Discovery of novel sulfonamide substituted indolylarylsulfones as potent HIV-1 inhibitors with better safety profiles

Abstract

Indolylarylsulfones (IASs) are classical HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs) with a unique scaffold and possess potent antiviral activity. To address the high cytotoxicity and improve safety profiles of IASs, we introduced various sulfonamide groups linked by alkyl diamine chain to explore the entrance channel of non-nucleoside inhibitors binding pocket. 48 compounds were designed and synthesized to evaluate their anti-HIV-1 activities and reverse transcriptase inhibition activities. Especially, compound R₁₀L₄ was endowed with significant inhibitory activity towards wild-type HIV-1 (EC_50(WT) = 0.007 μmol/L, SI = 30,930) as well as a panel of single-mutant strains exemplified by L100I (EC₅₀ = 0.017 μmol/L, SI = 13,055), E138K (EC₅₀ = 0.017 μmol/L, SI = 13,123) and Y181C (EC₅₀ = 0.045 μmol/L, SI = 4753) which were superior to Nevirapine and Etravirine. Notably, R₁₀L₄ was characterized with significantly reduced cytotoxicity (CC₅₀ = 216.51 μmol/L) and showed no remarkable in vivo toxic effects (acute and subacute toxicity). Moreover, the computer-based docking study was also employed to characterize the binding mode between R₁₀L₄ and HIV-1 RT. Additionally, R₁₀L₄ presented an acceptable pharmacokinetic profile. Collectively, these results deliver precious insights for next optimization and indicate that the sulfonamide IAS derivatives are promising NNRTIs for further development.

Keywords: Cytotoxicity; HIV-1; Indolylarylsulfone; NNRTIs; Sulfonamide.

Graphical abstract

Figure 1

Structures, anti-HIV-1 activities and cytotoxicities of some representative IAS derivatives.

Figure 2

Binding mode and design strategy of IAS analogs. (A) 3D view of interaction and surrounding residues of IAS-6 and HIV-1 RT (PDB ID: 2RF2). (B) 2D abstract diagram of general binding pockets and regions of IAS derivatives. (C) Design strategy and general formula of target compounds in this work.

Scheme 1

Reagents and conditions: (i) 1-(chloromethyl)-4-fluoro-1,4-diazabicyclo [2.2.2]octane-1,4-diium tetrafluoroborate (Selectflour™), acetonitrile (CH₃CN), r.t.; (ii) m-CPBA, dichloromethane (DCM), 0 °C; (iii) lithium hydroxide, H₂O, tetrahydrofuran (THF), r.t.; (iv) Et₃N, DCM, 0 °C–r.t.; (v) CF₃COOH, DCM, r.t.; (vi) 1H-1,2,3-triazolo [4,5-b] pyridinium-1-[bis(dimethylamino)-methylene]-3-oxide hexafluorophosphate (HATU), N,N-diisopropylethylamine (DIEA), DCM, 0 °C to r.t.

Figure 3

Schematic overview of SARs of IAS derivatives in this work.

Figure 4

Graphical representation of docking poses and interactions of R₁₀L₄ with WT HIV-1 RTs (PDB ID: 6C0N) (A and B), E138K (PDB ID: 6C0L) (C) and L100I (PDB ID: 2OPQ) (D). R₁₀L₄ and IAS-0 were shown as sticks with carbon atoms colored in magenta/green. Protein surface and residues were shown in pale cyan. Mutated residues were highlighted by yellow. H-bonds and π–π stackings were represented by yellow/green dashed lines.

Figure 5

Visualized results from in vivo toxicity experiment of R₁₀L₄. (A) Time courses of body weight in 7-days acute toxicity experiment. (B) Time courses of body weight in 12-days subacute toxicity experiment. (C) Images of organ slices from treated mice in subacute toxicity study. Heart, liver, spleen, lung and kidney were sectioned and stained with hematoxylin and eosin.