Synthesis of imidazoles as novel emivirine and S‐DABO analogues

Abstract

5-Alkyl-4-benzyl-1,3-dihydroimidazol-2-ones (3a-d) and 5-alkyl-4-benzyl-1,3-dihydroimidazole-2-thiones (7a-d) were prepared via Dakin West reaction on DL-phenylalanine with the appropriate aliphatic acid anhydrides followed by hydrolysis and reaction with potassium cyanate or potassium thiocyanate. Compounds 3a-d were alkylated with ethoxymethyl chloride to give the alkylated imidazoles 5a-d which were considered analogues of Emivirine with deletion of carbonyl group at the 4-position. Alkylation of 7a-d afforded the corresponding S-alkylated derivatives 8a-p which in a similar way were considered analogues of S-DABO. However all the imidazole derivatives were devoid of activity against HIV.

Methods for the synthesis of 1-substituted 1H-imidazol-2(3H)-ones

“…84 2'-Deoxyribonucleosides (α-and β-isomers) 1ao,ap were synthesized by glycosylation of 2-((trimethylsilyl)oxy)-1H-imidazole Y, obtained by reaction of imidazolone 5с with hexamethyldisilazane (HMDS), with 1-chloro-2-deoxy-3,5-di(о-tolyl)-α-D-erythro-pentafuranose 45 in the presence of SnCl 4 (Scheme 61). 85 After the removal of protective tolyl Chemistry of Heterocyclic Compounds 2015, 51(5), 395-420 groups, the α-isomer 1ao and β-isomer 1ap were isolated (Scheme 61).…”

Synthesis of Novel Fluoro Analogues of MKC442 as Microbicides

“…Data for 6-[(3,5-dimethylphenyl)hydroxymethyl]- (7). Sodium hydride (3.24 g, 0.135 mol, 55% suspension in paraffin oil) was added portionwise at 0 °C to a solution of 5-ethyl-2,4,6-trichloropyrimidine (9.36 g, 0.045 mol) and 3,5-dimethylbenzyl cyanide (6.53 g, 0.045 mol) in dry DMF (75 mL) using a CaCl 2 drying tube.…”

“…Several attempts have been made to increase the activity of MKC442 against NNRTI-resistant mutants. − Hopkins et al synthesized TNK651 (Chart ), and then El-Brollosy et al synthesized a series of hybrid analogues of MKC442 and TNK651. Some of these compounds showed activity in the picomolar range against the HIV-1 wt and in the submicromolar range against clinically relevant Y181C and K103N resistant mutants (MKC442-resistant mutants included).…”

Synthesis of 2‐Methylsulfanyl‐1H‐imidazoles as Novel Non‐nucleoside Reverse Transcriptase Inhibitors (NNRTIs)

“…2-Carbamoyloxymethyl-5-(3,5-dichlorophenyl)thio-4-isopropyl-1-(pyridin-4-yl)methyl-1H-imidazole (Capravirine, AG 1549) is in clinical testing [12], but its use has recently been restricted due to vasculitis (an inflammation of the blood vessels), in animals that received high doses of Capravirine [13].Therefore, further research is needed in order to find new drug candidates within this class of compounds. Compounds 3 a, b have been previously synthesized by Bullerwell and Lawson [19] and Loksha et al [17]. We have synthesized α-acylaminoketones by the Dakin-West reaction [14,15] by refluxing L-phenylalanine and L-cyclohexylalanine propionic anhydride and isobutyric anhydride in the presence of pyridine to induce the acylation of the chiral CH group and subsequent decarboxylation in the same manner as described by Cleland [18] and Loksha et al [17].…”