Novel Nonnucleoside Inhibitors of HIV-1 Reverse Transcriptase. 8. 8-Aryloxymethyl- and 8-Arylthiomethyldipyridodiazepinones

Abstract

Nevirapine (I) is the first human immunodeficiency virus type 1 (HIV-1) nonnucleoside reverse transcriptase (RT) inhibitor to reach regulatory approval. As a result of a second generation program around the tricyclic core system of nevirapine, 2-chloro-5, 11-dihydro-11-ethyl-5-methyl-8-(2-(pyridin-4-yl)ethyl)-6H-dipyrido[3, 2-b:2',3'-e][1,4]diazepin-6-one (II)1a and 2-chloro-5, 11-dihydro-11-ethyl-5-methyl-8-phenylethyl-6H-dipyrido[3,2-b:2', 3'-e][1,4]diazepin-6-one (III)1a were identified as broad spectrum HIV-1 RT inhibitors. A detailed examination of replacing either of the methylenes of the 8-ethyl linker of II or III is presented. It was found that 8-aryloxymethyl and 8-arylthiomethyl are the preferred pattern of substitution for potency against RT. The most potent compounds were further evaluated against a panel of clinically significant mutant RT enzymes (K103N, V106A, G190A, P236L) and in cytotoxicity and in vitro metabolism assays. The most potent compound was 2-chloro-8-phenylthiomethyl analogue 37 which displayed sub-100 nM activity against all HIV-1 RT enzymes tested.

Synthesis of [14C]‐ and [13C6]‐labeled potent HIV non‐nucleoside reverse transcriptase inhibitor

“…22 This was probably due to the use of partially degraded carbon-14 potassium cyanide. Reduction of acid (13) to alcohol (14) was accomplished using BH 3 /THF in 91% yield. 17 Mitsunobu's etherification with 4-hydroxyquinoline derivative gave (15) To prepare [ 13 C 6 ]-(1), Scheme 4, the commercially available [ 13 C 6 ]-aniline was condensed with diethyl ethoxymethylene malonate first at 1101C neat and then in phenyl ether at 2601C.…”

“…Purification by flash chromatography using a 12 g RediSep TM disposable column and a gradient ethyl acetate/hexane (0-50% EtOAc) gave 176 mg of a colorless oil of pure product in 28% yield. The low yield is maybe due to using a batch of K 14 CN that has been stored at À201C for more than 15 years. In the unlabeled run the yield was comparable to the literature.…”

Synthesis of substituted thieno[2,3-d]pyrimidine-2,4-dithiones and their S-glycoside analogues as potential antiviral and antibacterial agents

“…NNRTIs, being less toxic than NRTIs, had received great attention [3e5]. Three NNRTIs nevirapine [6], delavirdine [7], and efavirenz [8] have been approved by FDA. Not only being effective RT inhibitors, these three NNRTIs also acted as the key components of the combination therapy [9e11].…”

Synthetic studies of Alkoxy isoindole‐1,3‐diones tetra‐azabenzo[f]azulenes and their Antibacterial activity

“…A great deal of synthesis work has been done in last few years on various compounds having a condensed diazepine nucleus, especially benzodiazepin have attracted the attention of several chemist and biologists because of their valuable therapeutic properties like tranquillizer [1][2][3] , neuroleptic agents 4 , antineoplastic 5,6 , HIV-1 RT inhibitors 7,8 antileukemic 9 and antifungal 10 etc. It is interesting to note that pyrazoles are also reported as well known pharmacophores [11][12][13][14] .…”