Dual Antitubercular and Antileishmanial Profiles of Quinoxaline Di- N -Oxides Containing an Amino Acidic Side Chain

• Published in: Pharmaceuticals (Basel, Switzerland) Switzerland), 2024-04, Vol.17 (4), p.487
• Main Authors: González, Juan F, Dea-Ayuela, María-Auxiliadora, Huck, Lena, Orduña, José María, Bolás-Fernández, Francisco, de la Cuesta, Elena, Haseen, Nazia, Mohammed, Ashraf Ali, Menéndez, J Carlos
• Format: Article
• Language: English
• Subjects: antileishmanial; antitubercular; Chemotherapy; co-infections; drug design; Drugs; HIV; Human immunodeficiency virus; Infections; N-oxides; neglected tropical diseases; Parasites; Parasitic diseases; Toxicity; Tropical diseases; Tuberculosis
• ISSN: 1424-8247; 1424-8247
• DOI: 10.3390/ph17040487

We present a new category of quinoxaline di-N-oxides (QdNOs) containing amino acid side chains with dual antituberculosis and antileishmanial activity. These compounds were synthesized by combining a regioselective 2,5-piperazinedione opening and a Beirut reaction and were screened for their activity against and the promastigote and amastigote forms of representative species of the genus. Most QdNOs exhibited promising antitubercular activity with IC values ranging from 4.28 to 49.95 μM, comparable to clinically established drugs. Structure-activity relationship analysis emphasized the importance of substituents on the aromatic ring and the side chain. Antileishmanial tests showed that some selected compounds exhibited activity comparable to the positive control miltefosine against promastigotes of and . Notably, some compounds were found to be also more potent and less toxic than miltefosine in intracellular amastigote assays against . The compound showing the best dual antitubercular and leishmanicidal profile and a good selectivity index, , can be regarded as a hit compound that opens up new opportunities for the development of integrated therapies against co-infections.