Searching for novel scaffold of triazole non-nucleoside inhibitors of HIV-1 reverse transcriptase.
Azoles are a promising class of the new generation of HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs). From thousands of reported compounds, many possess the same basic structure of an aryl substituted azole ring linked by a thioglycolamide chain with another aromatic ring. In order to find novel extensions for this basic scaffold, we explored the 5-position substitution pattern of triazole NNRTIs using molecular docking followed by the synthesis of selected compounds. We found that heterocyclic substituents in the 5-position of the triazole ring are detrimental to the inhibitory activity of compounds with four-membered thioglycolamide linker and this substitution seems to be viable only for compounds with shorter two-membered linker. Promising compound, N-(4-carboxy-2-chlorophenyl)-2-((4-benzyl-5-methyl-4H-1,2,4-triazol-3-yl)sulfanyl)acetamide, with potent inhibitory activity and acceptable aqueous solubility has been identified in this study that could serve as lead scaffold for the development of novel water-soluble salts of triazole NNRTIs.
a Institute of Applied Radiation Chemistry, Lodz University of Technology , Lodz , Poland .
Tomasz
T
Frączek
a Institute of Applied Radiation Chemistry, Lodz University of Technology , Lodz , Poland .|b Department of Organic Chemistry , Faculty of Pharmacy, Medical University , Lublin , Poland , and.
Agata
A
Paneth
a Institute of Applied Radiation Chemistry, Lodz University of Technology , Lodz , Poland .
Rafał
R
Kamiński
a Institute of Applied Radiation Chemistry, Lodz University of Technology , Lodz , Poland .|c Department of Bioorganic Chemistry , Centre of Molecular and Macromolecular Studies, Polish Academy of Sciences , Lodz , Poland.
Agnieszka
A
Krakowiak
a Institute of Applied Radiation Chemistry, Lodz University of Technology , Lodz , Poland .
Piotr
P
Paneth
D004305:Dose-Response Relationship, Drug; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D020349:Surface Plasmon Resonance; D014230:Triazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*
D018894:Reverse Transcriptase Inhibitors; D014230:Triazoles; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase
Azoles; HAART; HIV reverse transcriptase; NNRTIs; triazoles