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Design, synthesis, in vitro and in vivo biological evaluation of pyranone-piperazine analogs as potent antileishmanial agents. 2021

Shachi Mishra, and Naveen Parmar, and Pragya Chandrakar, and Chandra Prakash Sharma, and Sajiya Parveen, and Ravi P Vats, and Anuradha Seth, and Atul Goel, and Susanta Kar
Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute, BS-10/1, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow, 226031, India.

The current therapeutic regimen for visceral leishmaniasis is inadequate and unsatisfactory due to toxic side effects, high cost and emergence of drug resistance. Alternative, safe and affordable antileishmanials are, therefore, urgently needed and toward these we synthesized a series of arylpiperazine substituted pyranone derivatives and screened them against both in vitro and in vivo model of visceral leishmaniasis. Among 22 synthesized compounds, 5a and 5g showed better activity against intracellular amastigotes with an IC50 of 11.07 μM and 15.3 μM, respectively. In the in vivo, 5a significantly reduced hepatic and splenic amastigotes burden in Balb/c mice model of visceral leishmaniasis. On a mechanistic node, we observed that 5a induced direct Leishmania killing via mitochondrial dysfunction like cytochrome c release and loss of membrane potential. Taken together, our results suggest that 5a is a promising lead for further development of antileishmanial drugs.

UI MeSH Term Description Entries
D007893 Leishmania donovani A parasitic hemoflagellate of the subgenus Leishmania leishmania that infects man and animals and causes visceral leishmaniasis (LEISHMANIASIS, VISCERAL). The sandfly genera Phlebotomus and Lutzomyia are the vectors. Leishmania (Leishmania) donovani,Leishmania leishmania donovani,Leishmania donovanus,Leishmania leishmania donovanus,donovani, Leishmania leishmania,donovanus, Leishmania,donovanus, Leishmania leishmania,leishmania donovanus, Leishmania
D011728 Pyridones Pyridine derivatives with one or more keto groups on the ring. Pyridinones
D002478 Cells, Cultured Cells propagated in vitro in special media conducive to their growth. Cultured cells are used to study developmental, morphologic, metabolic, physiologic, and genetic processes, among others. Cultured Cells,Cell, Cultured,Cultured Cell
D004305 Dose-Response Relationship, Drug The relationship between the dose of an administered drug and the response of the organism to the drug. Dose Response Relationship, Drug,Dose-Response Relationships, Drug,Drug Dose-Response Relationship,Drug Dose-Response Relationships,Relationship, Drug Dose-Response,Relationships, Drug Dose-Response
D000077489 Piperazine An anti-nematodal agent effective against the intestinal nematodes ASCARIS LUMBRICOIDES (roundworm) and ENTEROBIUS VERMICULARIS (pinworm, threadworm). It produces a neuromuscular block leading to flaccid muscle paralysis in susceptible worms, which are then dislodged from the gut and expelled in feces. 1,4-Diazacyclohexane,1,4-Piperazine,Piperazine Diacetate,Piperazine Dihydrochloride,Piperazine Hexahydrate,Piperazine Hydrate,Piperazine Hydrobromide,Piperazine Hydrochloride,Piperazine Monohydrochloride,Piperazine Phosphate,Piperazine Phosphate (1:1),Piperazine Phosphate Anhydrous,Piperazine Salt,Piperazine Sulfate,Piperazine Tartrate,Piperazine Tartrate (1:1), (R-(R*,R*))-isomer,Piperazine Tartrate, (R-(R*,R*))-isomer,Piperazinium Oleate,Pripsen,1,4 Diazacyclohexane,1,4 Piperazine
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D000981 Antiprotozoal Agents Substances that are destructive to protozoans. Schizonticides,Agents, Antiprotozoal
D013329 Structure-Activity Relationship The relationship between the chemical structure of a compound and its biological or pharmacological activity. Compounds are often classed together because they have structural characteristics in common including shape, size, stereochemical arrangement, and distribution of functional groups. Relationship, Structure-Activity,Relationships, Structure-Activity,Structure Activity Relationship,Structure-Activity Relationships
D015195 Drug Design The molecular designing of drugs for specific purposes (such as DNA-binding, enzyme inhibition, anti-cancer efficacy, etc.) based on knowledge of molecular properties such as activity of functional groups, molecular geometry, and electronic structure, and also on information cataloged on analogous molecules. Drug design is generally computer-assisted molecular modeling and does not include PHARMACOKINETICS, dosage analysis, or drug administration analysis. Computer-Aided Drug Design,Computerized Drug Design,Drug Modeling,Pharmaceutical Design,Computer Aided Drug Design,Computer-Aided Drug Designs,Computerized Drug Designs,Design, Pharmaceutical,Drug Design, Computer-Aided,Drug Design, Computerized,Drug Designs,Drug Modelings,Pharmaceutical Designs
D015394 Molecular Structure The location of the atoms, groups or ions relative to one another in a molecule, as well as the number, type and location of covalent bonds. Structure, Molecular,Molecular Structures,Structures, Molecular

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