Darivatization and Pharmacological Evaluation of New 4 Substituted 5 -Phenyl-3-Mercapto-1,2,4–Triazoles

 

M. Vidyasagar¹, B.Srinivas², P. Parameshwar¹, A. Ganesh³, R. Ramesh Kumar¹

¹Jyothishmathi Institute of Pharmaceutical Science, Ramakrishna colony, Karimnagar, AP, India

²Talla Padmavathi College of Pharmacy, ours, Karimabad, Warangal, AP, India

³Procadence Institute of Pharmaceutical Sciences. Gajwel, Medak,. A.P, India

*Corresponding Author E-mail: param_pabba@yahoo.com

 

An efficient method for synthesis of 4 substituted 5 -phenyl - 3- mercapto -1, 2, 4 –triazole, by the mode of ring cleavage of oxadiazoles, nucleophiles are readily attack 5-phenyl 1,3,4- oxadiazole-2 – thiols and they  are cleaved by acids and basis, in a reaction, which is the reverse of the ring closure, many nucleophilic ring cleavage reaction are followed by recyclization to give different heterocyclics, we were  sysnthsized 5 different compounds and characterized its physical data, spectral analysis  by IR and these compounds screened for possible CNS activity.

 

 

INTRODUCTION:

Triazole, a physiologically active nucleus, has attracted the attention of many researchers from the point of its chemistry and biological activity. The nitrogen congaing heterocyclics are found in abundance in most of the medicinal compounds the successes of oxadiazole as an important moiety of member of medicinal agents led to introduction of triazoles. The triazoles are five member rings which contain two carbons, three nitrogen atoms. According to the position of nitrogen atom triazoles exists isomeric forms. Two structural isomeric triazoles are known the 1, 2, 3- and 1, 2, 4- forms in which the former being known as osotraizoles in the latter is triazole. 1,2,4- triazole derivatives have received much attention due to there versatile biological properties including antifungal (Bijul Laxman A and R L Gupta- 2010), antibacterial, anti-inflammatory, anticancer (Gestel J V-1980) and antiprolifarative properties(Xiangl-2012) in the 1,2,4- nucleus has bean attached with new nucleophilic functional groups which gives tremendous activities of the compounds.

 

MATERIALS AND METHODS:

Keeping in view an array of application, it has been felt worthwhile to synthesize some new  4 substituted 5 -phenyl - 3- mercapto-1, 2, 4 –triazole, as such reactions are not reported so for and also to screen for the central nervous system. The synthesis of title compound achieved by the scheme-1

 

Synthetic procedure: 

Preparation of 4-methyl- 5-phenyl -3- mercapto-1,2,4- trizole:

5-phenyl-1,3,4-oxadiazole -2-thiol has been reported earlier (AJC12).

5-phenyl-1,3,4-oxadiazole -2-thiol (7grms, 0.036 mol) and methylamine (6ml) in absolute ethanol were refluxed in 250ml dried RB flask fitted with condenser and guard tube. The reaction time was monitor throw TLC technique (ethylacetate: benzene 1:2) after the completion of the reaction the solvent   and excess methylamine were removed by rotary evaporator. The residue was recrystalize from ethanol (M.P 168-170^oc), the purification of compound was achieved by recrystallization and purity of each compound was monitored by TLC.

 

Preparation of 4- ethyl- 5-phenyl – 3-mercapto-1, 2, 4-trizole:

5-phenyl-1,3,4-oxadiazole -2-thiol(7grms, 0.036 mol) and ethylamine(6ml) were reacted according to the general procedure, colour light yellow yield 63%(4.41grms) recrystallization from ethanol, M.P 170-172^oc.

 

 

Scheme – 1: general scheme for the synthesis of 4 substituted 5 -phenyl - 3- mercapto-1, 2, 4 –triazoles

 

 

Preparation of 4-hydroxy-5-phenyl – 3-mercapto-1, 2, 4-trizole:

5-phenyl-1,3,4-oxadiazole -2-thiol (7grms, 0.036 mol) and hydroxylamine were  reacted according to the general procedure, colour white yield 75% (5.25gms) recrystallization from ethanol, M.P 185-187^oc.

 

 

Preparation of 4 (4-chloro phenyl)-5-phenyl-3-mercapto-1, 2, 4-triazole:

5-phenyl-1,3,4-oxadiazole -2-thiol (7grms, 0.036 mol) and p-chloro aniline were  reacted according to the general procedure, colour yellow, yield 82% (5.74gms) recrystallization from ethanol, M.P 190-192^oc.

 

Preparation of 4 (2,4-dinitrophenyl)- 5-phenyl-3-mercapto-1, 2, 4-triazole:

5-phenyl-1, 3, 4-oxadiazole -2-thiol (7grms, 0.036 mol) and 2, 4-dinitroaniline were reacted according to the general procedure, colour orange, yield 53% (3.71gms) recrystallization from ethanol, M.P 198-200^oc.

 

Pharmacological evaluation procedure:

Selection of animals:

Male albino mice, weighing about 35-45 g obtained from the Mahaveer Enterprizes, Baghambarpet, Hyderabad (CPCSEA registration no: 146/1999/CPCSEA) and the animals were kept in the animal house of Jyothishmathi institute of Pharmaceutical Science, Ramkrishna colony, Karimnagar, A.P.  at room temperature of 25 - 30°C and at 45 - 55% relative humidity for 12 h, each of dark and light cycle. The animals were feed with rat pellets (Hindustan Lever Limited, Bangalore, India) and filtered water. Animal studies in the work have been strictly performed as per the Institutional Animal Ethical Committee (IAEC) constituted under the guidelines of Committee for the Purpose of Control and Supervision on experimental Animal (CPCSEA), Ministry of Environment, and Govt. of India

 

Locomotor activity:

The locomotor activity was studied by using actophotometer (Vogel H-2002), which operates on photoelectric cells, which are connected in circuit with a counter.  When animals cut of beam of light falling on the photocells, a count was recorded.  Healthy male mice weighing between 35-45 gm were used.  Animals were fasted for over night and divided into groups of six animals each group.  The test compounds suspended in 0.1% Sodium CMC are administered at a dose of 100 mg/kg body weight i.p.  The control group animal received only vehicle (0.1% sodium CMC).  The response (counts) was recorded after 30 minutes of administration of drug or test compounds. The animals were placed in actophotometer for 10 minutes and scores were recorded (no. of deflections) and compared the results with control. The results are presented in Table-III.

 

Action on central nervous system gross behavioural studies:

All the compounds tested for acute toxicity studies were also observed for gross behavioural changes (R A Turner-1965), continuously for 5 hours at 1 hour interval after administration of the compounds. There after the observations were recorded intermittently for 24 hours and compared with that of control group. In the behavioral profile, the animals have been observed for changes in their:

i)     Awareness (Alertness, Visual placing, Stereotypy, Passivity, Writhing)

ii)    Mood (Grooming, Vocalization, Restlessness, Irritability). The results are presented in Table-II

 

RESULTS AND DISCUSSION:

The compound IVa: 4-methyl- 5-phenyl -3- mercapto-1,2,4- triazole is confirmed by the single spot in the TLC system and IR spectral peaks at1321 (N-C str),2590 (S-H str),1575(C=C str), 1515(C=N str)

The compound IVc: 4-hydroxy-5-phenyl – 3-mercapto-1, 2, 4-trizole is confirmed by the single spot in the TLC system and IR spectral peaks at 3404 (-OH str), 2561(S-H str) 1580(C=C str), 1530(C=Nstr).

 

The compound IVd: 4 (4-chloro phenyl)-5-phenyl-3-mercapto-1, 2, 4-triazole is confirmed by the single spot in the TLC system and IR spectral peaks at 2606(S-H str), 1602 (C=C str), 1553(C=N str).

 

The compound IVe: 4 (2,4-dinitrophenyl)- 5-phenyl-3-mercapto-1, 2, 4-triazole triazole is confirmed by the single spot in the TLC system and IR spectral peaks at 2575(S-H str), 1572(C=C str),1525(C=N), 1532(-NO2).

 

Physical data of 4 substituted 5 -phenyl - 3- mercapto-1, 2, 4 –triazoles.

 

Table: I 

S.No.	Compound	Substituent R	Molecular formula	Melting point (°C)	Molecular weight	Yield %
1	IVa	R = -CH3	C9H11NS	168-170	192.21	63
2	IVb	R = -CH2-CH3	C10H13NS	172-174	206.21	63
3	IVc	R = -OH	C8H9NSO	185-187	194.21	75
4	IVd	R= - 4 Cl aryl	C14H13NSCl	190-192	288.77	82
5	IVe	R= 2-NO2, 4-NO2,  aryl	C14H13N3SO4	198-200	344.32	53

 

Gross behavioral studies of 4 substituted 5 -phenyl - 3- mercapto-1, 2, 4 –triazoles

 

Table: II

Compounds	Time in Hrs	Awareness					Mood
		Alert ness	Visual placing	Stereo type	Passivity	Writhing	Grooming	Vocali zation	Rest lessness	irritability
IVa R= CH3	½	-	-	-	+	-	+	-	-	-
	1	-	-	-	+	-	-	-	-	-
	2	-	-	-	+	-	-	-	-	-
	3	+	-	-	+	-	-	-	-	-
	4	+	+	-	+	-	-	-	-	-
	5	+	+	-	-	-	-	-	-	-
	24	+	+	-	-	-	-	-	-	-
IVd R = 4(4-Cl aryl)	½	-	-	-	+	-	-	-	-	-
	1	-	-	-	+	-	+	-	-	-
	2	-	-	-	+	-	-	-	-	-
	3	-	-	-	+	-	-	-	-	-
	4	-	-	-	-	-	-	-	-	-
	5	+	-	-	-	-	-	-	-	-
	24	+	-	-	-	-	-	-	-	-

Dose = 100mg/kg body weight; + - positive response,  - -negative response

 

 

All the new compounds screened for grass behavioral study. The behavioral study of the test compound related that all the test compounds exhibited central nerves system depressant in the mice. The compound IVa, IVd, shows the more depressant activity than compared with the others.

 

Locomotor activity of 4 substituted 5 -phenyl - 3- mercapto-1, 2, 4 –triazole

 

Table-III pertaining to the results of the locomotor activity of the  4 substituted 5 -phenyl - 3- mercapto-1, 2, 4 –triazoles (IV) in mice shows that all the test compounds reduced the locomotor activity.  The locomotor activity was studied by actophotometer.  The compound IVd exhibited more effect among all the compounds with 80.86% reduction in the locomotor activity.  The compound IVa reduced the locomotor activity by 79.24% and the remaining compounds were next in the order of reduction of locomotor activity. 

 

 

Table: III                   

Compound	Substituent R	Locomotor activity (scores) in 10 minutes, n=6		% Change in activity (↓)
		Before administration	After administration
IVa	R = -CH3	390	81	79.24
IVb	R = -CH2-CH3	359	152	57.67
IVc	R = -OH	375	138	63.2
IVd	R= -4 Cl aryl	397	76	80.86
IVe	R= 2-NO2, 4-NO2aryl	368	152	58.37

ACKNOWLEDGEMENT:

The authors thank to the management of Jyothishmathi Institute of Pharmaceutical Sciences for providing all the requirements.

 

REFERENCES:

1      Xiangl, xue Qiang-Li  et al. synthesis and evaluation of anti tumor activity of novel chiral 1,2,4- triazole Schiff bases bearing γ-butenolide moiety, Organic and Spinger Open J 2012

2        Hasn, S. Gapi and I Khan, Asian J. Chem, 23,2007(2011).

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4        Vogel H Gerhard: drug discovery and evaluation of pharmacological assays (Springer-Verlag Berlin Heidelberg New York 2002) 126-128

5        Bijul Laxman A and R L Gupta. Fungitoxicity and QSAR of 4-amino-5- substituted aryl-3-mercapto- (4H)-1,2,4- triazoles, Indian Journal of Chemistry, Vol 49B sep2010 pp1235-1242.

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7        Nizamuddin, Gupta M, Khan MH and Srivastava M K, J Scient Ind Res,58,1999,538.

8        cande SN and Jagtap S R, Indian J Chem.36B, 1997,199.

 

 

Received on 20.03.2013       Modified on 31.03.2013

Accepted on 19.04.2013      © AJRC All right reserved