Substitute of nitrile with chlorine in 7b was detrimental to the inhibitory activity (Table 2)

Substitute of nitrile with chlorine in 7b was detrimental to the inhibitory activity (Table 2). Non-nucleoside reverse transcriptase inhibitors (NNRTIs) have proven their performance as components of highly active antiretroviral therapy 1C3 . Their relatively low toxicity, as compared to other antiretroviral medicines, makes them a very attractive class of compounds used in treating HIV-1 infections 4C7 . Currently, you will find five authorized NNRTIs, first generation: nevirapine (NVP), efavirenz (EFV), delavirdine, and second generation: etravirine (ETV) and rilpivirine (RPV). Because HIV-1 reverse transcriptase (RT) has a low fidelity C its error rate was reported to be in the range of 10?3C10?5 per nucleotide addition 8C10 C there is a very high mutation rate of the virus, and strains resistant to antiretroviral medicines emerge. Consequently, the pharmacotherapy may become ineffective, moreover, cross-resistance between NNRTIs is possible 11C14 . Another problem is definitely the NNRTIs binding site of RT favours non-polar compounds, which are usually poorly soluble in water. This is especially the case in second-generation NNRTIs, as both ETV and RPV are practically insoluble in water and require unique formulations 15 , 16 . For these reasons there is a need to develop fresh NNRTIs with improved potency against resistant HIV mutants and better pharmacokinetics 17C19 . First generation NNRTIs like NVP and XMD8-92 EFV are rigid molecules that bind well to the wild-type RT, but a single amino acid mutation in XMD8-92 the binding site can significantly decrease their affinity to the enzyme. Second generation NNRTIs have flexible constructions which allows them to adapt to a revised binding site of mutant RT 20 . Usually, second generation NNRTIs have 2C3 aromatic rings with an ether, thioether, short alkyl or amino group located between the rings that functions as a hinge that allows the inhibitors to bind in different conformations and conquer resistance mutations 20 , 21 . An excellent review within the chemical diversity of NNRTIs was written by Zhan et?al. 18 . Diaryl ethers are one of the classes of second generation NNRTIs. There are several interesting inhibitors belonging to this class, including 1 C the most potent NNRTI reported to day (against crazy type RT) and doravirine (2), which is in phase III medical trials (Number 1) 22C24 . Open in a separate window Number 1. Structures of a catechol diether with the lowest EC50 reported to day (1) and doravirine (2). As mentioned above, poor solubility in water results in reduced bioavailability, and there is an increasing awareness of the need to design NNRTIs with improved pharmacokinetics. Several approaches were used by different authors to accomplish better solubility of NNRTIs: salt formation 25 , 26 , prodrug formation 27 , 28 , addition of polar substituents 29C31 , changes of crystal structure 23 or reduced halogenations 32 . Our goal was to design second generation NNRTIs with improved solubility and chemical stability. Building on common substructures of several diaryl ether (3C5) 33C35 and azole NNRTIs (6) 36 XMD8-92 we designed two fresh scaffolds: 7a and 8a (Number 2). The new constructions feature phenacyl moiety as an alternative to hydrolytically labile amide, found in some NNRTIs (Number 2). Open in a separate window Number 2. Constructions of several diaryl ether NNRTIs (3C5), RDEA806 (6), and our newly designed compounds (7a, 8a). Materials and methods Synthesis Compounds 7aCg (resorcinol type) and 8aCf (catechol type) were synthesised in several methods from commercially available starting materials. Diaryl ether parts (9aCf) of the XMD8-92 new NNRTIs were synthesised from phenols and aryl fluorides in N-methylpyrrolidone (Number 3) as explained earlier 34 , 35 . In case of 9b Chan-Lam coupling was XMD8-92 used 37 . Hydroxyacetophenones were O-alkylated with ethyl chloroacetate. Subsequent exchange Rabbit Polyclonal to GNE of ethyl to methyl afforded genuine and solid methyl esters, which were selectively brominated with N-bromosuccinimide and em p /em -toluenesulfonic acid in chloroform (10aCd) (Number 3) 38 . Final deesterification was performed using potassium carbonate in a mixture of.