SYNTHETIC STUDIES ON SOME NITROGEN AND SULPHUR CONTAINING COMPOUNDS AS POTENTIAL LOCAL ANAESTHETICS AND ANTIBACTERIALS

Abstract

The thesis consists of two parts. The first part of the thesis deals with the synthesis of certain compounds having potential local anaesthetic activity. Since it has been found that the essential structure requirements for a local anaesthetics are a lipolytic and containing an aromatic nucleus, a hydropylic end consisting of a tertiary amino group and an intermediate alkyl or substituted alkyl chain. Compounds having dialkylamino alkylamino group connected to an aromatic or heterocyclic nucleus as lipolytic moiety confer greater activity and less toxicity. Taking this view into consideration, it was thought worthwhile to synthesise some pyridine-2-aminoacetyl- 2-aminobenzothiazole, pyrimidine-2-aminoacetyl- 2-aminobenzothiazole, N:N-dimethylaniline-p-aminoacetyl-2-aminobenzothiazole and Morpholinoacetyl-2-aminobenzothiazole derivatives. These compounds were prepared by the condensa tion of chloroacetyl chloride with different 2-aminobenzothiazoles followed by treatment with 2-aminopyridine, 2- aminopyrimidine, p-amino-N:N-dimethylaniline, p-amino N:N-diethylaniline and Morpholine respectively. The hydrochlorides of the above compounds were prepared for biological evaluation. C1C0CH9C1 XV -N (i)Amines II (ii)HCl C- NHC0CH2C1 >- \A/ S -NHC0CH2HNR; HC1 (iv) Where X = Hydrogen; 4-methyl-; 6-methyl-; 4,7-dimethyl-; 5-methoxy-; 6-methoxy; 5-chloro; 6-chloro; and 6-bromo-, Similarly, 4-phenyl-2-aminothiazole was condensed with chloroacetyl chloride and chloroacetyl derivative so obtained was further treated with Dimethylamine, Diethylamine, Dipropylamine, I sopropylamine, Morpholine, Piperidine, Piperizine, 2-aminopyridine, 2-aminopyrimidine and p-amino-N:N-diethylaniline respectively. C6H5-T C-NH, C1C0CH2C1 C6H5-C G6H5-C -N C-NHCOCH^l (i)Amines ,r(ii)HCl •N ,C-MHC0CH2HNR;HC1 The two class of compounds thus synthesised were tested for their local anaesthetic activity. The activity was determined by employing (i) Surface anaesthesia in rabbit cornea and (ii) Infiltration anaesthesia in guinea-pig cornea. More or less all the compounds were found to be active. Few derivatives have shown greater activity in infiltration anaesthesia than procaine and lidocaine, (v) which is described in the second Chapter of the thesis. Second part of the thesis is an account of the synthesis of compounds with possible antibacterial activity. This part is further divided into two Chapters. Chapter one deals with the synthesis of certain typical substituted thioureas, which are well known to possess many pharmacological activities such as antituberculou s, antithyroidal, anti spasnodic, antiviral, antifungus etc. Hence, the following series of thioureas were prepared and some of which were screened for biological activity. 1. 1- Substituted-3-benzoylthiourea s:- RNHCNH(jJC6H5 S 0 R = Phenyl-, O-tolyl-, m-tolyl-, p-tolyl-, 0-anisyl-, m-anisyl-, p-anisyl-, p-phenetyl-, m-chlorophenyl-, p-chlorophenyl-, p-bromophenyl-, 2,3-dimethylphenyl-, 2,4-dimethylphenyl-, 2,5-dimethylphenyl-, 3,4- dimethylphenyl-, 2,4-dimethoxyphenyl-, 2,5-dimethoxyphenyl-, 2,3-dichlorophenyl-, 2,4-dichlorophenyl-, -naphthyl-, 2-pyridyl- and methyl-. 2, N-Sub sti tuted-N'-benzene sulfonyl thiourea s:- <f \s02NHCNHR _ S R = Phenyl-, 2-pyridyl-, 2-pyrimidino-, benzyl-, n-butyl-, ethyl-, Isopropyl-, N:N-dimethylaniline- p-amino-, 2,5-dimethylphenyl-, 2, 6-dimethylphenyl-, 2-chloro-6-methylphenyl-. (vi) 3. N- Sub stituted-N'-benzo thiazolyl thiourea s:- N II C-NHCHNR II S Where, X=hydrogen, 4-methyl-, 5-methyl-, 6-methyl-, 4,7-dimethyl-, 5-methoxy-, 6-methoxy-, 4-ethoxy-, 6-ethoxy-, E-chloro-, 6-chloro-, 6-bromoand, R=methyl-, phenyl-, and benzenesulfonyl-, 4. N-Aryl-N* - 2- (3-methylb enzo thi a zolyl) thiourea s:- C=NGNHR II S R=Phenyl-, O-tolyl-, m-tolyl-, p-tolyl-, O-anisyl-, m-anisyl-, p-anisyl-, p-phenetyl-, m-chlorophenyl-, p-chlorophenyl-. 5. N-2-(4-Substituted thiazolyl)-N*-arylthioureas:- R'-C N Where, C-NHCHNR Sx s R'=Methyl-, phenyl-, p-tolyl-, p-chloro phenyl-, p-bromophenyland, R=Phenyl-0-tolyl-, m-tolyl-, p-tolyl-, (vii) O-anisyl-, m-anisyl-, p-anisyl-, p-phenetyl-, m-chlorophenyl-, p-chlorophenyl- , benzenesulfonyl- . 6. M- Substituted-N'-2(benzenesulfonyl)thioureas:- \s02NHCNHR R=Phenyl-, O-tolyl-, m-tolyl-, p-tolyl-, O-anisyl-, p-anisyl-, p-phenetyl-, methyl-, p-chlorophenyl-, allyl-. 7, N- Sub stitut ed-N'- 2- (naphthothiazolyl) thioureas:- t C-NHCNHR ll V •* C- NttCf> W/ i R=Phenyl-, O-tolyl-, m-tolyl-, p-tolyl-, O-anisyl-, m-anisyl-, p-anisyl-, p-phenetyl-, m-chlorophenyl-, p-chlorophenyl-. 8. N-Substituted-N«-2- (pyridyl)thiourea s:- fMCNHR : R=Phenyl-, O-tolyl-, m-tolyl-, p-tolyl-, O-anisyl-, p-anisyl-, p-phenetyl-, methyl-, p-chlorophenyl-, allyl-. For compounds of above series, which have been screened have shown considerable antibacterial activity. (viii) Second chapter of the second part of the thesis deals with the synthesis of some thiosemicarbazides, amidinothioureas and thiosemicarbazones. Since thiosemicarbazones and their derivatives are known to possess considerable antitubercular activity, therefore, it was not without interest to synthesise some typical thiosemicarbazides, amidino-thioureas, and thiosemicarbazones and screen them for antibacterial activity. The following series of thioureas, thiosemicar bazides and thiosemicarbazones were synthesised: 1. N-a.ryl-fo rmami di no-N-b en zenesulfonylthiourea. ArNHtjJ-N - Cj - NH2 NH S C6H5 S02 Ar = Phenyl-, O-tolyl-, m-tolyl-, p-tolyl-, O-anisyl-, p-anisyl-, p-phenetyl-, m-chlorophenyl-, p-chlorophenyl-, p-bromophenyl-. 2. N-aryl-N,-(substituted)thiosemicarbazide:- Xk^ \.S02NHNHCNHR S Where, X = hydrogen; p-aminoacetyl. R = Phenyl-, O-tolyl-, m-tolyl-, p-tolyl-, O-anisyl-, m-anisyl-, p-anisyl-, p-phenetyl-, methyl-, p-chlorophenyl-. 3. 1- Substituted-4-arylformamidinothiosemicarbazone:- >C=NNHCNHCNHAr: HC1 R.*'/ SII NI'H (ix) Where, (i) R=CH3-; R'=CH3- (ii) R=CH3-; R,=G6H5- (iii) R=CH3-; R«=Cl0H7- Ar = Phenyl-, O-tolyl-, m-tolyl-, p-tolyl-, O-anisyl-, p-anisyl-, p-phenetyl-, m-chlorophenyl-, p-chlorophenyl-, p-bromophenyl-. The compounds so synthesised have been sent for biological testing and results of the biological screening of few compounds, which have been received so far are quite promising.