Anti-leishmanial effect of spiro dihydroquinoline-oxindoles on volume regulation decrease and sterol biosynthesis of Leishmania braziliensis

• Published in: Experimental parasitology Vol. 198; pp. 31 - 38
• Main Authors: Leañez, Jacques, Nuñez, Jorge, García-Marchan, Yael, Sojo, Felipe, Arvelo, Francisco, Rodriguez, Daniel, Buscema, Ignacio, Alvarez-Aular, Alvaro, Bello Forero, Josué S., Kouznetsov, Vladímir V., Serrano-Martín, Xenón
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.03.2019
• Subjects: chemotherapy; Leishmania braziliensis; parasite internal regulation; spiro dihydroquinoline-oxindoles; squalene epoxidase inhibitors; sterol pathway; Leishmania braziliensis; spiro dihydroquinoline-oxindoles; sterol pathway; chemotherapy; parasite internal regulation; squalene epoxidase inhibitors
• ISSN: 0014-4894; 1090-2449
• DOI: 10.1016/j.exppara.2019.01.011

Diverse spiro dihydroquinoline-oxindoles (JS series) were prepared using the BF3•OEt2-catalyzed imino Diels-Alder reaction between ketimine-isatin derivatives and trans-isoeugenol. Ten spiro-oxiindole derivatives were selected and evaluated at different stages of the life cycle of Leishmania braziliensis parasites, responsible for cutaneous leishmaniasis in South America. Among them, the 8′-ethyl-4‘-(4-hydroxy-3-methoxyphenyl)-3′-methyl-3′,4′-dihydro-1′H-spiro[indoline-3,2′-quinolin]-2-one called JS87 was able to inhibit the growth of promastigotes without affecting the mammalian cells viability, and to decrease the number of intracellular amastigotes of L. braziliensis. This spiro compound was found to act through the alteration of parasite internal regulation by disrupting the regulatory volume decrease (RVD), and to affect the sterol biosynthetic pathway at level of squalene epoxidase (SE) enzyme. These results revealed that the spiro annulation between quinoline and oxindole scaffolds enhances the anti-leishmanial activity, and could assist in the development of potent quinoline-oxindole hybrids against Leishmania braziliensis, the main etiological agent of cutaneous leishmaniasis in South America. [Display omitted] •Quinoline-oxindoles affects Leishmania braziliensis proliferation.•Spiro-quinolin alters parasite regulation, disrupting the regulatory volume decrease.•Quinoline-oxindoles affect the sterol biosynthesis in Leishmania braziliensis.•Spiro-quinolin is 90 times more effective on intracellular amastigotes than on BMDM.