ChemInform Abstract: Synthesis and Biological Activity of N1‐Substituted‐3‐Methyl‐5‐pyrazolones and Related Compounds.

Hogale, M. B.; Pawar, B. N.

doi:10.1002/chin.199004143

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“…When the hydrazide moiety was restricted in a pyrazolone structure, the anti-HIV-1 integrase activity was essentially dependent on the presence of the 2-hydroxyphenyl group (Table 4). All the compounds containing at least one hydroxyl group 9,10 (29-38) were potent inhibitors with IC 50 values for 3′-processing and strand transfer below 3 µM. Substitution of the ancillary phenyl group did not affect the potency.…”

Section: Resultsmentioning

confidence: 99%

Salicylhydrazine-Containing Inhibitors of HIV-1 Integrase: Implication for a Selective Chelation in the Integrase Active Site

et al. 1998

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In previous studies we identified N,N'-bis(salicylhydrazine) (1) as a lead compound against purified recombinant HIV-1 integrase. We have now expanded upon these earlier observations and tested 45 novel hydrazides. Among the compounds tested, 11 derivatives exhibited 50% inhibitory concentrations (IC50) of less than 3 microM. A common feature for activity among these inhibitors is the hydroxyl group of the salicyl moiety. Although the active inhibitors must contain this hydroxyl group, other structural modifications can also influence potency. Removal of this hydroxyl group or replacement with an amino, bromo, fluoro, carboxylic acid, or ethyl ether totally abolished potency against integrase. Several asymmetric structures exhibited similar potency to the symmetric lead inhibitor 1. The superimposition of the lowest-energy conformations upon one another revealed three sites whose properties appear important for ligand binding. Site A is composed of the 2-hydroxyphenyl, the alpha-keto, and the hydrazine moieties in a planar conformation. We propose that this site could interact with HIV-1 integrase by chelation of the metal in the integrase active site as inhibition of HIV-1 integrase catalytic activity and DNA binding were strictly Mn2+-dependent. The hydrophobic sites B and C are probably responsible for complementarity of molecular shape between ligand and receptor. Our data indicate that only those compounds which possessed sites A, B, and C in a linear orientation were potent inhibitors of HIV-1 integrase. Although all the active inhibitors possessed considerable cytotoxicity and no apparent antiviral activity in CEM cells, the study presents useful information regarding ligand interaction with HIV-1 integrase protein.

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Section: Resultsmentioning

confidence: 99%

Salicylhydrazine-Containing Inhibitors of HIV-1 Integrase: Implication for a Selective Chelation in the Integrase Active Site

et al. 1998

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ChemInform Abstract: Synthesis and Biological Activity of N1‐Substituted‐3‐Methyl‐5‐pyrazolones and Related Compounds.

Abstract: The pyrazolones (II), prepared by cyclization of the hydrazones (I), are coupled with the aldehydes (III) to produce the benzylidenepyrazolones (IV).

Cited by 1 publication

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Salicylhydrazine-Containing Inhibitors of HIV-1 Integrase: Implication for a Selective Chelation in the Integrase Active Site

Salicylhydrazine-Containing Inhibitors of HIV-1 Integrase: Implication for a Selective Chelation in the Integrase Active Site

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