ABSTRACT
We report the design (in silico ADMET criteria), synthesis, cytotoxicity studies (HepG-2 cells), and biological evaluation of 15 hydrazine/hydrazide quinoxaline 1,4-di-N-oxide derivatives against the 3D7 chloroquine sensitive strain and FCR-3 multidrug resistant strain of Plasmodium falciparum and Leishmania infantum (axenic amastigotes). Fourteen of derivatives are novel quinoxaline 1,4-di-N-oxide derivatives. Compounds 18 (3D7 IC50=1.40µM, FCR-3 IC50=2.56µM) and 19 (3D7 IC50=0.24µM, FCR-3 IC50=2.8µM) were identified as the most active against P. falciparum, and they were the least cytotoxic (CC50-values>241µM) and most selective (SI>86). None of the compounds tested against L. infantum were considered to be active. Additionally, the functional role of the hydrazine and hydrazide structures were studied in the quinoxaline 1,4-di-N-oxide system.
Subject(s)
Antiprotozoal Agents/chemistry , Antiprotozoal Agents/pharmacology , Hydrazines/chemistry , Hydrazines/pharmacology , Quinoxalines/chemistry , Quinoxalines/pharmacology , Humans , Leishmania infantum/drug effects , Leishmaniasis, Visceral/drug therapy , Malaria, Falciparum/drug therapy , Plasmodium falciparum/drug effects , Structure-Activity RelationshipABSTRACT
Malaria and leishmaniasis are two of the World's most important tropical parasitic diseases. Continuing with our efforts to identify new compounds active against malaria and leishmaniasis, twelve new 1,4-di-N-oxide quinoxaline derivatives were synthesized and evaluated for their in vitro antimalarial and antileishmanial activity against Plasmodium falciparum FCR-3 strain, Leishmania infantum and Leishmania amazonensis. Their toxicity against VERO cells (normal monkey kidney cells) was also assessed. The results obtained indicate that a cyclopentyl derivative had the best antiplasmodial activity (2.9 µM), while a cyclohexyl derivative (2.5 µM) showed the best activity against L. amazonensis, and a 3-chloropropyl derivative (0.7 µM) showed the best results against L. infantum. All these compounds also have a Cl substituent in the R7 position.
Subject(s)
Antiparasitic Agents/pharmacology , Leishmania/drug effects , Plasmodium/drug effects , Quinoxalines/pharmacology , Amides/chemistry , Animals , Antimalarials/chemistry , Antimalarials/pharmacology , Antimalarials/toxicity , Antiparasitic Agents/chemistry , Antiparasitic Agents/toxicity , Chlorocebus aethiops , Humans , Inhibitory Concentration 50 , Leishmania infantum/drug effects , Oxides/chemistry , Parasitic Sensitivity Tests , Plasmodium falciparum/drug effects , Quinoxalines/chemistry , Quinoxalines/toxicity , Structure-Activity Relationship , Vero CellsABSTRACT
Malaria and leishmaniasis are two of the World's most important tropical parasitic diseases. Thirteen new 2-cyano-3-(4-phenylpiperazine-1-carboxamido) quinoxaline 1,4-dioxide derivatives (CPCQs) were synthesized and evaluated for their in vitro antimalarial and antileishmanial activity against erythrocytic forms of Plasmodium falciparum and axenic forms of Leishmania infantum. Their toxicity against VERO cells (normal monkey kidney cells) was also assessed. None of the tested compounds was efficient against Plasmodium, but two of them showed good activity against Leishmania. Toxicity on VERO was correlated with leishmanicidal properties.
Subject(s)
Antiprotozoal Agents/pharmacology , Leishmania infantum/drug effects , Piperazines/pharmacology , Plasmodium falciparum/drug effects , Quinoxalines/pharmacology , Animals , Antiprotozoal Agents/chemical synthesis , Catalysis , Chlorocebus aethiops , Dimethylformamide/chemistry , Drug Evaluation, Preclinical , Ethylamines/chemistry , Inhibitory Concentration 50 , Piperazines/chemical synthesis , Quinoxalines/chemical synthesis , Solvents/chemistry , Structure-Activity Relationship , Vero CellsABSTRACT
Continuing with our efforts to identify new active compounds against malaria and leishmaniasis, 14 new 3-amino-1,4-di-N-oxide quinoxaline-2-carbonitrile derivatives were synthesized and evaluated for their in vitro antimalarial and antileishmanial activity against Plasmodium falciparum Colombian FCR-3 strain and Leishmania amazonensis strain MHOM/BR/76/LTB-012A. Further computational studies were carried out in order to analyze graphic SAR and ADME properties. The results obtained indicate that compounds with one halogenous group substituted in position 6 and 7 provide an efficient approach for further development of antimalarial and antileishmanial agents. In addition, interesting ADME properties were found.
Subject(s)
Antimalarials/chemistry , Leishmania mexicana/drug effects , Quinoxalines/chemistry , Salicylamides/chemistry , Sulfonamides/chemistry , Trypanocidal Agents/chemistry , Animals , Antimalarials/pharmacokinetics , Antimalarials/toxicity , Macrophages/drug effects , Macrophages/immunology , Mice , Plasmodium falciparum/drug effects , Salicylamides/pharmacokinetics , Salicylamides/toxicity , Structure-Activity Relationship , Sulfonamides/pharmacokinetics , Sulfonamides/toxicity , Trypanocidal Agents/pharmacokinetics , Trypanocidal Agents/toxicityABSTRACT
The increase in the prevalence of drug-resistant tuberculosis cases demonstrates the need of discovering new and promising compounds with antimycobacterial activity. As a continuation of our research and with the aim of identifying new antitubercular drugs candidates, a new series of quinoxaline 1,4-di-N-oxide derivatives containing isoniazid was synthesized and evaluated for in vitro anti-tuberculosis activity against Mycobacterium tuberculosis H37Rv strain. Moreover, various drug-like properties of new compounds were predicted. Taking into account the biological results and the promising drug-likeness profile of these compounds, make them valid leads for further experimental research.
