A chemotype that inhibits three unrelated pathogenic targets: the botulinum neurotoxin serotype A light chain, P. falciparum malaria, and the Ebola filovirus.
A 1,7-bis(alkylamino)diazachrysene-based small molecule was previously identified as an inhibitor of the botulinum neurotoxin serotype A light chain metalloprotease. Subsequently, a variety of derivatives of this chemotype were synthesized to develop structure-activity relationships, and all are inhibitors of the BoNT/A LC. Three-dimensional analyses indicated that half of the originally discovered 1,7-DAAC structure superimposed well with 4-amino-7-chloroquinoline-based antimalarial agents. This observation led to the discovery that several of the 1,7-DAAC derivatives are potent in vitro inhibitors of Plasmodium falciparum and, in general, are more efficacious against CQ-resistant strains than against CQ-susceptible strains. In addition, by inhibiting β-hematin formation, the most efficacious 1,7-DAAC-based antimalarials employ a mechanism of action analogous to that of 4,7-ACQ-based antimalarials and are well tolerated by normal cells. One candidate was also effective when administered orally in a rodent-based malaria model. Finally, the 1,7-DAAC-based derivatives were examined for Ebola filovirus inhibition in an assay employing Vero76 cells, and three provided promising antiviral activities and acceptably low toxicities.
Faculty of Chemistry, University of Belgrade, Studentski trg 16, PO Box 51, 11158 Belgrade, Serbia.
Igor
I
Opsenica
James C
JC
Burnett
Rick
R
Gussio
Dejan
D
Opsenica
Nina
N
Todorović
Charlotte A
CA
Lanteri
Richard J
RJ
Sciotti
Montip
M
Gettayacamin
Nicoletta
N
Basilico
Donatella
D
Taramelli
Jonathan E
JE
Nuss
Laura
L
Wanner
Rekha G
RG
Panchal
Bogdan A
BA
Solaja
Sina
S
Bavari
D000818:Animals; D000852:Anopheles / Q000469:parasitology; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000962:Antimalarials / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D019274:Botulinum Toxins, Type A / Q000037:antagonists & inhibitors*; D002460:Cell Line; D002522:Chlorocebus aethiops; D002911:Chrysenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D029043:Ebolavirus / Q000187:drug effects*; D006420:Hemeproteins / Q000037:antagonists & inhibitors; D008288:Malaria / Q000188:drug therapy; D051379:Mice; D008958:Models, Molecular; D010962:Plasmodium berghei; D010963:Plasmodium falciparum / Q000187:drug effects*; D011804:Quinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000900:Anti-Bacterial Agents; D000962:Antimalarials; D000998:Antiviral Agents; D002911:Chrysenes; D006420:Hemeproteins; D011804:Quinolines; C020753:hemozoin; D019274:Botulinum Toxins, Type A
Nat Rev Drug Discov. 2009 Nov;8(11):879-91
19834482
Nature. 2007 Aug 9;448(7154):645-6
17687303
Malar J. 2010 Feb 11;9:51
20149249
FEBS Lett. 2002 Dec 18;532(3):423-6
12482605
Antimicrob Agents Chemother. 2008 Feb;52(2):684-93
17999964
N Engl J Med. 2002 Nov 28;347(22):1739-46
12456849
Nat Struct Biol. 2000 Aug;7(8):617-9
10932240
Virology. 2008 Mar 15;372(2):221-32
18063004
Infect Disord Drug Targets. 2007 Mar;7(1):47-57
17346211
Antimicrob Agents Chemother. 1979 Dec;16(6):710-8
394674
Arch Virol Suppl. 2008;20:13-360
18637412
Nature. 2009 May 14;459(7244):270-3
19357645
Nat Rev Microbiol. 2010 Apr;8(4):272-80
20208550
J Inorg Biochem. 2008 May-Jun;102(5-6):1288-99
18226838
J Med Chem. 2006 Jun 29;49(13):3790-9
16789736
J Clin Microbiol. 1981 Apr;13(4):791-3
7014628
Virology. 2005 Feb 5;332(1):20-7
15661137
Science. 2002 Oct 4;298(5591):74-5
12364772
Antimicrob Agents Chemother. 2009 Nov;53(11):4588-97
19704124
J Med Chem. 2000 Aug 24;43(17):3274-82
10966746
Trends Mol Med. 2003 Jul;9(7):291-9
12900216
Bioorg Med Chem. 2009 Sep 15;17(18):6560-6
19703776
Proc Natl Acad Sci U S A. 2005 Jul 12;102(28):9984-9
15985558
FEBS Lett. 1998 Sep 11;435(1):61-4
9755859
Biochemistry. 2009 Dec 1;48(47):11152-4
19883122
Bioorg Med Chem Lett. 2009 Dec 15;19(24):6970-4
19879133
J Protein Chem. 1995 Nov;14(8):703-8
8747431
J Med Chem. 2010 Jun 10;53(11):4555-9
20476788
J Med Chem. 2010 Jan 14;53(1):481-91
19924861
Malar J. 2009 Aug 10;8:192
19664280
J Med Chem. 2008 Aug 14;51(15):4388-91
18637666
Appl Environ Microbiol. 2003 Jan;69(1):297-303
12514008
J Appl Toxicol. 2003 May-Jun;23(3):139-70
12794937
J Med Chem. 2007 May 3;50(9):2127-36
17417831
Bioorg Med Chem Lett. 2009 Oct 1;19(19):5811-3
19703771
Recent Pat Antiinfect Drug Discov. 2007 Jun;2(2):95-114
18221166
J Med Chem. 2010 Jan 28;53(2):916-9
20088608
Antimicrob Agents Chemother. 2010 May;54(5):2152-9
20211898
Bioorg Med Chem. 2009 Dec 1;17(23):8032-9
19879150
Curr Top Med Chem. 2008;8(7):563-78
18473883
Proc Natl Acad Sci U S A. 2008 Jul 1;105(26):9059-64
18579783
JAMA. 2001 Feb 28;285(8):1059-70
11209178
Mutat Res. 2005 Sep 5;586(1):87-95
16087391
Antiviral Res. 2004 Sep;63(3):209-15
15451189
Nat Rev Drug Discov. 2005 Apr;4(4):281-97
15803193
J Biomol Screen. 2010 Aug;15(7):755-65
20639507
Antimicrob Agents Chemother. 1985 Apr;27(4):525-30
3890727
J Med Chem. 2008 Oct 9;51(19):6216-9
18774792
J Med Chem. 2010 May 27;53(10):4103-9
20443628
Bioorg Med Chem Lett. 2010 Feb 15;20(4):1347-51
20097070
Bioorg Med Chem Lett. 2009 Jan 15;19(2):481-4
19054674
Exp Parasitol. 2000 Dec;96(4):249-56
11162378
ChemMedChem. 2008 Dec;3(12):1905-12
19006141
Trends Biochem Sci. 2002 Nov;27(11):552-8
12417130
Bioorg Med Chem Lett. 2010 Feb 1;20(3):1078-80
20034790
J Protein Chem. 1997 Jan;16(1):19-26
9055204
J Med Chem. 2009 Jan 22;52(2):502-13
19113955
ChemMedChem. 2008 Nov;3(11):1649-53
18846586
J Infect Dis. 2007 Nov 15;196 Suppl 2:S142-7
17940942
Molecules. 2009 Aug 04;14(8):2868-87
19701131
J Biol Chem. 2007 Feb 16;282(7):5004-5014
17092934
Angew Chem Int Ed Engl. 2008;47(44):8360-79
18844202
Proc Natl Acad Sci U S A. 2008 Nov 11;105(45):17579-84
18987321
Antiviral Res. 2009 Sep;83(3):245-51
19523489
Proc Natl Acad Sci U S A. 2004 Mar 2;101(9):3242-7
14978283
Anal Biochem. 2001 Sep 1;296(1):130-7
11520041
J Biol Chem. 1994 Jan 21;269(3):1617-20
8294407
J Biol Chem. 2003 Jan 10;278(2):1363-71
12381720
Biochem Biophys Res Commun. 2003 Oct 10;310(1):84-93
14511652