Synthesis of Polycyclic Ether-Benzopyrans and In Vitro Inhibitory Activity against Leishmania tarentolae

• Published in: Molecules (Basel, Switzerland) Switzerland), 2020-11, Vol.25 (22), p.5461
• Main Authors: Singh, Sarita, Grabowski, Jacob P, Pohani, Shilpa, Apuzzo, C Fiore, Platt, David C, Jones, Marjorie A, Mitchell, T Andrew
• Format: Article
• Language: English
• Subjects: Acid phosphatase; Acid Phosphatase - metabolism; Acids; Alcohol; Aromatic compounds; benzopyran; Benzopyrans - chemical synthesis; Benzopyrans - chemistry; Benzopyrans - pharmacology; Bromides - chemistry; Catalysis; Cell Count; Chemical compounds; Construction; Cross coupling; Cycloaddition; Cycloaddition Reaction; Drug resistance; Drug therapy; Enzyme Assays; Ether - chemical synthesis; Ether - pharmacology; Infectivity; Leishmania; Leishmania - drug effects; Leishmania - enzymology; Leishmania - growth & development; Leishmania tarentolae; Leishmaniasis; Natural products; Neuroglia - drug effects; Neuroglia - metabolism; Nitric oxide; oxabicyclo[3.2.1]-octane; oxidopyrylium; Palladium - chemistry; Parasites; Parasitic diseases; Pharmacology; Polycyclic Compounds - chemical synthesis; Polycyclic Compounds - chemistry; Polycyclic Compounds - pharmacology; Protozoa; Side effects; Suzuki-Miyaura; Tropical diseases; Vector-borne diseases
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules25225461

Construction of a focused library of polycyclic ether-benzopyrans was undertaken in order to discover new therapeutic compounds that affect growth and infectivity. This is especially of interest since there are few drug therapies for leishmaniasis that do not have serious drawbacks such high cost, side effects, and emerging drug resistance. The construction of these polycyclic ether-benzopyrans utilized an acetoxypyranone-alkene [5+2] cycloaddition and the Suzuki-Miyaura cross-coupling. The multi-gram quantity of the requisite aryl bromide was obtained followed by effective Pd-catalyzed coupling with boronic acid derivatives. Compounds were tested in vitro using the parasitic protozoan, . Effects of concentration, time, and exposure to light were evaluated. In addition, the effects on secreted acid phosphatase activity and nitric oxide production were investigated, since both have been implicated in parasite infectivity. The data presented herein are indicative of disruption of the and thus provide impetus for the development and testing of a more extensive library.