 12.88 36.68 3.61 12.71 IV C6H9N3S4 251 28.68 3.58 16.73 28.52 3.41 16.66 V C10H9N5S2 263 45.62 3.42 26.61 45.53 3.40 26.55 VIa C9H8N4S2O 252 42.85 3.17 22.22 42.77 3.11 22.15 VIb C9H8N4S3 268 40.29 2.98 20.89 40.12 2.82 20.81 VIIa C12H8N4O3S2 320 45.10 2.50 17.50 45.02 2.44 17.47 VIIb C12H8N4O2S3 336 42.85 2.38 16.66 42.79 2.29 16.58 302 | Chemistry @a@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@ÚÓ‘Ój�n€a@Î@Úœäñ€a@‚Ï‹»‹€@·rÓ:a@Âig@Ú‹©@Ü‹127@@ÖÜ»€a@I1@‚b«@H2014 Ibn Al-Haitham Jour. for Pure & Appl. Sci. Vol. 27 (1) 2014 Table (2): Physical properties of prepared compounds Com. No . Colour m.p. co Yield % Infrared data(V max Cm -1) IIa Pale yellow 170-172 65 (C=N)1670;(C=S)1310;(C-H arom)3000–3100 IIb Yellow 185-187 62 (C=N)1670;(C=S)1325;(C-H arom)3020-3100 IIc Yellow 157-159 66 (C=N)1645;(C=S)1290;(C-H arom)3000–3080 IIIa Brown 130-132 63 (C=N)1650;(C=S)1315;( C = O ) 1680 IIIb Reddish–yellow 144-146 50 ( C = N ) 1665 ; ( C = S ) 1315 ; ( C = O ) 1675 IIIc Reddish–yellow 151-153 56 ( C = N ) 1645 ; ( C = S ) 1305 ; ( C = O ) 1670 IV Pale–yellow 177-179 62 (C=N)1620;(CH3–S)1415;(C–H alph)2920–2980 V Brown 230-232 55 ( C = N ) 1615 ;(CH3–S)1415;(N–H)3340– 3350 VIa Brown 191-193 45 ( C = N ) 1625;(C=O) 1670 ; (N–H) 3200 – 3300 VIb Reddish yellow 188-190 59 ( C = N ) 1658;(C=S) 1240 ; (N–H) 3247 – 3217 VIIa Brown 210-212 71 ( C = N ) 1620;(C=O) 1680 ; (C=S) 1265 VIIb Brown 220-222 63 ( C = N )1610 ; (C=S) 1255 Table(3): Response of various microorganisms to synthesized Denivatives in vitro Compo und Bacillus cereus Escherichacoli Aspergillusniger Peniciliumnotatum A (MIC) A (MIC) A (MIC) A (MIC) IIa ++ 125 + 250 ++ 125 + 250 IIb ++ 250 ++ 250 ++ 250 ++ 125 IIc ++ 125 + 250 + 250 + 250 IVa ++ 250 ++ 250 + 250 ++ 250 IVb + 250 + 250 + 250 + 125 IVc + 250 + 250 + 250 + 250 VI ++ 125 ++ 250 +++ 125 ++ 125 VII + 250 + 250 + 250 + 250 VIIIa ++ 125 + 250 ++ 125 + 250 VIIIb + 250 ++ 250 + 125 + 125 IV +++ 125 ++ 250 ++ 125 +++ 250 V ++ 125 ++ 250 +++ 125 ++ 125 A : antimicrobial activity of tested compounds ; the width of the zone of inhibition indicates the potency of antimicrobial activity , no antimicrobial activity , + weak activity width diameter equal to 0.5-0.7cm , ++ moderate activity with the diameter zone equal to 1.0-1.2cm . +++ marked activity with the diameter zone equal to 1.6-1.8cm. MIC : minimum inhibition concentration / ( Mg cm-3 ) . 303 | Chemistry @a@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@ÚÓ‘Ój�n€a@Î@Úœäñ€a@‚Ï‹»‹€@·rÓ:a@Âig@Ú‹©@Ü‹127@@ÖÜ»€a@I1@‚b«@H2014 Ibn Al-Haitham Jour. for Pure & Appl. Sci. Vol. 27 (1) 2014 304 | Chemistry @a@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@ÚÓ‘Ój�n€a@Î@Úœäñ€a@‚Ï‹»‹€@·rÓ:a@Âig@Ú‹©@Ü‹127@@ÖÜ»€a@I1@‚b«@H2014 Ibn Al-Haitham Jour. for Pure & Appl. Sci. Vol. 27 (1) 2014 ثایادایازول 1,3,4تحضیر وتقییم الفعالیة البایلوجیة لمشتقات جدیدة من مركبات فیصل مصطفى ایمان ایمان محمد حسین جامعة بغداد /كلیة التربیة للعلوم الصرفة ( ابن الھیثم ) /قسم الكیمیاء 2014شباط 2، قبل البحث : 2013تشرین أالول 20استلم البحث في : الخالصة مع االلدیھایدات االروماتیة للحصول على قواعد شف ، [ I ]تم في ھذا البحث معاملة المركب امینوثایادایازول ثایوكالیكولك .–بعدھا غلقت للحصول على مشتقات تحوي على حلقات الثایازولیدایون من خالل مفاعلتھا مع الحامض تم مع كاربون ثنائي الكبریت ویودید المثیل للحصول على مركب ثنائي مثیل ثایو الذي [ I ]ثم فوعل المركب امیدازو ثایازولیل امین . - N معاملتھ مع االورثوفنیلین ثنائي االمین ،حیث اعطى الناتج مع فنیل ایزوسیانیت أو مع فنیل ایزوثایوسیانیت للحصول [ I ]فیما بعد حضرت سلسلة اخرى من مفاعلة المركب FTIRعلى المشتقات كاربامایدوكارباثایاماید على التوالي ، شخصت ھذه المركبات من خالل درجات االنصھار وتقنیة وتحلیل العناصر . یدون ، امیدوزول ثایوزویل امین .ثایودایازول ، ثایوزول – 4، 3، 1الدراسة البایلوجیة لمركبات :الكلمات المفتاحیة 305 | Chemistry @a@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@ÚÓ‘Ój�n€a@Î@Úœäñ€a@‚Ï‹»‹€@·rÓ:a@Âig@Ú‹©@Ü‹127@@ÖÜ»€a@I1@‚b«@H2014 Ibn Al-Haitham Jour. for Pure & Appl. Sci. Vol. 27 (1) 2014