title: Bis-acridines as lead antiparasitic agents: structure-activity analysis of a discrete compound library in vitro.
abstract: Parasitic diseases are of enormous public health significance in developing countries-a situation compounded by the toxicity of and resistance to many current chemotherapeutics. We investigated a focused library of 18 structurally diverse bis-acridine compounds for in vitro bioactivity against seven protozoan and one helminth parasite species and compared the bioactivities and the cytotoxicities of these compounds toward various mammalian cell lines. Structure-activity relationships demonstrated the influence of both the bis-acridine linker structure and the terminal acridine heterocycle on potency and cytotoxicity. The bioactivity of polyamine-linked acridines required a minimum linker length of approximately 10 A. Increasing linker length resulted in bioactivity against most parasites but also cytotoxicity toward mammalian cells. N alkylation, but less so N acylation, of the polyamine linker ameliorated cytotoxicity while retaining bioactivity with 50% effective concentration (EC(50)) values similar to or better than those measured for standard drugs. Substitution of the polyamine for either an alkyl or a polyether linker maintained bioactivity and further alleviated cytotoxicity. Polyamine-linked compounds in which the terminal acridine heterocycle had been replaced with an aza-acridine also maintained acceptable therapeutic indices. The most potent compounds recorded low- to mid-nanomolar EC(50) values against Plasmodium falciparum and Trypanosoma brucei; otherwise, low-micromolar potencies were measured. Importantly, the bioactivity of the library was independent of P. falciparum resistance to chloroquine. Compound bioactivity was a function of neither the potential to bis-intercalate DNA nor the inhibition of trypanothione reductase, an important drug target in trypanosomatid parasites. Our approach illustrates the usefulness of screening focused compound libraries against multiple parasite targets. Some of the bis-acridines identified here may represent useful starting points for further lead optimization.
authors: Sandler Center for Basic Research in Parasitic Diseases, BH508, University of California, San Francisco, 1700 4th Street, San Francisco, CA 94158-2330, USA. caffrey@cgl.ucsf.edu
authors: Conor R
authors: CR
authors: Caffrey
authors: Dietmar
authors: D
authors: Steverding
authors: Ryan K
authors: RK
authors: Swenerton
authors: Ben
authors: B
authors: Kelly
authors: Deirdre
authors: D
authors: Walshe
authors: Anjan
authors: A
authors: Debnath
authors: Yuan-Min
authors: YM
authors: Zhou
authors: Patricia S
authors: PS
authors: Doyle
authors: Aaron T
authors: AT
authors: Fafarman
authors: Julie A
authors: JA
authors: Zorn
authors: Kirkwood M
authors: KM
authors: Land
authors: Jessica
authors: J
authors: Beauchene
authors: Kimberly
authors: K
authors: Schreiber
authors: Heidrun
authors: H
authors: Moll
authors: Alicia
authors: A
authors: Ponte-Sucre
authors: Tanja
authors: T
authors: Schirmeister
authors: Ahilan
authors: A
authors: Saravanamuthu
authors: Alan H
authors: AH
authors: Fairlamb
authors: Fred E
authors: FE
authors: Cohen
authors: James H
authors: JH
authors: McKerrow
authors: Jennifer L
authors: JL
authors: Weisman
authors: Barnaby C H
authors: BC
authors: May
mesh_terms: D000166:Acridines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D000818:Animals; D000977:Antiparasitic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D020650:Combinatorial Chemistry Techniques / Q000379:methods*; D056890:Eukaryota / Q000145:classification / Q000187:drug effects* / Q000254:growth & development; D018922:HL-60 Cells; D006801:Humans; D021261:Parasitic Sensitivity Tests; D010963:Plasmodium falciparum / Q000187:drug effects; D011073:Polyamines / Q000737:chemistry; D012550:Schistosoma mansoni / Q000187:drug effects* / Q000254:growth & development; D013329:Structure-Activity Relationship; D014346:Trypanosoma brucei brucei / Q000187:drug effects
chemical_list: D000166:Acridines; D000977:Antiparasitic Agents; D011073:Polyamines; C484811:bis-acridine