Structure and Photochemistry of a Saccharyl Thiotetrazole

Abstract

The molecular structure and photochemistry of 5-thiosaccharyl-1-methyltetrazole (TSMT) were studied by means of matrix-isolation FTIR spectroscopy, X-ray crystallography, and theoretical calculations. The calculations predicted two conformers of TSMT that differ in energy by more than 15 kJ mol(-1). The infrared spectrum of TSMT isolated in solid argon was fully assigned on the basis of the spectrum calculated (O3LYP/6-311++G(3df,3pd)) for the most stable conformer. In the crystal, TSMT molecules were found to assume the same conformation as for the isolated molecule, with each molecule forming four hydrogen bonds with three neighboring molecules, leading to a network of TSMT oligomers. Upon UV (λ = 265 nm) irradiation of the matrix-isolated TSMT, two photodegradation pathways were observed, both arising from cleavage of the tetrazolyl ring. Pathway a involves cleavage of the N1-N2 and N3-N4 bonds with extrusion of N2, leading to photostable diazirine and thiocarbodiimide derivatives. The photostability of the photoproduced diazirine under the conditions used precluded its rearrangement to the nitrile imine, as reported for 5-phenyltetrazole by Bégué et al. ( J. Am. Chem. Soc. 2012 , 134 , 5339 ). Pathway b involves cleavage of the C5-N1 and N4-N3 bonds, leading to a thiocyanate and methyl azide, the latter undergoing subsequent fragmentation to give CNH.

New endoperoxides highly active in vivo and in vitro against artemisinin-resistant Plasmodium falciparum

“…Resistance to ARTs in vivo is characterized by a delayed parasite-clearance time. Up to now this phenotype could not be evidenced using the standard in vitro 48–72 h inhibitory assay, expressed as IC 50 [ 13 , 21 , 27 – 31 ], probably due to the elevated resistance of the very young-ring stages of the parasites. Hence, the phenotypic assay, ring-stage survival assay (RSA), was used to assess the activity of the 8 compounds selected (LC92, LC129, LC130, LC131, LC132, LC136, LC163 and MIS13).…”

“…The saccharyl substituent present in compounds LC129 and LC130 is also electron withdrawing and metabolically stable. Additionally, the saccharyl system is thermally and photochemically more stable than the tetrazole system and is generally found to improve the overall stability of the molecule [ 27 ], although it is worth noting that LC129 is prone to Chapman-type isomerization [ 27 ]. The anti-malarial profile exhibited by the trioxolane–saccharyl conjugates LC129 and LC130 was slightly inferior to that of their tetrazole analogues (Tables 1 , 2 ).…”

“…ARTs resistance cannot be evidenced by the standard in vitro IC 50 assay [ 13 , 21 , 27 – 31 ]. Critical for the development of anti-malarials is the evaluation of their activity against ART-R parasites, which has been defined as delayed parasite clearance in patients [ 53 ].…”

Insights into the photochemistry of 5-aminotetrazole derivatives with applications in coordination chemistry. Effect of the saccharyl moiety on the photostability

“…Taking advantage of the properties of both classes of heterocycles, we designed new scaffolds, termed as tetrazole-saccharinates (Scheme 1), with the aim of exploring their applications as multidentate nitrogen ligands. In recent years we prepared a representative library of tetrazole-saccharinates and investigated their structure in detail, prior to exploring their reactivity and applications [8][9][10].…”

“…Thus, when considering the applications of tetrazole-saccharinates, the low stability of this heterocycle steams as a concern. In this context we considered relevant to investigate the photochemistry of tetrazole-saccharinates, as the electron withdrawing saccharyl system, known to be relatively photostable, will probably affect the photostability of the tetrazole moiety [10].…”