Indolylarylsulfones Bearing Natural and Unnatural Amino Acids. Discovery of Potent Inhibitors of HIV-1 Non-Nucleoside Wild Type and Resistant Mutant Strains Reverse Transcriptase and Coxsackie B4 Virus

Abstract

New potent indolylarylsulfone (IAS) HIV-1 NNRTIs were obtained by coupling natural and unnatural amino acids to the 2-carboxamide and introducing different electron-withdrawing substituents at position 4 and 5 of the indole nucleus. The new IASs inhibited the HIV-1 replication in human T-lymphocyte (CEM) cells at low/subnanomolar concentration and were weakly cytostatic. Against the mutant L100I, K103N, and Y181C RT HIV-1 strains in CEM cells, sulfones 3, 4, 19, 27, and 31 were comparable to EFV. The new IASs were inhibitors to Coxsackie B4 virus at low micromolar (2-9 microM) concentrations. Superimposition of PLANTS docked conformations of IASs 19 and 9 revealed different hydrophobic interactions of the 3,5-dimethylphenyl group, for which a staking interaction with Tyr181 aromatic side chain was observed. The binding mode of 19 was not affected by the L100I mutation and was consistent with the interactions reported for the WT strain.

Synthesis and SARs of indole-based α-amino acids as potent HIV-1 non-nucleoside reverse transcriptase inhibitors

“…Overall, the compounds with an electron-withdrawing group on the phenyl ring exhibited excellent inhibition (entries 3-9). The same trend was observed when the substitution occurred at the 6-position of the phenyl ring (entries [13][14][15][16][17]. Exhilaratingly, the compounds with an electron-donating group on the same position provided superior inhibitory activity to the corresponding indolealkyl trifluoropyruvate derivatives (entries [10][11][12].…”

Arylsulfone-Based HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitors

“…Compounds 46 (EC 50 = 2 nM) and 48 (EC 50 = 3 nM) were the most potent inhibitors of the HIV-1 WT IIIB strain in MT-4 cells, and 46 showed the highest selectivity index (table 4) Against the HIV-1 K103N mutated RT, compounds 46 and 48 showed relative resistance (ID 50_mutant /ID 50_WT ) values 1.6-and 80-fold, respectively, whereas the same mutation showed a relative resistance >300-fold toward EFV [50].…”

“…Coupling of natural and unnatural amino acids to the indole-2-carboxamide resulted in a new series of IAS HIV-1 NNRTI with inhibitory activities comparable to EFV in CEM cells (table 6) [50]. Some new IASs inhibited the Coxsackie B4 virus at 2-9 µM concentrations.…”

“…Significant examples are diaryltriazine (Janssen [NJ, USA]) [71], dipyridodiazepinone BIRL 355 BS (Boehringer Ingelheim [CT, USA]) [72,73] and the pyrrolidin-1-ylsulfone (Merck [PA, USA]) [74] HIV-1 NNRTIs. The binding poses of IAS derivatives carrying an (hetero)cyclic moiety at the 2-carboxamide bridging group were predicted to resemble those of 53, 55 and 71 [50,51] establishing novel binding interactions in the solvent accessible cleft of the NNBS formed by residues R172, I180, V179 and E138:B, and T139:B. The observations prompted the design of new IAS derivatives characterized by a basic nitrogen atom and small hydrophobic groups at the 2-carboxamide side chain that could form striking interactions respectively with the E138:B acid function and hydrophobic residues in the NNRTI cleft [75].…”

An efficient and facile synthesis of N-Cbz-β-aminoalkanesulfonamides

“…Inversely, there is still growing interest in -aminoalkanesulfonamides due to the fact that they can be considered as stable mimetics of tetrahedral transition states in hydrolysis and formation of esters and amides [2]. Therefore, they have been widely used as enzyme inhibitors [3,4], antibacterial [57] and anticancer agents [8]. Additionally, N-protected -aminoalkanesulfonamides as useful building blocks have been successfully employed in the synthesis of sulfonopeptides [1] and hybrid sulfonophosphinopeptides [9,10].…”