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Title: Synthesis and bioactivity study of 4,6-diamino-1,3,5-triazines
Authors: MA XIANG
Keywords: dihydrofolate reductase inhibitors, sodium channel blockers, antimicrobial activity, antiproliferative activity, 4,6-diamino-1,3,5-triazines
Issue Date: 13-Feb-2007
Citation: MA XIANG (2007-02-13). Synthesis and bioactivity study of 4,6-diamino-1,3,5-triazines. ScholarBank@NUS Repository.
Abstract: The 2-amino-1,3-diaza structural motif is a common feature found in many pharmaceutically useful agents. Studies have shown that some of these triazines are found to be potent DHFR inhibitors. As an extension to these studies, it was the intent of this dissertation to explore further if 4,6-diamino-1,3,5-triazines would also possess other forms of pharmacological activities. Therefore, the first objective of this dissertation was to design and synthesize five libraries of 4,6-diamino-1,3,5-triazine and its analogues; while the second objective was to investigate whether the triazines exhibit inhibitory activity against various microorganisms, cancer cells and neuronal sodium channels in addition to the antifolate activity.A small library M-I consisting of seven aromatic 1,3,5-triazines was synthesized by an alkoxide-catalyzed condensation of biguanide hydrochlorides with suitably substituted carboxylic acid esters at room temperature. Another fourteen 1,2-dihydro-1,3,5-triazines in library M-II were prepared based on a two-step reaction: the first step involved the preparation of 4,6-diamino-2,2-dimethyl-1-phenyl-1,2-dihydro-1,3,5-triazine (I), then the target compounds were derived via a base-catalyzed Dimroth rearrangement of I. In the synthesis of library M-III, a two-component reaction was carried out between benzylbiguanide and ketones or aldehyde with the use of water scavengers. The synthesis of M-IV involved a three-component synthesis that employed cyanoguanidine, O-aminophenylalkyl alcohol hydrochloride and various ketones. The fifth library M-V was produced using fragment coupling synthesis strategy by alkylation with substituted phenoxyalkyl bromide of an N-hydroxytriazines. In the first two libraries (M-I and M-II), all the compounds were screened for inhibitory activity against bovine DHFR, neuronal sodium channels and an array of microorganisms. Limited bovine DHFR inhibitory activity was observed in both libraries. However, both libraries exhibited moderate to potent neuronal sodium channel blockade activity in vitro; among them, M-II-12 showed the best blockade activity with an IC50 value of 12.57 A?M, which was ten times lower than positive control, phenytoin. While M-II exhibited limited antibacterial activity, some compounds in M-I library demonstrated relatively good antifungal activity against C. albicans and A. niger. The M-III library was designed based on the same side chain found in TMP. Twenty-three 4,6-diamino-1,2-dihydro-1,3,5-triazines in M-III were synthesized and screened against S. aureus and M. smegmatis for their antibacterial activity. All compounds in this library did not exhibit activity against S. aureus that was noteworthy; however, most of them possessed unique activity against M. smegmatis. Compound M-III-15 was most active within the whole library of M-III providing a zone ratio of 0.98 against M. smegmatis at a dose of 100 I?g. In the libraries of M-IV and M-V, biological screening against bovine DHFR revealed that they were very potent DHFR inhibitors. However, only M-V library demonstrated potent antiproliferative activity against the three cancer cell lines MDA-MB-231, MCF-7 and A549. M-V-20 was the most potent inhibitor found which exhibited an IC50 value of 27 nM against the lung cancer cells A549. Further experiments involving the use of hypoxanthine and thymidine as rescue agents confirmed that the inhibition of cancer cell growth was mainly due to DHFR inhibition. Therefore, M-V-20 is a novel triazaspiroalkane which emerged from this study as having the potential for further development into a new drug candidate.In conclusion, the hypothesis that 4,6-diamino-1,3,5-triazines would possess other forms of bioactivity in addition to DHFR inhibition was demonstrated to be partially true.
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