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.
Starting from 4‐chlorocoumarin‐3‐carbaldehyde (1) and Wittig phosphoranes 2a‐d the title compounds 6a‐c have been synthesized via a four‐step sequence. The intermediate 4‐alkylamino‐3‐vinylcoumarins 5a‐k have been prepared by the reaction of 4‐chloro‐3‐vinylcoumarins 3a‐d with primary amines 4a‐h. The coumarin derivatives 5 (except 5k) underwent an unusual pyridine ring closure under Vilsmeier conditions to form the benzopyrano[4,3‐b]pyridines 6. When the aminoaldehydes 7 were treated with the Wittig reagent 2b the fused N‐alkyl‐2(1H)‐pyridinones 8 have been obtained as expected.
The title compounds 5a‐c and 7a‐m have been prepared by Vilsmeier formylation of 4‐aminocoumarins 1 yielding aldehydes 2, and subsequent condensation of 2 with C‐H acids in the presence of piperidine. This condensation probably proceeds via the intermediate ylidenemalonic esters 4. By means of detailed 1H‐ and 13C‐NMR studies a Dimroth‐type rearrangement of intermediates 6f‐m has been found to take place in the course of the formation of products 7f‐m.
The direct synthesis of 4-(monoalkylamino)coumarins from primary amines [1] was developed on the basis of the reaction of 4-hydroxycoumarin with ammonium acetate in acetic acid as reported by Joshi et al. [2].[...]
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