Improved guanide compounds which bind the CXCR4 co-receptor and inhibit HIV-1 infection

Abstract

The G-protein coupled receptor CXCR4 is a co-receptor for HIV-1 infection and is involved in signaling cell migration and proliferation. In a previous study of non-peptide, guanide-based CXCR4-binding compounds, spermine and spermidine phenylguanides inhibited HIV-1 entry at low micromolar concentrations. Subsequently, crystal structures of CXCR4 were used to dock a series of naphthylguanide derivatives of the polyamines spermidine and spermine. Synthesis and evaluation of the naphthylguanide compounds identified our best compound, spermine tris-1-naphthylguanide, which bound CXCR4 with an IC50 of 40nM and inhibited the infection of TZM-bl cells with X4, but not R5, strains of HIV-1 with an IC50 of 50–100nM.

Multi-objective active machine learning rapidly improves structure–activity models and reveals new protein–protein interaction inhibitors

“…2 , compounds 7–9 ). For example, compound 7 is a close structural analog of KRH-1636 (EC 50 = 18 nM), 34 compound 8 contains a presumable CXCR4-binding guanidine moiety, 35 and compound 9 expresses a secondary amine pattern that is observed in structurally related potent CXCR4 antagonists. 32 The random forest SAR model rightfully lacked confidence regarding the activity of these inactive analogues, which suggests that they are valuable for improving the understanding of the SAR.…”

“…In fact, with their elongated shape and terminal aromatic rings, some of our hits seem to constitute hybrids of known CXCR4 ligands, suggesting that the model successfully generalized over the known SARs. We tested this hypothesis by investigating the reference compounds used for predicting the most potent thiourea compound 10 , and found that the model coupled this chemical structure with distinct types of CXCR4 antagonists, including diamines, 32 cyclam AMD3100 derivatives, 16 isothiourea 38 and guanidine-containing compounds 35 (Table S6 † ). The notable chemical similarity to known antagonists is attractive for model interpretation.…”

Antibacterial Activity of THAM Trisphenylguanide against Methicillin-Resistant Staphylococcus aureus

“…Some of these compounds were previously found to be effective as antagonists of CXCR4 and inhibited HIV infection by X4 strains [4], [5] and the formation of metastatic tumors [6]. The biguanide series of compounds are chemically related to some commercially important biocidal agents found in common household items such as disinfectants, mouthwashes, contact lens solutions, and cosmetics.…”

Exposure of Methicillin-Resistant Staphylococcus aureus to Low Levels of the Antibacterial THAM-3ΦG Generates a Small Colony Drug-Resistant Phenotype

“…The synthesis of THAM-3ΦG described previously 60 was modified to increase compound yields as follows: 1-BOC hexanediamine (1 equiv.) was initially treated with S-methyl-phenylisourea (1.1 equiv.…”

“…in water and refluxed at 120 °C to obtain THAM-3ΦG. THAM-3ΦG was purified by preparative reverse phase HPLC as previously reported (95% acetonitrile, 95% H 2 O, and 0.1% TFA) 60 . THAM-3ΦG stocks were prepared at 5.33 mg/mL in 50% acetonitrile and H 2 O.…”