Imidazo[1,2-a]pyridin-3-amines as HIV-1 nonucleoside reverse transcriptase inhibitors (NNRTIs)
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2018
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Abstract
Imidazo[1,2-a]pyridin-3-amine compounds have been reported to exhibit activity against a number of viruses. Their biological activity against the highly mutative HI virus is of specific interest to this research. Reported molecular modelling studies on 2-(2-chlorophenyl)-N-cyclohexylimidazo[1,2-a]pyridin-3-amine in the allosteric site of HIV reverse transcriptase enzyme revealed that their activity might be improved by increasing the H-bonding ability of these compounds by adding groups with hydrogen bonding abilities to the cyclohexyl group of the molecule. Two approaches on how to access these modified compounds were explored and are described in this dissertation.
In the first approach a cyclohexyl isocyanide possessing a group (acetate) with Hbonding abilities was prepared from 2-hydroxyl-cyclohexylamine in a three step synthetic route; the amine was initially subjected to a formylation reaction which gave 2-hydroxyl-cyclohexylformamide as a product. This was followed by an acetylation reaction (obtaining 2-formamidocyclohexyl acetate) in order to protect the hydroxyl group before the final step, which was the dehydration of the formamide. Both the formylation and acetylation reactions gave products that existed as a mixture of rotamers of different concentrations in solution; with a ratio of 1:2 (minor rotamer: major rotamer) for the formylated product, and 1:3 (minor rotamer: major rotamer) for the acetylated product.
The successful preparation of the isocyanide through dehydration was followed by its use in the GBB multicomponent reaction with an aminopyridine and aldehyde to successfully give a small number of novel 2-(phenyl)-N-(2-acetatecyclohexyl)imidazo[1,2-a]pyridin-3-amine derivatives with a H-bonding group on the cyclohexyl ring, and thus possessing improved H-bonding ability. However, the acetate was not the H-bonding group of interest, but rather the hydroxyl group. So we subjected these compounds to a hydrolysis reaction with potassium hydroxide in order to liberate the hydroxyl functional group, and only two compounds from those synthesized were successfully hydrolysed. However, the liberated hydroxyl group was found to participate in an intramolecular nucleophilic displacement of the fluorine atom to give two 7-membered ring (fused to the imidazo-pyridine scaffold) novel compounds.
The second approach explored for accessing these compounds with increased Hbonding involved the development of an alternative methodology to the first approach. The initial step of the successfully developed methodology involved the use of a convertible isocyanide (tert-butyl isocyanide or 1,1,3,3-tetramethylbutyl isocyanide), aminopyridine and aldehyde in the GBB reaction. The use of tert-butyl isocyanide led to the successful preparation of a small library of 2-(phenyl)-N-(tert-butyl)imidazo[1,2a]pyridin-3-amine derivatives, while the use of 1,1,3,3-tetramethylbutyl successfully gave two 2-(phenyl)-N-(1,1,3,3-tetramethylbutyl)imidazo[1,2-a]pyridin-3-amine derivatives.
These compounds were subsequently used in a dealkylation reaction in which some of them gave their corresponding primary amine derivatives. The primary amine derivatives successfully participated in a reductive amination with cyclohexanone to give the target compounds, 2-(phenyl)-N-(cyclohexyl)imidazo[1,2-a]pyridin-3-amine derivatives. The versatility of the reductive amination reaction was also briefly investigated, and a number of primary amine derivatives were found to successfully react with 2-chlorobenzaldehyde, thus illustrating that the reductive amination reaction employed might possess some versatility. This successfully developed three step methodology (GBB, dealkylation and reductive amination) could possibly be utilized in the synthesis of 2-(phenyl)-N-(cyclohexyl)imidazo[1,2-a]pyridin-3-amine derivatives (with improved H-bonding) by using cyclohexanone derivatives functionalized with groups that have H-bonding abilities in the reductive amination reaction.
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A dissertation submitted to the Faculty of Science University of the Witwatersrand Johannesburg in fulfillment for the requirements of the degree of Master of Science, February, 2018
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Citation
Mokone, William Katlego (2018) Imidazo[1,2-a]pyridin-3-amines as HIV-1 non-nucleoside reverse transcriptase inhibitors, University of the Witwatersrand, Johannesburg, https://hdl.handle.net/10539/24927