Halolactones are potent HIV-1 non-nucleoside reverse transcriptase inhibitors

Abstract

Herein, we report the discovery of halolactone derivatives as efficient non-nucleoside reverse transcriptase inhibitors (NNRTIs) and the study of their structure-activity 10 relationships (SARs). Among them, 5-exo lactone 3-(chloro(2chlorophenyl)-methyl)isobenzofuran-1(3H)-one 13a, showed excellent potency against WT HIV-1 in the reverse transcriptase gene with low EC 50 value of 0.45 µM. In most cases, the property and the position of the substituents had a 15 definite effect on the activities of anti-HIV-1 activity. In contrast, the 6-endo lactones (isochroman-1-ones) had inferior inhibitory activities against HIV-1. This work offered a structurally simple scaffold (isobenzofuran-1(3H)-one) for the development of novel anti-HIV drugs. 20 45 and co-workers. [16][17][18][19][20][21][22] Scheme 1. Current anti-HIV RT inhibitors 55 Efavirenz (EFV), as the second-generation NNRTIs, is a key component of highly active antiretroviral therapy (HAART) with a lactam-lactone scaffold forming hydrogen-bonding interactions with the K101 of RT. 23 Based on this structure, there are many active compounds owning this similar scaffold having been 60 designed. Recently, Lee group reported that chromone derivatives had significant anti-HIV activity. 24,25 At the same time, Robin group developed series of flavonoid derivatives as potent anti-HIV with micromolar level. 26 More recently, Keri and co-workers also identified that chromones were a privileged scaffold in drug 65 design with a wide range of pharmacological activity such as anti-HIV, anti-cancer, anti-bacterial and so on. 27 In 2014, Long and co-workers developed flavonoid-based HIV-1 integrase inhibitors in enzyme-based assays and these compounds also blocked the integrase-LEDGF/p75 interaction with low-to sub-70 micromolar IC 50 values in cell-based assays. 28 Moreover, several RT inhibitors based on chromone skeleton have been developed, for example, a chromone moiety was covalently linked to the 5'end of various oligonucleotides (ODN) as a RT inhibitor. 29 As part of our long term interest to explore the small molecule 75 NNRTIs, we have developed the indole-based alcohol 30 and αamino acids (IAA) 31 inhibitors of reverse transcriptase (RT) of HIV-1 based on trifluoromethylated indoles (TFMIs) by a TZMbl cell assay (5, Scheme 1). [30][31][32] Despite the effectiveness of the

Synthesis, Characterization, Cytotoxicity, and Antibacterial Properties of trans‐γ‐Halo‐δ‐lactones

“…Recently, promising antibacterial properties was also shown for bicyclic lactones with three or four methyl groups . Halolactones were also considered as potential inhibitors of HIV‐1 non‐nucleoside reverse transcriptase …”

“…[39] Halolactonesw ere also considered as potentiali nhibitors of HIV-1 non-nucleoside reversetranscriptase. [52]…”

Manganese‐Catalyzed ortho‐C−H Alkenylation of Aromatic N−H Imidates with Alkynes: Versatile Access to Mono‐Alkenylated Aromatic Nitriles

“…The C=C bond and the cyano group could be selectively reduced to form amine 8aa and ortho ‐alkylated benzonitrile 9aa , respectively ,. Besides, simple hydrolysis of the cyano functionality of 4aa gave styrylbenzoic acid 10aa in high yield, which could be further elaborated for the synthesis of diverse products 11aa – 13aa through redox‐neutral, oxidative, and olefin‐oxychlorinated cylizations, respectively …”

Recent Advances in the Design and Development of Non‐nucleoside Reverse Transcriptase Inhibitor Scaffolds

“…Someo ft hem are benzofluorenones, such as 135, [84] and halolactones, such as 136,w ith the isobenzofuran-1-one moiety,w hich were designedo nt he basis of the structure of the second-generation NNRTIe favirenz. [85] Somem ore examples are N-heteroaryl 137, [86] imidazole-5-one 138, [87] 4-arylamino-quinoline-3-carbonitrile 139, [88] and phenyl hydrazone 140 ( Figure 62). [89] Because most NNRTIs contain at least one heterocycle in their structures, to introduce more heterocyclesi no ne mole- www.chemmedchem.org cule of NNRTIs, Arafa and co-workersp repared an umber of pyrazolo[4,3-d]isoxzadoles as new NNRTIs.…”