Several new analogues of adenosine bearing a lipophilic side chain at the 5'-position have been synthesized and investigated for their ability to inhibit histamine N-methyltransferase (HNMT). The 5'-deoxy-5'-[4-(3-indolyl)but-l-yl] thio}adenosine (2e), exhibited a pl 50 of 5.00 against guinea pig brain HNMT. Interestingly, the polar methyl sulphonium analogue (7c) was a more potent inhibitor of this enzyme (pl 50 =5.26). Both compounds were relatively ineffective inhibitors of rabbit adrenal phenylethanolamine N-methyltransferase (PNMT), rabbit lung indoleamine N-methyltransferase (INMT), and rat brain catechol O-methyltransferase (COMT). 5 -[N(4-phenylbutyl)] -amino-5 cieoxyadenosine (2a) and 5 -[N-methyl,N-(4-phenylbutyl] -amino-5 cleoxyadenosine (2b) also exhibited potent and selective inhibition against guinea pig brain HNMT. Results from kinetic studies indicate that the above compounds are inhibitors that compete for both the histamine and the S-adenosylmethionine (SAM) binding sites of HNMT. Compound lc is one of the most potent adenosine analogue inhibitors of HNMT known. Fig. 1: The histamine N-methyltransferase-catalyzed reaction.
2(2-Tetrahydropyranylthio) methyl cyclopropyl amines were synthesized from allylmercaptan through several steps. The structures of the intermediates and the final products where confirmed through IR, NMR and elemental analysis, these compounds may be of value in the treatment of diseases where free radicals are implicated in their pathogensis, since the thio and the amino groups of the synthesized compounds may act as free radical scavengers.
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