Rational Design and Synthesis of Novel Dimeric Diketoacid-Containing Inhibitors of HIV-1 Integrase:  Implication for Binding to Two Metal Ions on the Active Site of Integrase

Abstract

Discovery of diketoacid-containing compounds as HIV-1 integrase (IN) inhibitors played a major role in validating this enzyme as an important target for the development of therapeutics against HIV infection. In fact, S-1360, the first clinically used IN inhibitor containing a triazole ring as a bioisostere of a carboxylic acid moiety belongs to this class of compounds. To understand the role of divalent metal-chelating in the inhibition of IN (J. Med. Chem. 2002, 45, 5661-5670), we designed and synthesized a series of novel dimeric diketo-containing compounds with the notion that such dimeric compounds may simultaneously bind to two divalent metal ions on the active site of IN. We rationalized that the two diketo subunits separated by uniquely designed linkers can potentially chelate two metal ions that are either provided from one IN active site or two active sites juxtaposed together in a higher order tetramer. Herein, we show that all the new compounds are highly potent against purified IN with varied selectivity for strand transfer, and that some of the analogues exert potent inhibition of the cytopathic effect of HIV-1 in infected CEM cells. This study represents the first attempt to rationally target two divalent metal ions on the active site of IN and may have potential implications for the design of second generation diketoacid-containing class of inhibitors.

Inhibition of Human Immunodeficiency Virus Type 1 Reverse Transcriptase, RNase H, and Integrase Activities by Hydroxytropolones

“…However, it is not completely clear whether these inhibitors bind one or two metal ions (19,23). Recently, a rationally designed IN inhibitor that can bind two Mg 2ϩ ions has been described (33).…”

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

“…This family of DNA-processing enzymes typically contain a canonical Asp, Asp, Glu motif, which in HIV-1 IN is formed by Asp-64, Asp-116 and Glu-152, with the two aspartic acid residues forming a coordination complex with a divalent metal [39][40][41][42]. Although it is well accepted that a metal co-factor is required for catalysis, to date no definitive conclusions have been reached regarding the type, Mg 2+ of Mn 2+ , or number of metal ions required [43,44]. However, it is generally accepted that Mg 2+ is a more likely cofactor given its one million-fold abundance over Mn 2+ in cells [45,46].…”

Microwave-assisted synthesis of 5-arylbenzofuran-2-carboxylates via Suzuki coupling using 2-quinolinealdoxime-Pd(II)-complex

“…Palladium-catalyzed Suzuki-Miyaura cross-coupling reaction of aryl halides with arylboronic acids, [1][2][3][4] is one of the most valuable synthetic routes for the preparation of symmetric and asymmetric biaryls, which are important skeletons in the structures of biologically active compounds, 5 agrochemicals, pharmaceuticals, [6][7][8] polymers, 9 ligands, 10 and functional materials. 11 The key advantages of the Suzuki-Miyaura cross-coupling are: (i) the mild conditions under which it is conducted, (ii) the high tolerance toward functional groups, (iii) the commercial availability and stability of boronic acids to heat, oxygen and water, and (iv) the ease of handling and separation of boron-containing byproducts from the reaction mixtures.…”