Synthesis, antimalarial, antileishmanial, antimicrobial, cytotoxicity, and methemoglobin (MetHB) formation activities of new 8-quinolinamines.
We report the synthesis, in vitro antiprotozoal (against Plasmodium and Leishmania), antimicrobial, cytotoxicity (Vero and MetHb-producing properties), and in vivo antimalarial activities of two series of 8-quinolinamines. N1-{4-[2-(tert-Butyl)-6-methoxy-8-quinolylamino]pentyl}-(2S/2R)-2-aminosubstitutedamides (21-33) and N1-[4-(4-ethyl-6-methoxy-5-pentyloxy-8-quinolylamino)pentyl]-(2S/2R)-2-aminosubstitutedamides (51-63) were synthesized in six steps from 6-methoxy-8-nitroquinoline and 4-methoxy-2-nitro-5-pentyloxyaniline, respectively. Several analogs displayed promising antimalarial activity in vitro against Plasmodium falciparum D6 (chloroquine-sensitive) and W2 (chloroquine-resistant) clones with high selectivity indices versus mammalian cells. The most promising analogs (21-24) also displayed potent antimalarial activity in vivo in a Plasmodium berghei-infected mouse model. Most interestingly, many analogs exhibited promising in vitro antileishmanial activity against Leishmania donovani promastigotes, and antimicrobial activities against a panel of pathogenic bacteria and fungi. Several analogs, notably 21-24, 26-32, and 60, showed less MetHb formation compared to primaquine indicating the potential of these compounds in 8-quinolinamine-based antimalarial drug development.
Kaur
Kirandeep
K
Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research, Sector 67, S.A.S. Nagar, Punjab, India 160 062, India.
Patel
Sanjay R
SR
Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research, Sector 67, S.A.S. Nagar, Punjab, India 160 062, India.
Patil
Premanand
P
Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research, Sector 67, S.A.S. Nagar, Punjab, India 160 062, India.
Jain
Meenakshi
M
Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research, Sector 67, S.A.S. Nagar, Punjab, India 160 062, India.
Khan
Shabana I
SI
National Center for Natural Products Research, School of Pharmacy, University of Mississippi, MS 38677, USA.
Jacob
Melissa R
MR
National Center for Natural Products Research, School of Pharmacy, University of Mississippi, MS 38677, USA.
Tekwani
Babu L
BL
National Center for Natural Products Research, School of Pharmacy, University of Mississippi, MS 38677, USA.
Jain
Rahul
R
Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research, Sector 67, S.A.S. Nagar, Punjab, India 160 062, India.
D000634:Aminoquinolines / Q000138:chemical synthesis* / Q000494:pharmacology*; D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D000935:Antifungal Agents / Q000138:chemical synthesis / Q000494:pharmacology; D000962:Antimalarials / Q000138:chemical synthesis* / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D000977:Antiparasitic Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D001419:Bacteria / Q000187:drug effects; D002522:Chlorocebus aethiops; D004912:Erythrocytes / Q000187:drug effects / Q000378:metabolism / Q000469:parasitology; D005658:Fungi / Q000187:drug effects; D006801:Humans; D007202:Indicators and Reagents; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D007893:Leishmania donovani / Q000187:drug effects; D009682:Magnetic Resonance Spectroscopy; D008706:Methemoglobin / Q000378:metabolism*; D016106:Methicillin Resistance; D051379:Mice; D008826:Microbial Sensitivity Tests; D010962:Plasmodium berghei / Q000187:drug effects; D010963:Plasmodium falciparum / Q000187:drug effects; D013329:Structure-Activity Relationship; D014709:Vero Cells / Q000187:drug effects
D000634:Aminoquinolines; D000900:Anti-Bacterial Agents; D000935:Antifungal Agents; D000962:Antimalarials; D000970:Antineoplastic Agents; D000977:Antiparasitic Agents; D007202:Indicators and Reagents; D008706:Methemoglobin; D007770:L-Lactate Dehydrogenase; C080436:8-aminoquinoline