Design, synthesis and biological evaluation of a series of thioamides as non-nucleoside reverse transcriptase inhibitors.
A series of thioamides were designed as bio-isosteres to the non-nucleoside reverse transcriptase inhibitor trovirdine by replacement of the thiourea NH groups with methylene groups. Eight thioamides were synthesized and in vitro tested for inhibitory effects on the activity of HIV-1 reverse transcriptase wild and mutant types. Three of the 8-thioamides exhibited enzyme inhibitory activities with IC(50) values below 100 microM. While compound (2) exhibited activity against the mutant strain L100I with IC(50) of 70.1 microM, compound (4) showed activity against the mutant strain K103N with IC(50) of 92.7 microM, and compound (8) with activity against the wild type enzyme with IC(50) of 8.9 microM. Each of the three thioamides could serve as a lead compound for further activity optimization.
Department of Pharmaceutical Sciences, Massachusetts College of Pharmacy & Health Sciences, 179 Longwood Avenue, Boston, Massachusetts 02115, USA. ahmed.mehanna@mcphs.edu
Ahmed S
AS
Mehanna
Jitendra D
JD
Belani
Charles J
CJ
Kelley
Luke A
LA
Pallansc
D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D015195:Drug Design; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors*; D020128:Inhibitory Concentration 50; D009154:Mutation; D011725:Pyridines; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013854:Thioamides / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use
D019380:Anti-HIV Agents; D011725:Pyridines; D018894:Reverse Transcriptase Inhibitors; D013854:Thioamides; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase; C095511:trovirdine