ABSTRACT
Some novel MC-1220 analogs were synthesized by condensation of 4,6-dichloro-N-methylpyrimidin-2-amine derivatives (1a,b and 15) and/or 4-chloro-6-methoxy-N,N,5-trimethylpyrimidin-2-amine (2a) with the sodium salt of 2,6-difluorophenylacetonitrile followed by treatment with aqueous sodium hydroxide in methanol, alkylation, reduction, halogenation, and/or acidic hydrolysis. All synthesized compounds were evaluated for their activity against HIV-1. The most active compound in this study was compound 7, which showed activity against HIV-1 comparable to that of MC-1220. The only difference in structure between compound 7 and MC-1220 is a fluoro atom instead of a CH3 group.
Subject(s)
Anti-HIV Agents/chemical synthesis , Anti-HIV Agents/pharmacology , Fluorobenzenes/pharmacology , HIV Reverse Transcriptase/antagonists & inhibitors , Pyrimidinones/pharmacology , Reverse Transcriptase Inhibitors/chemical synthesis , Reverse Transcriptase Inhibitors/pharmacology , Cell Line , Cells, Cultured , HIV-1/drug effects , Microbial Sensitivity Tests , Models, Molecular , Structure-Activity RelationshipABSTRACT
Prophylactic prevention is considered as the most promising strategy to tackle STI/HIV. Twenty-five dithiocarbamate-thiourea hybrids (14-38) were synthesized as woman controlled topical vaginal microbicides to counter Trichomonas vaginalis and sperm along with RT inhibition potential. The four promising compounds (18, 26, 28 and 33) were tested for safety through cytotoxic assay against human cervical cell line (HeLa) and compatibility with vaginal flora, Lactobacillus. Docking study of most promising vaginal microbicide (33) revealed that it docked in a position and orientation similar to known reverse transcriptase inhibitor Nevirapine. The preliminary in vivo pharmacokinetics of compound 33 was performed in NZ-rabbits to evaluate systemic toxicity in comparison to Nonoxynol-9.
Subject(s)
Anti-Infective Agents/pharmacology , Thiocarbamates/pharmacology , Thiourea/pharmacology , Vagina , Anti-Infective Agents/chemistry , Female , HIV/drug effects , HeLa Cells , Humans , Microbial Sensitivity Tests , Molecular Docking Simulation , Thiocarbamates/chemistry , Thiourea/chemistry , Trichomonas vaginalis/drug effectsABSTRACT
UC781, a very potent HIV-1 non-nucleoside reverse transcriptase inhibitor with extreme hydrophobicity and poor water solubility, is under development as a topical vaginal microbicide product to prevent HIV transmission. In this study, the thermodynamic behavior of the interaction between UC781 with three cyclodextrins (CDs): ß-cyclodextrin (ßCD), hydroxypropyl-ß-cyclodextrin (HPßCD) and methyl-ß-cyclodextrin (MßCD), was investigated using a reversed-phase HPLC method. A mobile phase consisting of acetonitrile: H2O (30:70) solution containing various CD concentrations was used. The retention time at different temperatures was determined to evaluate the inclusion process. The influence of ßCDs on the solubility and hydrophobicity of UC781 was characterized by retention time values. The results showed that the inclusion capacity of cyclodextrins follows the order MßCD > ßCD > HPßCD. An enthalpy-entropy compensation effect was also observed. In addition, the results revealed that the change of ΔH is greater than that of ΔS. These results suggested that the complexation of UC781 with ßCDs is an enthalpy driven process. The modification on ß-cyclodextrin will influence the inclusion process.