Design and Synthesis of Novel Indole β-Diketo Acid Derivatives as HIV-1 Integrase Inhibitors

Abstract

Diketo acids such as S-1360 (1A) and L-731,988 (2) are potent and selective inhibitors of HIV-1 integrase (IN). A plethora of diketo acid-containing compounds have been claimed in patent literature without disclosing much biological activities and synthetic details (reviewed in Neamati, N. Exp. Opin. Ther. Pat. 2002, 12, 709-724). To establish a coherent structure-activity relationship among the substituted indole nucleus bearing a beta-diketo acid moiety, a series of substituted indole-beta-diketo acids (4a-f and 5a-e) were synthesized. All compounds tested showed anti-IN activity at low micromolar concentrations with varied selectivity against the strand transfer process. Three compounds, the indole-3-beta-diketo acids 5a and 5c, and the parent ester 9c, have shown an antiviral activity in cell-based assays. We further confirmed a keto-enolic structure in the 2,3-position of the diketo acid moiety of a representative compound (4c) using NMR and X-ray crystallographic analysis. Using this structure as a lead for all of our computational studies, we found that the title compounds extensively interact with the essential amino acids on the active site of IN.

An Integrated Biological Approach to Guide the Development of Metal-Chelating Inhibitors of Influenza Virus PA Endonuclease

“…Compound 7 was obtained from Sigma-Aldrich (St. Louis, MO). The procedures for chemical synthesis of 8-11 and 30-47 were reported elsewhere (Tomassini et al, 1994;Sechi et al, 2004Sechi et al, , 2005Sechi et al, , 2006Maurin et al, 2004;Zeng et al, 2008;Bacchi et al, 2008Bacchi et al, , 2011Reddy et al, 2011). Ribavirin (Virazole; ICN Pharmaceuticals, Costa Mesa, CA) and chloroquine diphosphate salt (Sigma-Aldrich) were included as reference compounds.…”

“…In this research, we investigated a series of DKAs (and DKAbioisosteric compounds) incorporating different chemical scaffolds that were synthesized as specific PAIs (1-6, Table 1) or were originally designed toward HIV IN (7-47, Tables 1 and 2) (Maurin et al, 2004;Sechi et al, 2004Sechi et al, , 2005Sechi et al, , 2006Bacchi et al, 2008Bacchi et al, , 2011Zeng et al, 2008;Reddy et al, 2011). Although these compounds contain relevant scaffolds for PAI development, information on their activity against PA-Nter is lacking.…”

Control of HIV Through the Inhibition of HIV-1 Integrase: A Medicinal Chemistry Perspective

“…Moreover, while a number of the indole derivatives exhibited potent in vitro activity, the majority displayed limited antiviral activity and the select few analogues displaying in vivo inhibition (e.g. 56 Figure 15) [112,120] were cytotoxic. In keeping with the indole DKAs, purine (57 & 58, Figure 16) 121 and pyrimidine (59 & 60) [122] analogues displayed potent in vitro activity, reduced in vivo activity and reduced strand-transfer selectivity.…”

Iodine-mediated one-pot synthesis of indoles and 3-dimethylaminoindoles via annulation of enaminones

“…5 For instance, tryptophan and serotonin are key molecules in the human diet and in neurotransmitters, 6 respectively, while indomethacin, vincristine, and pindolol are typical clinically used drugs. 7 In particular, 2-carboxyindoles are enzyme inhibitors, such as hyaluronidase, 8 tubuline polymerization, 9 HIV-1 integrase, 10 human cytosolic phospholipase A 2  11 and factor Xa. 12 In the case of 3-aminoindoles and cyclic-fused analogues, they have been found to be effective as anticancer, 13 antiplasmodial and cytotoxic agents.…”