ABSTRACT
In the present work, we described the design, synthesis and biological evaluation of a novel series of potential dual-target prodrugs targeting the HIV-1 reverse transcriptase (RT) and nucleocapsid protein 7 (NCp7) simultaneously. Among them, the most effective compound 7c was found to inhibit HIV-1 wild-type (WT) strain at double-digit nanomolar concentration (EC50 = 42 nM) in MT-4 cells, and sub-micromole (EC50 = 0.308 µM) to inhibit HIV-1 NL4-3 strain in TZM-bl cells. This is a significant improvement over the parent drug MT. In addition, it showed moderate inhibitory potency (EC50 = 1.329 µM) against the HIV-1 K103N/Y181C double mutant strain (MT-4 cells). The metabolic stability in human plasma of compound 7c indicated that it can release the active forms of the parent drugs MT and AZT in a linear time-independent manner and turn out to be a potential prodrug.
Subject(s)
Anti-HIV Agents/pharmacology , HIV Reverse Transcriptase/antagonists & inhibitors , HIV-1/drug effects , Prodrugs/pharmacology , Reverse Transcriptase Inhibitors/pharmacology , gag Gene Products, Human Immunodeficiency Virus/antagonists & inhibitors , Anti-HIV Agents/chemical synthesis , Anti-HIV Agents/chemistry , Cell Survival/drug effects , Dose-Response Relationship, Drug , Drug Discovery , HIV Reverse Transcriptase/metabolism , Humans , Microbial Sensitivity Tests , Molecular Structure , Prodrugs/chemical synthesis , Prodrugs/chemistry , Reverse Transcriptase Inhibitors/chemical synthesis , Reverse Transcriptase Inhibitors/chemistry , Structure-Activity Relationship , Tumor Cells, Cultured , gag Gene Products, Human Immunodeficiency Virus/metabolismABSTRACT
Crystallographic overlap studies and pharmacophoric analysis indicated that diarylpyrimidine (DAPY)-based HIV-1 NNRTIs showed a similar binding mode and pharmacophoric features as indolylarylsulfones (IASs), another class of potent NNRTIs. Thus, a novel series of DAPY-IAS hybrid derivatives were identified as newer NNRTIs using structure-based molecular hybridization. Some target compounds exhibited moderate activities against HIV-1 IIIB strain, among which the two most potent inhibitors possessed EC50 values of 1.48µM and 1.61µM, respectively. They were much potent than the reference drug ddI (EC50=76.0µM) and comparable to 3TC (EC50=2.54µM). Compound 7a also exhibited the favorable selectivity index (SI=80). Preliminary structure-activity relationships (SARs), structure-cytotoxicity relationships, molecular modeling studies, and in silico calculation of physicochemical properties of these new inhibitors were also discussed.
