Search

Meta nitro benzoic acid has been reduced to 3-aminocyclohexa-1,5-diene-1-carboxylic acid with three different Birch like reduction condition (Method I, II, III) to 3-aminocyclohexa-1,4-diene-1-carboxylic acid. 3-aminocyclohexa-1,4-diene-1-carboxylic acid is found to be structurally more super impossible on gama-amino butyric acid (GABA) and hence the synthesized compounds was tested for the CNS depressant and muscle relaxant activities. A series of new 3-[5-substituted phenyl-1,3,4-thiadiazole-2-yl]-2styryl 5,8-dihydroquinazoline-4 (3H)-ones were synthesized and evaluated for anticonvulsant, sedativehypnotic and CNS depression activities. Various derivatives of 3-[5-substituted phenyl-1,3,4-thiadiazole-2yl]-2-styryl 5,8-dihydroquinazoline-4 (3H)-ones were examined in the maximal electroshock (MES) induced seizures and subcutaneous pentylenetetrazole (scPTZ) induced seizure models in mice. Rotorod method was employed to determine the neurotoxicity. Out of 9 compounds only 3 compounds showed anticonvulsant activity in one or more test models. All except compound (a) exhibited significant sedativehypnotic activity via actophotometer screen. Forced swim pool method to determine CNS depressant activity resulted in some potent compounds. It can be concluded that synthesized compounds exhibited better sedative-hypnotic and CNS depressant activities than anticonvulsant activity. Introduction The Birch reduction has been a synthetically useful and powerful method for the partial reduction of aromatic and heteroaromatic rings for more than 60 years [1]. Numerous compounds have been subjected to reducing conditions that include alkali metal and ammonia with various modifications extensions and development of the Birch reduction [2]. The scope of the Birch reduction covers a variety of aromatic and heteroaromatic systems such as pyridines, indoles, furans and thiophenes [3]. Recently, we have been concerned with the reduction of organic compounds by various methods, which resembles to Birch reduction in terms of mechanism. Methods like use of Hydroxyl ions as an electron source in the presence of Ultra Violet light [4], THF (no ammonia) with lithium metal and catalytic amounts of naphthalene used as an electron source[5,6]. Indigenously developed method like use of ammonia gas instead of Liquid Ammonia with Methanol (Dried) can be satisfactorily useful for the reduction of aromatic compounds with varied yields. In the preceding paper we described three different Birch reduction processes for the reduction of Meta nitro benzoic acid by maintaining different Birch like conditions (Method I, II, III). We also have reduced anthranillic acid to 2-aminocyclohexa-1,4-diene1-carboxylic acid which is then converted into 3[5-substituted 1,3,4-thiadiazole-2-yl]-2-styryl 5,8dihydroquinazoline-4 (3H)-ones which were then tested for Anticonvulsant activity, Behavioral and CNS studies. Attempts have not been made to reduce the Meta nitro benzoic acid till date by birch reduction. It can be hypothesized that after the reduction of the compound Meta nitro benzoic acid, the chemical moieties so obtained may have GABA agonist or antagonistic activities. Superimposibility of 3-aminocyclohexa-1,4-diene1-carboxylic acid on GABA has promoted us to select compound Meta nitro benzoic acid for birch reduction by three different methods (I, II, III). Other most frequently and important encountered heterocycles in medicinal chemistry is quinazoline with wide applications including anticonvulsant, sedative, tranquilizer, analgesic, antimicrobial, anesthetic, anticancer, antihypertensive, antiinflammatory, diuretic and muscle relaxant properties [7-9]. Literature survey revealed that the presence of substituted aromatic ring at position 3 and methyl group at position 2 are necessary requirement for the central nervous system (CNS) depression and anticonvulsant activities. In spite of the fact that literally hundreds of quinazolinones related to 2methyl3-o-tolyl-4(3H)-quinazolinone (methaqualone) have been synthesized and Study of new developments in birch reduction process International Journal of Drug Discovery, ISSN: 0975–4423, Volume 2, Issue 1, 2010 18 tested for central nervous system (CNS) depression and anticonvulsant activities, none of the drugs currently in use contain the 4(3H)quinazolinone ring system. With this previous literature survey we tried to synthesis various analogous of 2-methyl-5,8-dihydroquinazolin4(3H)-one [10]. Among the few reports in the literature our attention was drawn to the earlier discovery by Boltze et al. [11] andWolfe et al. [12] that modification of methyl group by some other chemical moiety yielded structural analogues with anticonvulsant activity. Medicinal chemists over the years have substituted different heterocyclic rings at position 3 of the 4(3H)-quinazolinone to get potent CNS acting drugs. 1,3,4-Thiadiazoles nucleus itself exhibits anticonvulsant, sedativehypnotic and CNS neurotoxicity activities [13]. In hope of getting synergistic response of 4(3H)quinazolinone nucleus itself, substitution of 1,3,4thiadiazoles nucleus at third position and chemically modifying second position of 4(3H)dihydroquinazolinone, the present paper reports on the synthesis, anticonvulsant, neurotoxicity, CNS depressant activity and behavioral study of 9 new 3-(1-3-4-thiadiazol-2-yl)2-styryl 5,8dihydroquinazoline-4 (3H)-ones. Experimental All the chemicals used in the synthesis were of analytical grade, procured from E-Merck (India) Limited, Mumbai; Loba Chemie Pvt.Ltd., Mumbai; S.D. Fine-Chem,Ltd.,Mumbai; Burgoynes and Co., Bombay; Thomas Baker(Chemicals) Ltd, Mumbai; Himedia Laboratories Pvt.Limited, Mumbai and were used without further purification. The solvents used were of spectroscopic grade. The elementary analysis was performed at University Department of Pharmaceutical Sciences; RTM University of Nagpur, Nagpur, India. Elementary analyses for C, H, N were within ±0.4% of theoretical values. The visible absorption spectrum was obtained on Shimadzu 1601 spectrophotometer. IR spectrum was recorded using KBr pellets on FTIR-Vector 22, Bruker, France spectrophotometer at Indian Bureau of Mines, Nagpur. 1 H NMR spectrum was taken on a Varian EM 390 spectrophotometer at Department of Chemistry, University of Pune, Pune, India. GCMS spectrum of the compound was recorded using DMSO as solvent on Shimazdu GCMA QP-2010 at Department of Chemistry, Institute of Science, Mumbai. The melting point of synthesized dye was determined by Veego’s Precision Melting Point apparatus. The purity and homogeneity of compound was checked using thin layer chromatography technique. Reduction of m-nitrobenzoic acid by ammonia gas method (Method I) In a three neck round bottom flask which was equipped with pressure equalizing funnel, 6.2 g of sodium metal was added in 100ml of dry ethanol and flask was kept in the cooling mixture of crystalline calcium chloride and crust ice [14](practical vogal). Ammonia solution was heated on the heating mental at temp of 30 0 C to liberate the ammonia gas. The ammonia gas was then allowed to pass through the calcium chloride (Fused) guard tube to remove the moisture ammonia gas was then bubbled in the mixture of dry ethanol and sodium metal for 3 hr. A solution of 10 g of m-nitrobenzoic acid in 50 ml of dry ethanol was then added slowely from the pressure-equalizing funnel followed by 14.6g of ammonium chloride. In three neck round bottom flask ammonia gas was continuously passed through mixture for 4 hr. Ammonia was then evaporated and the residual material was dissolved in ice (500ml). After acidification with 10% HCl, the solution was extracted with four 100 ml portions of ether, the ether washed once with saturated sodium chloride solution dried over magnesium sulfate and concentrated in vacuum. The remaining pale yellow oil was distilled at 9698 0 C to give 3-aminocyclohexa-1,4-diene-1carboxylic acid. Reduction of m-nitrobenzoic acid by photochemical electron transfer method [4] (Method II) The photoreduction of (I) was carried out in Pyrex vessels (>300 nm) with a 500 W high-pressure mercury lamp under an argon atmosphere at room temperature.The excitation of a 2-propanol solution of m-nitrobenzoic acid 1 (5 mM) and NaOH (200 mM) for 6 h exclusively afforded 5aminocyclohex-2-ene-carboxylic acid in 72% isolated yield. The efficiency of this photoreduction was highly dependent on both the nature of the substrate and the concentration of NaOH; further, the use of KOH or tetrabutylammonium hydroxide instead of NaOH resulted in a low yield of the reduction product fig. 1 [4]. Reduction of m-nitrobenzoic acid by THF and naphthalene method (Method III) [5] We also, discovered that the same reduction of m-nitrobenzoic acid could be performed in THF (no ammonia) with lithium metal and catalytic amounts of naphthalene used as an electron shuttle. We feel that removing the need for ammonia solvent will make the partial reduction reaction more practicable, especially on a large scale, and may also allow us to quench reduction reactions with sensitive electrophiles that would otherwise react with ammonia itself. Above three different reduction procedures has been carried out to check the practical yield of different modifications in Birch reduction. The compound selected for the birch reduction is m-nitrobenzoic acid as its was hypothise that the reduce product to m-nitrobenzoic acid i.e the 3-aminocyclohexaCharbe NB, Mehere AP, Dravyakar B, kawade D, Vimal Kumar Varma M, Chaitanya Ch Copyright © 2010, Bioinfo Publications, International Journal of Drug Discovery, ISSN: 0975–4423, Volume 2, Issue 1, 2010 19 1,5-diene-1-carboxylic acid have structural similarity with GABA. The percentage yield of 3aminocyclohexa-1,4-diene-1-carboxylic acid with three modifications is 84,72, 69 % respectively.