Pentacyclic ingamine alkaloids, a new antiplasmodial pharmacophore from the marine sponge Petrosid Ng5 Sp5.
Two new pentacyclic ingamine alkaloids, namely 22(S)-hydroxyingamine A (2) and dihydroingenamine D (3), together with the known ingamine A (1), have been isolated from marine sponge Petrosid Ng5 Sp5 (family Petrosiidae) obtained from the open repository of the National Cancer Institute, USA. The structures of compounds 1-3 were determined using 1D and 2D NMR, and HRESIMS techniques. The absolute configuration of both the C9 and C22 of 2 was determined as (S) using a modified Mosher esterification method. Compounds 1 and 3 showed strong antiplasmodial activity against chloroquine-sensitive (D6) and -resistant (W2) strains of Plasmodium falciparum with IC₅₀ values of 90 and 78 ng/mL and 72 and 57 ng/mL, respectively, while 2 was found to be less active (IC₅₀ values of 200 and 140 ng/mL, respectively). Compounds 1-3 were found to be devoid of in vitro cytotoxicity against human solid tumor cells of breast (BT-549), ovary (SK-OV-3), and epidermoid (KB) carcinomas and skin melanoma (SK-MEL), as well as against noncancerous monkey kidney fibroblasts (VERO) and pig kidney epithelial (LLC-PK₁₁) cells, up to a maximum concentration of 10 µg/mL. Compounds 1-3 also displayed weak antimicrobial and moderate antileishmanial activities against Leishmania donovani promastigotes. These polycyclic ingamine alkaloids represent the first example of antiplasmodial leads without a β-carboline ring, which is known to be responsible for the cytotoxicity of the well-known manzamine class of marine alkaloids related to 1-3.
National Center for Natural Products Research, School of Pharmacy, Research Institute of Pharmaceutical Sciences, The University of Mississippi, University, MS, USA. milias@olemiss.edu
Muhammad
M
Ilias
Mohamed A
MA
Ibrahim
Shabana I
SI
Khan
Melissa R
MR
Jacob
Babu L
BL
Tekwani
Larry A
LA
Walker
Vladimir
V
Samoylenko
D000470:Alkaloids / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D000818:Animals; D000871:Anthelmintics / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D000890:Anti-Infective Agents / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D000962:Antimalarials / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D002457:Cell Extracts / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002522:Chlorocebus aethiops; D003455:Cryptococcus neoformans / Q000187:drug effects; D005260:Female; D006576:Heterocyclic Compounds, 4 or More Rings / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D006801:Humans; D007893:Leishmania donovani / Q000187:drug effects; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects; D008958:Models, Molecular; D015394:Molecular Structure; D015269:Mycobacterium avium Complex / Q000187:drug effects; D010963:Plasmodium falciparum / Q000187:drug effects; D011161:Porifera / Q000737:chemistry*; D014709:Vero Cells
C579704:22(S)-hydroxyingamine A; D000470:Alkaloids; D000871:Anthelmintics; D000890:Anti-Infective Agents; D000962:Antimalarials; D000972:Antineoplastic Agents, Phytogenic; D002457:Cell Extracts; D006576:Heterocyclic Compounds, 4 or More Rings; C579705:dihydroingenamine D