title: A Parallel Synthesis Approach to the Identification of Novel Diheteroarylamide-Based Compounds Blocking HIV Replication: Potential Inhibitors of HIV-1 Pre-mRNA Alternative Splicing.
abstract: A 256-compound library was evaluated in an anti-HIV screen to identify structural "mimics" of the fused tetracyclic indole compound 1 (IDC16) that conserve its anti-HIV activity without associated cytotoxicity. Four diheteroarylamide-type compounds, containing a common 5-nitroisobenzothiazole motif, were identified as active. In subsequent screens, the most potent compound 9 (1C8) was active against wild-type HIV-1IIIB (subtype B, X4-tropic) and HIV-1 97USSN54 (subtype A, R5-tropic) with EC50's of 0.6 and 0.9 μM, respectively. Compound 9 also inhibited HIV strains resistant to drugs targeting HIV reverse transcriptase, protease, integrase, and coreceptor CCR5 with EC50's ranging from 0.9 to 1.5 μM. The CC50 value obtained in a cytotoxicity assay for compound 9 was >100 μM, corresponding to a therapeutic index (CC50/EC50) of approximately 100. Further comparison studies revealed that, whereas the anti-HIV activity for compound 9 and the parent molecule 1 are similar, the cytotoxic effect for compound 9 was, as planned, markedly suppressed.
authors.affiliation: British Columbia Centre for Excellence in HIV/AIDS , 608-1081 Burrard Street, Vancouver, British Columbia V6Z 1Y6, Canada.
authors.forename: Peter K
authors.initials: PK
authors.lastname: Cheung
authors.forename: David
authors.initials: D
authors.lastname: Horhant
authors.forename: Laura E
authors.initials: LE
authors.lastname: Bandy
authors.forename: Maryam
authors.initials: M
authors.lastname: Zamiri
authors.forename: Safwat M
authors.initials: SM
authors.lastname: Rabea
authors.forename: Stoyan K
authors.initials: SK
authors.lastname: Karagiosov
authors.forename: Mitra
authors.initials: M
authors.lastname: Matloobi
authors.forename: Steven
authors.initials: S
authors.lastname: McArthur
authors.affiliation: British Columbia Centre for Excellence in HIV/AIDS , 608-1081 Burrard Street, Vancouver, British Columbia V6Z 1Y6, Canada.
authors.forename: P Richard
authors.initials: PR
authors.lastname: Harrigan
authors.affiliation: Département de microbiologie et d'infectiologie, Faculté de médecine et des sciences de la santé, Université de Sherbrooke , 3201, rue Jean-Mignault, Sherbrooke, Québec J1E 4K8 Canada.
authors.forename: Benoit
authors.initials: B
authors.lastname: Chabot
authors.forename: David S
authors.initials: DS
authors.lastname: Grierson
mesh_terms: D017398:Alternative Splicing / Q000187:drug effects* / Q000235:genetics; D019380:Anti-HIV Agents / Q000737:chemistry / Q000494:pharmacology*; D052160:Benzothiazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D054303:HIV Reverse Transcriptase / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development*; D006801:Humans; D019426:Integrases / Q000378:metabolism; D015394:Molecular Structure; D010447:Peptide Hydrolases / Q000378:metabolism; D011728:Pyridones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D012322:RNA Precursors / Q000235:genetics / Q000378:metabolism*; D012367:RNA, Viral / Q000235:genetics / Q000378:metabolism*; D054380:Receptors, CXCR5 / Q000037:antagonists & inhibitors; D013329:Structure-Activity Relationship; D014779:Virus Replication / Q000187:drug effects*
chemical_list: C000609919:1-methyl-N-(5-nitrobenzo(d)isothiazol-3-yl)-4-oxo-1,4-dihydropyridine-3-carboxamide; D019380:Anti-HIV Agents; D052160:Benzothiazoles; D011728:Pyridones; D012322:RNA Precursors; D012367:RNA, Viral; D054380:Receptors, CXCR5; D019426:Integrases; D054303:HIV Reverse Transcriptase; D010447:Peptide Hydrolases