Structure-activity relationship studies of manzamine A: amidation of positions 6 and 8 of the beta-carboline moiety.
Twenty manzamine amides were synthesized and evaluated for in vitro antimalarial and antimicrobial activities. The amides of manzamine A (1) showed significantly reduced cytotoxicity against Vero cells, although were less active than 1. The structure-activity analysis showed that linear, short alkyl groups adjacent to the amide carbonyl at position 8 are favored for antimalarial activity, while bulky and cyclic groups at position 6 provided the most active amides. Most of the amides showed potent activity against Mycobacterium intracellulare. The antimicrobial activity profile for position 8 series was similar to that for antimalarial activity profile, in which linear, slightly short alkyl groups adjacent to the amide carbonyl showed improved activity. Two amides 14 and 21, which showed potent antimalarial activity in vitro against Plasmodium falciparum were further evaluated in vivo in Plasmodium berghei infected mice. Oral administration of 14 and 21 at the dose of 30mg/kg (once daily for three days) caused parasitemia suppression of 24% and 62%, respectively, with no apparent toxicity.
Wahba
Amir E
AE
Department of Pharmacognosy, The School of Pharmacy, The University of Mississippi, Oxford, MS 38677, USA.
Peng
Jiangnan
J
Kudrimoti
Sucheta
S
Tekwani
Babu L
BL
Hamann
Mark T
MT
D000284:Administration, Oral; D000577:Amides / Q000737:chemistry*; D000818:Animals; D000962:Antimalarials / Q000008:administration & dosage / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D002227:Carbazoles / Q000008:administration & dosage / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D002243:Carbolines / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D051379:Mice; D015269:Mycobacterium avium Complex / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism; D010962:Plasmodium berghei / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism; D010963:Plasmodium falciparum / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism; D013329:Structure-Activity Relationship
D000577:Amides; D000962:Antimalarials; D002227:Carbazoles; D002243:Carbolines; C078290:manzamine A