Design, Synthesis, and Biological Evaluation of Novel 2H‐Pyran‐2‐one Derivatives as Potential HIV‐1 Reverse Transcriptase Inhibitors. Issue 1 (19th December 2014)

• Record Type: Journal Article
• Authors: Defant, Andrea; Mancini, Ines; Tomazzolli, Rossella; Balzarini, Jan
• Is Part Of: Archiv der Pharmazie. Volume 348:Issue 1(2015:Jan.)
• Page Start: 23
• Page End: 33
• Publication Date: 2014-12-19
• Subjects: Pharmaceutical chemistry -- Periodicals; Pharmacology -- Periodicals; 615.19
• DOI: 10.1002/ardp.201400235
• Languages: English
• ISSNs: 0365-6233

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <sec id="ardp201400235-sec-0001" sec-type="section"> <p>In search for more effective drugs against HIV infection acting as non‐nucleoside reverse transcriptase inhibitors (NNRTIs), a series of new molecules with hybrid structures based on the natural product (+)‐calanolide A and the synthetic molecule α‐APA, known as potent and selective inhibitors of this enzyme, were selected by docking calculations. A convergent synthetic strategy gave 21 compounds with a 2<italic>H</italic>‐pyran‐2‐one structural unit and bearing isosteric modifications, which were tested against HIV‐infected CEM cell cultures. Only compound <bold>6</bold> (4‐((2‐(1<italic>H</italic>‐indol‐3‐yl)ethyl)amino)‐6‐methyl‐2<italic>H</italic>‐pyran‐2‐one) displayed inhibitory activity (EC<sub>50</sub>: 25–50 µM). However, it was associated with a relatively high cytostatic effect on human T lymphocyte (CEM) cell cultures, not easily predictable, neither by the chemical structure nor by the computational approach. Although this drug design has failed in selecting a novel scaffold for NNRTIs, the results have driven the interest towards new potential antitumor molecules showing activity against L1210 murine leukemia and HeLa cervix carcinoma cells, among which compound <bold>21</bold> (6‐methyl‐4‐((2‐(naphthalen‐1‐yl)ethyl)sulfonyl)‐2<italic>H</italic>‐pyran‐2‐one) was the most effective (IC<sub>50</sub>: 0.95 and 2.9 µM, respectively).</p> </sec> </abstract>