INTRODUCTION:

Heterocycles have attracted the presence of sulphonamide fragments in the attention of chemists because of their important biological properties and their role as pharmacofores [1–5].

Thiazole ring1system has been1consistently 1 rewarded as a1promising 1 molecule1because of its broad 1 spectrum1of pharmaceutical activities like1antimicrobial and 1 anticancer [6-8].

Furthermore, derivaties containing Schiff base (azomethine) are a species of1important compounds1 in medical chemistry and pharmacological field [9,10]. 2-Azetidinone have been found to be an important moiety in creation of novel medical drugs and they encompass pharmacological activities [11-14].

On the other hand, the 4-thiazolidinone 1scaffold is very 1versatile and has 1featured in a number of 1medicinal chemistry. They 1have found uses as antitubercular, antimicrobial and anticancer [13-15]. Tetrazole and their derivatives are found in many of the bioactive heterocyclic compounds that are of great interest due to various biological, and clinical applications [16,17].

MATERIALS AND METHODS:

Materials and physical measurements:

All1reactants1 and11solvents 1used in this 1study were 11reagents 11grade and1they are available1 from 1Sigma‐Aldrich and 1Fluka companies. 1Melting 1points were determined1 on1 Electro1‐ thermal1 capillary1 apparatus1 and are 1uncorrected. 1Purity of the 1compounds was 11checked 1on1silica1 coated 11Merck-TLC 1plates 1using 1water, chloroform1 benzene1 and 1acetone as11mobile1phase. FTIR 1measurements were recorded1 on 1Shimadzumodel FT-IR-8400S. ¹H NMR 11spectra were 1recorded by 1using Ultra11 Shield 1Bruker1model1 in 300 MHz uisg DMSO-d₆ as a 1solvent1 and 1 TMS as internal111standard.1Elementanaly1sesweredoneon111EUROEA1instrument.

Synthesis of N-(4-acetylphenyl)-4- methylbenzenesulfonamide (1)

A mixture1 oftoluene1 -4- 1Sulfonyl 1chloride (tosyl chloride) (0.01 mole,2.62 g) and 4-aminoacetophenone (0.01 mole) with (0.01 mole) 1Triethyl1 amine in 1dry1 benzene (20 mL) was 1refluxed for 7hrs. After that, the1excess 1of 1solvent 1evaporated 1and the 1product was filtered off 1and 1recrystallized 1from dioxaneto give 1compound 1 with. Yield: 82% , M.P: 260-262°C , FT-IR (KBr, υ, cm^-1): 3217 υ (NH),2983, 2872 υ (C-H)), 1668 υ (C=O), 1332, 1174 υ (SO2).¹H NMR1 (300 MHz1, δ, ppm, 1DMSO-D61 ):7.55-6.28(m, 8H, Ar-H) 1, 8.75(2H, NH) , 2.24 (s, 3H, CH₃) 1.Anal. % 1calc./found for C₁₅H₁₅NO₃S1(M.w. 289) C, 62.28 /63.09; H,5.19/ 4. 89; N, 4.84 /4.15; S, 11.07/ 11.43.

Synthesis of N-(4-(2-aminothiazol-4-yl) phenyl)-4-methylbenzenesulfonamide (2):

A mixture11 of iodine (0.03 mol, 7.61g), 1thiourea (0.03 mol,4.56 g) and compound 1 (0.03 mol,8.67gm) was 1refluxed 1for 7 hrs. then (15 mL) of1 ethanol was1 added 1and reflux1 was 1continued 1for 8 hrs1precipitate 1was 1fillered, washed with 1diethylether, dried and 1recrystallized 1from 1ethanol. Yield: 76%, M.P: 102-104°C, FT-IR (KBr, υ, cm^-1): 3402, 3294υ (NH₂), 3165 υ (NH), 1367, 1151 υ (SO2).¹H1 NMR (300 11MHz, δ, 1ppm, 11DMSO-1D6 ):8.77-7. 28 (m,18H, Ar-H, CH of1thiozole), 5.57(2H, NH₂), 8.78 (s, 1H, NH), 2.23 (s, 3H, CH₃);1Anal. % 1calc./ 1found forC₁₆H₁₅NO₂S₂ (m.w.345) C,55.65/56.45; H,4.34 /4.72; N,12. 17 /12.85; S, 18.55/ 18.92.

Synthesis of Schiff bases (3-5):

A mixture11 of 1compound12 (0.02 mol., 10.35gm) and 1aromatic1aldehyde (0.02 mol)) was refluxed11 in absolute 111 ethanol (25 mL) for 7 h. The11mixture 1was 11cooled 1and the 11 product 1 obtained 11 recrystallized 11 from of 11 reaction 11mixture was then1stirred for 6-10 h, then 1poured into1ice-water. The 11solid was 11filtered and111recrystallized 1from 11dioxane.

N-(4-(2-((4-aminobenzylidene) amino) thiazol-4-yl) phenyl)-4-methylbenzenesulfonamide (3):

Yield: 89% , M.P: 152-153°C , FT-IR (KBr, υ, cm^-1): 3392 ,3229υ (NH₂), 3225 υ (NH), 1641(C=N), 1359, 1176 υ (SO2).¹H1NMR (1300 1MHz, δ, ppm, 1DMSO-1D6 ):8.82-6.77 (m,1 8H, 1Ar-H, CH of thiozole1, ),9.67 (s, 1H, NH),4.2(2H, NH₂) , 2.32 (s, 3H, CH₃).Anal.% calc./found for C₂₃H₂₀N₄O₂S₂ (m.w.4 48) C,61.60/59.65; H,4.46 /3.94; N,12. 5 /12.9 ; S, 14.28/ 14.85.

N-(4-(2-(4-nitrobenzylidene) amino) thiazol-4-yl) phenyl)-4-methylbenzenesulfonamide (4):

Yield: 72% , M.P: 177-178°C , FT-IR (KBr, υ, cm^-1): 3294 υ (NH),1634 υ(C=N), 1575, 1367 υ (NO₂), 1330, 1155 υ (SO2).¹H NMR (300 MHz, δ, ppm, DMSO-D6 ):8.72-6.4 8 (m, 14H, Ar-H,CH=N, CH of thiozole, ),8.91 (s,1H, NH), 2.2 (s, 3H, CH₃), Anal. % calc./found for C₂₃H₁₈N₄O₄S₂ (m.w.4.78) C,57.74 /56.98; H,3.67 /3.94; N,11. 71/11.98; S, 13.38 / 13.79.

N-(4-(2-((4-chloro benzylidene) amino) thiazol-4-yl)phenyl)-4-methylbenzenesulfonamide(5):

Yield: 88% , M.P: 13-132°C , FT-IR (KBr, υ, cm^-1): 3214 υ (NH),1640 υ(C=N), 1365, 1185 υ (SO2).¹H NMR (300 MHz, δ, ppm, DMSO-D6 ):8.2 5-6.29 (m, 13H, Ar-H, CH=N, CH of thiozole, ),8.7 (s, 1H, NH), 2.24 (s, 3H, CH₃). Anal.% calc./found for C₂₃H₁₈N₃O₂S₂Cl (m.w.467.5) C,59.03 /58.61; H,3.85 /4.24; N,8. 98/8.23; S, 13.68 / 14.18.

Synthesis of oxoazetidine derivatives (6,7):

Compounds1 (3,4) (0.001mol), 1triethyl amine (0.025 mol) in 1dry 1,4-1dioxane (10mL) was stirred1 in ice water1 bath (0-5°C).1chloroacetylchloride1 (0.01mol) was11added 1drop 1wise to mixture1, then stirred1 for 3 hrs.The1 mixture1 was 1refluxed for 6 hrs. 1Mixture was 1filtrated and the 1solvent was 1removed 1under 1reduced 1pressure, the 1product was 1collected by filtration1 and washed1 with11water, 1dried and 11recrystallization1from 1chloroform.

N-(4-(2-(2-(4-aminophenyl)-3-chloro-4-oxoazetidin-1-yl) thiazol-4-yl) phenyl) -4-methylbenzenesulfonamide (6):

Yield: 87% , M.P: 222-223°C , FT-IR (KBr, υ, cm^-1): 3348 ,3302υ (NH₂), 3271υ (NH),1710υ (C=O), 1332, 1157 υ (SO2).¹H NMR (300 MHz, δ, ppm, DMSO-D6 ):8.46-6.29 (m, 12H, Ar-H, CH of thiozole,),8.7 (s, 1H, NH), 6.32 (2H, NH₂) , 2.24 (s, 3H, CH₃). Anal.% calc./found for C₂₅H₂₁N₄O₃S₂Cl (m.w.524) C,57.25 /56. 15; H,4.0 /3.7; N,10. 68/11.12; S, 12.21/ 11.64

N-(4-(2-(2-(4-chlorophenyl)-3-chloro-4-oxoazetidin-1-yl) thiazol-4-yl)phenyl)-4-methylbenzenesulfonamide (7):

Yield:79 % , M.P: 187-189°C , FT-IR (KBr, υ, cm^-1): 3348 ,3302υ (NH₂), 3283υ (NH),1725 υ (C=O), 1342, 1168 υ (SO2).¹H NMR (300 MHz, δ, ppm, DMSO-D6 ):7.9 5-6.3 7 (m, 12H, Ar-H, CH of thiozole, ),8.83 (s, 1H, NH),5.6 -5.0 (dd, 2H, CH ), 2.23 (s, 3H, CH₃). Anal.% calc./found for C₂₅H₁₉N₃O₃S₂Cl₂ (m.w.545) C,55.04/56.69; H,3.48 /3.94; N,7.70/8.54; S, 11.74/ 11.48.

2.1.8 Synthesis of oxothiazolidinone derivateves (8,9):

A mixture of Compounds (4,5) (0.001mol) was solved in 25mL chloroform with ZnCl₂(0.01g) and (0.005mol) of thioglycolic acid was added to the mixture, the mixture was refluxed for 10hrs. The reaction completion was monitored by thin layer chromatography (TLC) using ethylacetate: hexane system (3:7). The solvent was removed under reduced pressure, residue treated by solution of 10% NaHCO₃ to removed excess of mercaptoacetic acid, washed with water, dried and recrystallization from chloroform

N-(4-(2-(2-(4-nitrophenyl)-4-oxothiazolidin-3-yl)thiazol-4-yl)phenyl)-4-methylbenzenesulfonamide (8):

Yield: 76% , M.P: 159-160°C , FT-IR (KBr, υ, cm^-1): Yield: 82% , M.P: 182-184 °C , FT-IR (KBr, υ, cm^-1): 3273υ (NH),1693υ (C=O), 1558, 1394 υ (NO₂), 1330, 1155 υ (SO2).¹H NMR (300 MHz, δ, ppm, DMSO-D6 ): 8.85 (s, 1H, NH), 8.43 -6.54 (m, 12H, Ar-H, CH of thiozole), 5.70 (s, 1H, CH-N), 3.95 (s, 2H, CH₂) 2.24 (s, 3H, CH₃).Anal.% calc./found for C₂₅H₂₀N₄O₅S₃ (m.w.552) C,54.34/ 53.65; H,3.62 /3.94; N,10.14/10.9; S, 17.39/ 16.86.

N-(4-(2-(2-(4-nitrophenyl)-4-oxothiazolidin-3-yl) thiazol-4-yl) phenyl)-4-methylbenzenesulfonamide (9):

Yield: 81% , M.P: 111-113°C , FT-IR (KBr, υ, cm^-1): 3217υ (NH), 1338, 1689υ(C=O), 1157 υ (SO2).¹H NMR (300 MHz, δ, ppm, DMSO-D6 ):8.69-6.42 (m, 12H, Ar-H, CH of thiozole), 9.21 (s, 1H, NH),5.52 (s, 1H, CH-N), 3.94 (s, 2H, CH₂), 2.22 (s, 3H, CH₃). Anal.% calc./found forC₂₅H₂₀N₃O₃S₃Cl (m.w.541.5) C,55.54/54.87; H,3.69 /3.9 4; N,7.75/7.10; S, 17.72/ 17.43.

Synthesis of tetrazol derivatives (11,12)

Compounds (4,5) (0.001mol) was melted in (20mL) solvent (tetrahydrofuran) and mixed with (0.001mol, 0.134g) sodium azide. This mixture was stirred and refluxed for 10hours.Excess solvent was distilled, the precipitate was filtered and recrystallized from methanol.

4-methyl-N-(4-(2-(5-(4-nitrophenyl)-1H-tetrazol-1-yl) thiazol-4-yl) phenyl) benzenesulfonamide (10):

Yield: 78% , M.P: 140-141°C , FT-IR (KBr, υ, cm^-1): 3402υ (NH), 3296 υ (NH), 1573, 1367υ(NO₂), 1336, 1151 υ (SO2),1457 cm⁻¹ N=N and at 1618 cm⁻¹ for C=N.¹H NMR (300 MHz, δ, ppm, DMSO-D6 ):8.34 (s, 1H, NH),7.94-6.28 (m, 12H, Ar-H,, CH of thiozole), 4.85 (s, 1H, NH),4.34 (s, 1H,CH-N), 2.24 (s, 3H, CH₃).Anal.% calc./found forC₂₃H₁₇N₇O₄S₂ (m.w.519) C,53.30/54.88; H, 3.27 /3.98; N,18.88/18.18; S, 12.30/ 12.85.

4-methyl-N-(4-(2-(5-(4-nitrophenyl)-1H-tetrazol-1-yl) thiazol-4-yl) phenyl) benzenesulfonamide (11)

Yield: 77% , M.P: 165-166°C , FT-IR (KBr, υ, cm^-1): 3329υ (NH), 3217υ (NH), 1332, 1174 υ (SO2),1489 cm⁻¹ N=N and at 1608 cm⁻¹ C=N.¹H NMR (300 MHz, δ, ppm, DMSO-D6 ):8.7 (s, 1H, NH), 8.63-6.56(m, 12H, Ar-H, CH of thiozole),4.72(s, 1H, NH),4.21(s, 1H,CH-N), 2.24 (s, 3H, CH₃). Anal.% calc./found forC₂₃H₁₇N₆O₂S₂Cl (m.w.508.5) C,54.27/53.72; H,3.34 /3.24; N,16. 51/16.92; S, 12.58/12.96.

Antimicrobial Activity:

Biological Activities:

In1 vitro 1antimicrobial 1testing1 effects of 1sulfonamide 1derivatives were 1estimated against1 four 1bacterial 1strains 1namely. 1The 1antimicrobial 1activitywas 1determined using1 the agar well 11diffusion 1method [18].111Dimethyl 11sulfoxide 1worked as a 1control and1 the test was 1outright at 100mg/mL and by1 adding 50ϻl to each11 disc (i.e.5ϻg/disc) concentration1using (DMSO) as 1solvent. The1fungi and 41bacteria was 1sub cultured in agar. The 1zone of 11inhibition was 1compared 1with the 11standard 1drug 1after 24 h and incubation at 37^OC. for1antibacterial 1activity and 72 h at 25^OC. for1antifungal. Table1.

Table 1: Antimicrobial evaluation compounds (2-11)

Heterocyclic Derivative	Inhibition1 zone (mm) at 100 mg/mL
	1Gram 1positive		1Gram 1negative		Fungi
	*S. aureus*	S.1epidermidis	E.1coli	*Klebsiella spp*	C.1albicanus
2	-	-	14	16	-
3	-	10	-	8	10
4	14	10	-	-	-
5	11	12	20	13	12
6	16	18	22	19	-
7	17	20	19	17	13
8	18	18	20	14	16
9	22	19	23	19	15
10	19	12	-	12	15
11		15	14	19	11
Amoxicillin	20	21	12	18	0
Fluconazole	0	0	0	0	25

Condensation1 of compound (2) with1corresponding aryl aldehyde in 1ethanol 1afforded 1Schiff 1base (3-5). The 1formulation of Schiff 1base was showed by the 1disappearance of NH₂1stretching1 band of compound (2) and 1carbonyl group of substituted 1benzaladehyde combined1 with the 1presence of 11azomethine (CH=N) 1stretching band at(1641-1634) cm⁻.¹ The¹ 1H -NMR 1spectrum of 1compound (3) showed singlet signals at2.32 ppm due to methyl proton, at 4.2 ppm due to NH₂ and a singlet at 9.67 ppm related to NH, while 1amultiplet signals at( 8.82 -6.77) ppm 1due to aromatic protons ,1CH- of thiazole and CH=N proton.

Figure (3): The FT-IR spectrum of compound3.

Figure (4): The ¹H- NMR spectrum of compound 3.

On the other hand, azetidinyl derivatives (6,7) obtained by reaction of compounds (3-5) with Et₃N and chloroacetyl chloride (C₂H₂OCl₂) in dioxone. The FT-IR spectrum indicated the 1appearance of 1band at 1725-1710 cm⁻¹ (C=O) due to β-lactam with disappearance band of imine (N=CH) in the region 1641 cm⁻¹. The ¹H-NMR of compound (7)1showed doublet 1signals at 5.6 -5.0 ppm due to 1azetidinyl ring proton, aromatic protons and CH of thiazole1exhibited a 1multiplet signals at 8.83-6.37ppm.

Furthermore, The generation of thiazolidenone (8,9) by the reaction of Schiff bases (3,4) with mercapto acetic acid in chloroform the structures of these 1compounds were confirmed by the presence of1 carbonyl 1stretching 1band at (1693-1689) cm-¹due to thiazolidinone ring was the characteristic evidence for success of cyclization. ¹H- NMR spectrum indicated singlet signal at 2.24 ppm due to for proton (CH₃) group at 3.95 ppm was assigned CH-N and at 8.85 ppm connected to NHproton,1while a 1signal as 1multiplet at 8.43-6.54 ppm due1 to aromatic 1protons and 1CH thiazole.

Cyclization1 of Schiff base (4,5) with in NaN₃ the presence of tetrahydrofuran as solvant1afforded tetrazole (10,11).The FTIR of compound (11) showed1 characteristic bands of1tetrazole ring at 1489 cm⁻¹due to N=N and at 1408 cm⁻¹ for C=N, while the ¹H-NMR spectrum 1exhibited 1singlent signals at 2.24 ppm and at 7.8 ppm were assigned to CH₃ and NH protons, 1aromatic protons were 1appeared at 8.63-6.56 ppm

Antimicrobial Activity:

The synthesized sulfonamide carrying thiazole, Schiff base, azetidinone, thiazolidinone moieties, which are accountable for antimicrobial activity. The 1 chloramphenicol and fluconazole1 were used as standard for comparison of antibacterial and antifungal activities respectively. its appear that the azetidinone and thiazolidinone derivatives (6-9) are show very considerable activity against (G+) and (G-) bacterial. Figure (2).

Figure (5): Antimicrobial evaluation of compounds (2-11)

CONCLUSION:

New 1sulfonamide 1derivatives are 11synthises and are 1characterized on the basis of analytical1 and 1spectraldata. 1Screening of these 1derivatives 1against 1pathogenic microorganism 1reveals that 1these 1compounds have1thecapacity of11inhibiting metabolic 1growth of 1some 11microorganisms to 11different extent.1It seems that compounds1 (6- 9) are very 11significant for 1activity 1against both 11bacteria and 1fungi. All the 11compounds 1were found to1 exhibit 1moderate to 1good 11antifungal1 activity

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Received on 08.09.2018 Modified on 18.10.2018

Research J. Pharm. and Tech. 2019; 12(6):2943-2948.

DOI: 10.5958/0974-360X.2019.00495.5