Design and Synthesis of DiselenoBisBenzamides (DISeBAs) as Nucleocapsid Protein 7 (NCp7) Inhibitors with anti-HIV Activity

Abstract

The interest in the synthesis of Se-containing compounds is growing with the discovery of derivatives exhibiting various biological activities. In this manuscript, we have identified a series of 2,2'-diselenobisbenzamides (DISeBAs) as novel HIV retroviral nucleocapsid protein 7 (NCp7) inhibitors. Because of its pleiotropic functions in the whole viral life cycle and its mutation intolerant nature, NCp7 represents a target of great interest which is not reached by any anti-HIV agent in clinical use. Using the diselenobisbenzoic scaffold, amino acid, and benzenesulfonamide derivatives were prepared and biologically profiled against different models of HIV infection. The incorporation of amino acids such as glycine and glutamate into DISeBAs 7 and 8 resulted in selective anti-HIV activity against both acutely and chronically infected cells as well as an interesting virucidal effect. DISeBAs demonstrated broad antiretroviral activity, encompassing HIV-1 drug-resistant strains including clinical isolates, as well as simian immunodeficiency virus (SIV). Time of addition experiments, along with the observed dose dependent inhibition of the Gag precursor proper processing, confirmed that their mechanism of action is based on NCp7 inhibition.

Synthesis of new alkylated and methoxylated analogues of ebselen with antiviral and antimicrobial properties

“…[8][9][10][11][12][13][14][15]20,21 Ebselen (2-phenylbenzisoselenazol-3(2H)-one) and its analogues have received particular attention as glutathione peroxidase mimics, 8,11,15 antioxidant and anti-inflammatory agents. [13][14][15] Furthermore, the continuing interest in this class of compounds has led to the development of various structures with antiviral [22][23][24][25][26] and antimicrobial [24][25][26][27] properties. In this work we report a convenient synthetic route to a series of new alkylated and methoxylated benzisoselanazol-3(2H)-ones 4 and bis(2-carbamoylaryl)diselenides 6 which were tested for antiviral and antimicrobial activity in biological studies.…”

Preclinical evaluation of a mercaptobenzamide and its prodrug for NCp7-targeted inhibition of human immunodeficiency virus

“…Since the discovery of inhibitors which attack the zinc finger, a variety of classes of inhibitors have been described (Rice et al, 1993;Ryser et al, 1994;Turpin et al, 1999;Sancineto et al, 2015;Kim et al, 2015), many of which are described in a recent review (Mori et al, 2015). Some NCp7 inhibitors act by covalent modification of the target, although these molecules typically lead to undesirable toxicity.…”

“…Some NCp7 inhibitors act by covalent modification of the target, although these molecules typically lead to undesirable toxicity. The recent report using diselenobisbenzamides to inhibit HIV replication via covalent modification of NCp7 is a promising new development in this area (Sancineto et al, 2015). Another strategy to inhibit NCp7 is to screen for non-covalent inhibitors.…”

Water-dependent synthesis of biologically active diaryl diselenides

“…Direct reduction of benzisoselenazolones with different reducing agents -sodium borohydride, hydrazine, ascorbate or phosphoric acid (h), [33][34][35][36] nucleophilic substitution of o-iodobenzamides with lithium diselenide (i), 37 under radical conditions from the reaction of 2-benzylselenobenzamides with triphenyltin hydride and further treatment with benzoyl peroxide (j) 38 and few protocols starting from 2,2-diselenobis(benzoic acid) -through the formation of the corresponding dichloride and further reaction with amine (k) 39 or by EDC (l) 40 and DCCmediated (m) 41 coupling reactions (Scheme 2).…”