INTRODUCTION:

During recent years there has been intense investigation of different classes of thiadiazole compounds, many of which were found to be pharmacologically active. The family of sulfur-nitrogen heterocycles includes highly stable aromatic compounds that display physicochemical properties with relevance in the design of new materials, especially those relating to molecular conductors and magnets, which are currently under intense investigation. The interesting properties of many of these heterocycles has increased the need for rapid syntheses of new, potentially useful sulfur-nitrogen heterocycles. Thiadiazoles and their derivatives are found to be associated with various biological activities such as antibacterial¹, antifungal², anti-inflammatory³ activities. Organic compounds bearing thiazoles of different pharmacodynamic nuclei were found to possess potent anti-inflammatory activities⁴. The development of thiadiazole is a fascinating and informative area in medicinal chemistry, highlighting the role of skilful planning and serendipity in drug research. Thiadiazole derivatives are widely used in various conditions including gastrointestinal⁵ and urinary tract infections⁶. They are preferred due to the ease of administration, wide spectrum of antimicrobial activity⁷, non-interference with the host defence mechanism.

As part of program aimed at developing a new class of 1,3,4-thiadiazole synthesized the title compounds bearing certain sulfur containing amine side chain similar to pendent residue in tinidazole⁸ molecule were synthesized and evaluated their fungicidal activity. There are linked to respectively thiadiazole ring as heterocydic compounds obtained could have better fungicidal activity⁹. The reported that some thiadiazoles are fused to electron donating ring as diphenylamine¹⁰ was more active than reported for attached group¹¹. In view of the above and in continuation of our research^12-13 fused secondary amine as diphenylamine on thiadiazoles¹⁴ shows promising activity as insecticides¹⁵, herbicides¹⁶and fungicides¹⁷. Synthesised of 5-(4-(phenylamino)phenyl)-1,3,4-thiadiazol-2-amine derivatives table 4 reported here for promising antifungal activity against C.albican, A.niger.

Chemistry:

The title compounds were prepared using a synthetic method closely related to the general procedure that for this study synthesized first step is represented by compounds (1a-f) which displays an electron donating NH₂ group on phenyl ring and halogen in para position on benzoic acid. Found to normally employed to obtain bicyclic 4-(phenylamino)benzoic acid derivatives (1a-f) in the presence of potassium carbonate and catalyse by copper in isoamyl alcohol solvent. Whereas the intermediate compound 4-(phenylamino)benzoic acid was formed. Elimination of hydrogen Chloride under goes to the reaction Mechanism of Nucleophilic Aromatic Substitution reactions¹⁸. Cyclization of the further intermediate product was obtained in heating with polyphosphoric acid (ten times of the acid) in normal condition. The involved mechanism of reaction attack of Nucleophilic Addition Reaction¹⁹ followed by dehydrocyclisation of the intermediate and tautomaric form loss a water molecule to yield 5-(4-(phenylamino)phenyl)-1,3,4-thiadiazol-2-amine (2a-f). Substitution with a bulky group on diphenyl amine did result in a slight increase in activity. Unsubstitution of diphenylamine in entire the compound enhanced the antifungal activity. Bicyclic ring diphenylamine with electron donating amine on 1,3,4-thiadiazole ring to produce better lipophilicity²⁰. Find out of physico-Chemical and thermodynamic properties are shown better response of requirement of drug design, given in table 2 and 3.

For this study we synthesized six classes of 1,3,4-thiadiazole derivatives shown in Fig.1. The formed the available 5-(4-(phenylamino)phenyl)-1,3,4-thiadiazol-2-amine derivative (2a-f) which was shown in Scheme 1. All compounds were characterized by their analytical and spectroscopic data. Substitution with a halogen as Chloro and bromo (2d, 2e) did result in a slight increase in activity²¹. The introduction of a substituted methoxy group gave rise to compounds. Introduction of various groups at the para position gave compounds less potent than the unsubstituted²² 2a. Both electron-withdrawing as well as electron-donating groups showed similar results. Substitution at the meta position, both with electron withdrawing as well electron-donating groups, gave rise to compounds with lower activity, except for the methoxy-substituted compound²³ 2c.

MATERIALS AND METHODS:

Preparation of 4-(phenylamino)benzoic acid²⁴ (1a):

This Reaction undergoes – Ullmann condensation: In a flat bottomed flask, mixture of p-chlorobenzoic acid 10 g (0.064 mol) aniline 5.84 ml (0.064 mol) and copper powder 0.2 g in 60 ml isoamylalcohol, dry potassium carbonate 10 g was slowly added and the contents were allowed to reflux for 6 h on an oil bath. After completion of reaction isoamylalcohol was removed by steam distillation and the mixture poured into 1: l of hot water and acidified with concentrated hydrochloric acid. Precipitate formed was filtered, washed with hot water and collected. The crude acid was dissolved in aqueous sodium hydroxide solution, boiled in the presence of activated charcoal and filtered. On acidification of the filtrate with concentrated hydrochloric acid, light yellowish precipitate was obtained which was washed with hot water and recrystallized from aqueous methanol to give a light yellow product, 80% yield, m.p. 182-183°C.

4-(p-tolylamino)benzoic acid (1b):

Mixture of p-chlorobenzoic acid 10 g (0.064 mol) p-toluidine 6.86ml (0.064 mol) was taken and copper powder 0.2 g in 60 ml isoamylalcohol, dry potassium carbonate 10 g was slowly added and applied above procedure, light yellowish precipitate of 4-(p-tolylamino)benzoic acid, was obtained 76% yield, m.p. 186-187°C.

4-(4-methoxyphenylamino)benzoic acid (1c):

Starting reaction reagents of p-chlorobenzoic acid 10 g (0.064 mol) 4-methoxybenzenamine 7.88ml (0.064 mol) was taken and copper powder 0.2 g in 60 ml isoamylalcohol, dry potassium carbonate 10 g was slowly added and applied above procedure, light yellowish precipitate of 4-(4-methoxyphenylamino)benzoic acid, was obtained, 72% yield, m.p. 173-175°C.

4-(4-chlorophenylamino)benzoic acid (1d):

Mixture of p-chlorobenzoic acid 10 g (0.064 mol) p-chlorobenzenamine 8.16 ml (0.064 mol) was taken and copper powder 0.2 g in 60 ml isoamylalcohol, dry potassium carbonate 10 g was slowly added and applied above procedure, light yellowish precipitate of 4-(4-chlorophenylamino)benzoic acid, was obtained, 60% yield, m.p. 192-193°C.

4-(4-bromophenylamino)benzoic acid (1e):

Starting reaction reagents of p-chlorobenzoic acid 10 g (0.064 mol)p-bromobenzenamine 11.00 ml (0.064 mol) was taken and copper powder 0.2 g in 60 ml isoamylalcohol, dry potassium carbonate 10 g was slowly added and applied above procedure, light yellowish precipitate of 4-(4-bromophenylamino)benzoic acid, was obtained, 64% yield, m.p. 189-190°C.

4-(4-nitrophenylamino)benzoic acid (1f):

Reagent of p-chlorobenzoic acid 10 g (0.064 mol) p-nitrobenzenamine 8.84 ml (0.064 mol) was taken and copper powder 0.2 g in 60 ml isoamylalcohol, dry potassium carbonate 10 g was slowly added and applied above procedure, light yellowish precipitate of 4-(4-nitrophenylamino)benzoic acid, was obtained, 76% yield, m.p. 197-199°C.

5-(4-(phenylamino)phenyl)-1,3,4-thiadiazol-2-amine²⁵ (2a):

In a ground mixture of the 4-(phenylamino)benzoic acid 5.54 g. (0.026 mol) and thiosemicarbazide 2.4 g. (0.026 mol) was added in portions over 0.5h to polyphosphoric acid (10 times the weight of carboxylic acid) to vigorously stirred at 80-90°C, the mixture was stirred at this temperature for 2-4 h. The mixture was kept at this temperature for a further 0.5 h and cooled, water/ice was added, and the mixture was finally basified with NH₃ (0.88g/mL). The solids isolated by filtration were washed with water and air-dried to obtained slightly coffee colored solid and recrystallized by ethanol.

5-(4-(p-tolylamino)phenyl)-1,3,4-thiadiazol-2-amine (2b):

Reaction mixture of the 5-(4-(p-tolylamino)phenyl)-1,3,4-thiadiazol-2-amine 5.9 g. (0.026 mol) and thiosemicarbozide 2.4 g.(0.026 mol) was added and followed above method for isolation to give 5-(4-(p-tolylamino)phenyl)-1,3,4-thiadiazol-2-amine, slightly coffee colored solid was obtained and recrystallized by ethanol.

(a) Cu (b) K₂CO₃ (c) PPA (d) NH₂CSNHNH₂

Fig. 1 Graphical abstract of synthesised title compounds.

Table 1 Characterization of Synthesized Compounds.

Comp name	Spectroscopic data
2a	IR(KBr/cm^-1)=3340(N-H), 3041 (Ar.C-H), 2910 (C-H), 1576 (C=N), 1667 (Ar.C=C), 1497 (N-N); ¹H-NMR (DMSO-d6, δ ppm) 2.5 (s, 2H, NH), 6.6-6.8(m, 9H,CH, Ar-H, diphenylamine). Electron absorption spectra (UV) λ_max,302.97(methanol)
2b	IR(KBr/cm^-1)=3390 (N-H), 3105 (Ar.C-H), 2878 (C-H), 1560 (C=N), 1650 (Ar.C–C), 1524 (N-N), 1210 (C-S); ¹H-NMR (DMSO-d6, δ ppm) 2.1 (s, 2H, NH), 2.6(s, 3H, CH), 6.8-6.99(m, 9H,CH, Ar-H, diphenylamine) Electron absorption spectra (UV) λ_max301 (methanol)
2c	IR(KBr/cm^-1)=3420 (N-H), 3020(Ar.C-H), 2915 (C-H), 1720 (C-O), 1570 (C=N), 1645 (Aromatic C=C), 1440 (N-N), 1210(C-S); ¹H-NMR (DMSO-d6, δ ppm) 2.5 (s, 2H, NH), 2.5-2.8(s,3H,CH), 6.6-6.8(m, 9H,CH, Ar-H, diphenylamine). Electron absorption spectra (UV) λ_max324.3 (methanol
2d	IR(KBr/cm^-1)=3420 (N-H), 3000 (Ar-CH), 2950 (C-H), 1540 (C=N), 1540 (Ar. C=C), 1550 (N-N), 1210 (C-S); ¹H-NMR (DMSO-d6, δ ppm) 2.4 (s, 2H, NH), 6.5-6.9(m, 9H,CH, Ar-H, diphenylamine). Electron absorption spectra (UV) λ_max308.6 (methanol)
2e	IR(KBr/cm^-1)=3130 (N-H), 3010 (Ar.C-H), 2960 (CH₂) 1660 (C=N), 1580(C-N), 1510 (Ar. C-C), 1515 (N-N), 1095 (Ar. C-Cl); ¹H-NMR (DMSO-d6, δ ppm) 2.1 (d, 2H, NH), 7.0-7.5(m, 9H,CH, Ar-H, diphenylamine). ). Electron absorption spectra (UV) λ_max248 (methanol
2f	IR(KBr/cm^-1)=3240 (N-H), 3060 (Ar.CH), 2910 (CH₂), 1620 (C=N), 1610 (C-N)1540 (Ar. C-C), 1540 (N-N), 1486 (N-O), 1210(C-S);¹H-NMR (DMSO-d6, δ ppm), 3.3(s, 2H,NH) 6.5-6.9(m, 9H,CH, Ar-H, diphenylamine). Electron absorption spectra (UV) λ_max321.8 (methanol)

Table 2 Physiochemical Properties of synthesized compounds.

Com.	R	Molecular formula	Molecul weight	Melting Point(°C)	% yield	R_fvalue
2a	H	C₁₄H₁₂N₄S	268	180	67	0.76
2b	CH₃	C₁₅H₁₄N₄S	282	167	77	0.68
2c	OCH₃	C₁₅H₁₄N₄OS	298	192	70	0.72
2d	Cl	C₁₄H₁₁ClN₄S	302.5	214	79	0.72
2e	Br	C₁₄H₁₁BrN₄S	347	213	76	0.65
2f	NO₂	C₁₄H₁₁N₅O₂S	313.33	221	68	0.59

Table 3 Physicochemical and thermodynamic properties of the title Compounds.

Com.	Log P	CLogP	Henry's Law	MR[cm3/mol]	Critical V [cm3/mol]	Heat of Form [kJ/mol]	Gibbs Energy [kJ/mol]
2a	4.22	3.26649	3.11	80.86	725.5	500.84	716.91
2b	4.71	3.76549	3.11	86.76	781.5	468.73	715.7
2c	4.1	3.20454	3.11	88.11	799.5	336.51	610.7
2d	4.78	4.08891	3.11	85.47	774.5	473.63	695.35
2e	5.05	4.23891	3.11	88.55	787.5	515.7	721.6
2f	4.62	3.46451	3.11	84.68	783.5	483.57	713.6

5-(4-(4-chlorophenylamino)phenyl)-1,3,4-thiadiazol-2-amine (2d):

Reaction mixture of the 4-(4-chlorophenylamino)benzoic acid 6.44 g. (0.026 mol) and thiosemicarbozide 2.4 g.(0.026 mol) was added and to isolate the product followed above method, to give 5-(4-(4-chlorophenylamino)phenyl)-1,3,4-thiadiazol-2-amine, slightly coffee colored solid was obtained and recrystallized by ethanol.

5-(4-(4-bromophenylamino)phenyl)-1,3,4-thiadiazol-2-amine (2e):

The 4-(4-bromophenylamino)benzoic acid 7.6 g. (0.026 mol) and thiosemicarbozide 2.4 g.(0.026 mol) was added and to isolate the product followed above method, to give 5-(4-(4-bromophenylamino)phenyl)-1,3,4-thiadiazol-2-amine, slightly coffee colored solid was obtained and recrystallized by ethanol.

5-(4-(4-nitrophenylamino)phenyl)-1,3,4-thiadiazol-2-amine (2f):

Mixture of 4-(4-nitrophenylamino)benzoic acid 6.7 g. (0.026 mol) and thiosemicarbozide 2.4 g.(0.026 mol) was added and to isolate the product followed above method, to give 5-(4-(4-nitrophenylamino)phenyl)-1,3,4-thiadiazol-2-amine, slightly coffee colored solid was obtained and recrystallized by ethanol.

Characterization of the synthesized compounds:

The 5-(4-(phenylamino)phenyl)-1,3,4-thiadiazol-2-amine derivatives (2a-f) are synthesized by the reaction between substituted of 4-(phenylamino)benzoic acid and thiosemicarbazide (1a-f). All melting points (m.p.) were determined in open capillary method using Jindal melting point apparatus and were uncorrected. The purity of the compounds was routinely checked by thin layer chromatography (TLC) using silica gel G (Merck). The instruments used for spectroscopic data are FTIR: Bruker tensor-27 spectrophotometer (ATR) with diffuse reflectance method. H¹NMR: JEOL GSX-400, 60MHz spectrometer in CDCl₃, TMS (tetra methyl saline) as an internal standard. H¹NMR, and IR spectra were consistent with the assigned structure. The results obtained which are shown in table 1 indicates, 5-(4-(phenylamino)phenyl)-1,3,4-thiadiazol-2-amine derivatives (2a-f) were synthesized under conventional method. All compounds were conformed to the structures envisaged. The structures were proved on the basis of spectral data which are shown table 2, thermodynamics properties, chemical property and constant are given table 3 and 3 D structure of synthesized title compounds 2 and 3 are shown fig.2 and 3.

Fig. 2 Three dimension Structure of synthesized title Compound with Energy minima-(1a-f).

Fig.3Three dimension Structure of synthesized title Compound with Energy minima-2a-f).

Biological evaluation:

Antifungal Activity method of testing:^26-27

Antifungal activity of the synthesized compounds (2a-f) was screened, in vitro, against the pathogenic fungi Candida albicans and Aspergillus niger. The method utilized in the evaluation of this activity was cup plate method²⁷. Twenty five milliliter of molten sterile medium [Sabouraud’s Dextrose Agar (pH 5.6)] was poured in to sterilized Petri dishes and allowed to solidify at room temperature. Broth cultures of the test fungi were used as inoculums under sterile conditions. The agar plates were seeded with 0.1 ml (1 x 10⁸ cells / ml) of fungal strain for 10 hours by spreading on the surface of agar medium with the help of a glass speeder. Subsequently cups of 12mm diameter were bored within these agar plates using a sterile cork borer. Dimethyl formamide (DMF) was used as control and as solvent to prepare the stock solutions of the synthesized compounds and of standard drug Fluconazole²⁸. The concentration of the prepared stock solutions was 100μg / ml²⁹.

Table 4 Results of in vitro antifungal activity of the synthesized compounds (2a-f).

Com	*A. niger*		*C. albicans*
Com	Zone of Inhibition (mm)	% Inhibition	Zone of Inhibition (mm)	% Inhibition
2a	13	68.42	05	31.25
2b	10	52.63	06	37.50
2c	11	57.89	08	50.00
2d	18	94.73	15	93.75
2e	10	52.63	17	106.25
2f	11	57.89	04	25.00
Std(fluconazole)	19	100.00	16	100.00

Graph 1 Comparison of the in vitro antifungal activity exhibited by the test compounds (2a-f) and standard drug Fluconazole

Then 250 μl of the stock solution was poured into each cup, the Petri dishes were incubated at 25°C± 2°C for 48 hours and were examined for zone of inhibition (in mm) and % inhibition, exhibited by the test and standard compounds, which is given in Tables 4.

RESULT AND DISCUSSION:

The research work was aimed to synthesized 5-(4-(phenylamino)phenyl)-1,3,4-thiadiazol-2-amine derivatives (2a-f) are synthesized by the reaction between substituted of 4-(phenylamino)benzoic acid and thiosemicarbazide (1a-f) and to evaluate the synthesized compounds for antifungal activity that exhibits potent pharmacological activities as compare to the standard drugs.

The titled project was undertaken on the basis of literature survey which revealed that the 5-(4-(phenylamino)phenyl)-1,3,4-thiadiazol-2-amine derivatives possess excellent pharmacological activities of antifungal. On the basis of above observation it was assumed that the presence of both the heterocyclic molecules in a single structure may enhance these activities.

1,3,4-thiadiazole has a pharmacophor, so it is assumed that 1,3,4-thiadiazole and heterocyclic compounds chain were shown synergetic effect in antifungal activity. Hence such compounds will be prone to be attacked to the some range of fungal stain and may gives rise to potent antifungal agents. All the synthesized compounds were screened in vitro against the pathogenic fungal strains A. niger and C. albicans. None of the tested compounds exhibit activity less than 36.84% of inhibition. When compared with the standard drug fluconazole, most of the compounds showed high to moderate activities. Compounds 2a (68.42% inhibition), 2d (94.73% inhibition), 2e (106% inhibition), showed excellent activity. The compounds 2a contains unsubstituted phenyl ring, compound 2d and 2e contain halogen –C1 and -Br at para position on phenyl ring respectively. The anti-fungal % of inhibition values are given in Table 4

SUMMARY AND CONCLUSION:

In summary, designed and synthesized a series of 5-(4-(phenylamino)phenyl)-1,3,4-thiadiazol-2-amine derivatives and characterization of the synthesized compounds was carried out by determining their melting points, IR Spectra, UV, Mass spectra and R_f value.

Synthesized series of 5-(4-(phenylamino)phenyl)-1,3,4-thiadiazol-2-amine derivatives by the cyclyzation of 4-(phenylamino)benzoic acid and thiosemicarbazide in the presence of polyphosphoric acid. Among the synthesized compounds, unsubstitution of phenyl ring and substitution at the 4- position of halogen as –Cl, Br showed good antifungal activity. Pyrazole derivatives shown in-vitro evaluation of anti-bacterial activity and revealed that the newer targets for the development of novel therapeutic agents by chemists all over the world has lead to the discovery of pyrazole derivatives as novel anti-bacterial compounds. The present work involved the synthesis of pyrazol derivatives then characterization and in-vitro evaluation of anti-bacterial activity Chlorine substitution at the position–2 in compound 9 and position–2,4 in compound 11 have significant anti-bacterial activity. In conclusion, pyrazole derivatives cyclic analogues showed comparable activity. We may say that their pharmacophoric groups are similar and the possible structure of suitable fused heterocyclic could be accepted to give antibacterial activity and may have various pharmacological activities given in table 4.

ACKNOWLEDGEMENT:

The author is thankful to the Principal, Bhupal Nobles P.G. College of Pharmacy, Udaipur, Rajasthan- India for providing necessary laboratory facilities. Author is thanks to head, University College of Science, Department of microbiology Mohan lal Sukhadia University, Udaipur, for carry out antifungal activity and Author is also thanks to head, sophisticated instrumental lab, Punjab University, Chandigarh, for providing spectroscopic analysis facilities.

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Received on 18.09.2010 Modified on 30.09.2010

Asian J. Research Chem. 4(2): February 2011; Page 221-226