title: From ligand to complexes: inhibition of human immunodeficiency virus type 1 integrase by beta-diketo acid metal complexes.
abstract: beta-Diketo acid-containing compounds are a promising class of human immunodeficiency virus type 1 (HIV-1) integrase (IN) inhibitors. Starting from the hypothesis that these inhibitors are able to coordinate ions in solution before interacting on the active site, a series of potentiometric measurements have been performed to understand the coordination ability of the diketo acid pharmacophore toward the biologically relevant Mg(2+). Moreover, by using beta-diketo acid/ester as model ligands with a set of divalent metal ions (Mg, Mn, Ni, Co, Cu, and Zn), we obtained a series of complexes and tested them for anti-HIV-1 IN activity. Results demonstrate that the diketo acid functionality chelates divalent metal ions in solution, and complexes with metals in different stoichiometric ratios are isolated. We postulate that the diketo acids act as complexes in their active form. In particular, they predominantly form species such as Mg(2)L(2+) and Mg(2)L(2) (derived from diketo acids, H(2)L), and MgL(+) and MgL(2) (derived from diketo esters, HL) at physiological pH. Furthermore, the synthesized mono- and dimetallic complexes inhibited IN at a high nanomolar to low micromolar range, with metal dependency in the phenyl diketo acid series. Retrospective analysis suggests that the electronic properties of the aromatic framework influence the metal-chelating ability of the diketo acid system. Therefore, the difference in activities is related to the complexes they preferentially form in solution, and these findings are important for the design of a new generation of IN inhibitors.
authors.affiliation: Dipartimento Farmaco Chimico Tossicologico, Università di Sassari, Via Muroni 23/A, 07100 Sassari, Italy. mario.sechi@uniss.it
authors.forename: Mario
authors.initials: M
authors.lastname: Sechi
authors.forename: Alessia
authors.initials: A
authors.lastname: Bacchi
authors.forename: Mauro
authors.initials: M
authors.lastname: Carcelli
authors.forename: Carlotta
authors.initials: C
authors.lastname: Compari
authors.forename: Elenia
authors.initials: E
authors.lastname: Duce
authors.forename: Emilia
authors.initials: E
authors.lastname: Fisicaro
authors.forename: Dominga
authors.initials: D
authors.lastname: Rogolino
authors.forename: Paul
authors.initials: P
authors.lastname: Gates
authors.forename: Marco
authors.initials: M
authors.lastname: Derudas
authors.forename: Laith Q
authors.initials: LQ
authors.lastname: Al-Mawsawi
authors.forename: Nouri
authors.initials: N
authors.lastname: Neamati
mesh_terms: D002413:Cations, Divalent / Q000737:chemistry*; D002614:Chelating Agents / Q000138:chemical synthesis* / Q000737:chemistry; D003035:Cobalt / Q000737:chemistry; D003300:Copper / Q000737:chemistry; D018360:Crystallography, X-Ray; D019427:HIV Integrase / Q000737:chemistry*; D019428:HIV Integrase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D007651:Keto Acids / Q000138:chemical synthesis* / Q000737:chemistry; D008024:Ligands; D008274:Magnesium / Q000737:chemistry; D008345:Manganese / Q000737:chemistry; D009532:Nickel / Q000737:chemistry; D009942:Organometallic Compounds / Q000138:chemical synthesis* / Q000737:chemistry; D013237:Stereoisomerism; D015032:Zinc / Q000737:chemistry
chemical_list: D002413:Cations, Divalent; D002614:Chelating Agents; D019428:HIV Integrase Inhibitors; D007651:Keto Acids; D008024:Ligands; D009942:Organometallic Compounds; D003035:Cobalt; D008345:Manganese; D003300:Copper; D009532:Nickel; D019427:HIV Integrase; D008274:Magnesium; D015032:Zinc