Design of HIV-1 integrase inhibitors targeting the catalytic domain as well as its interaction with LEDGF/p75: A scaffold hopping approach using salicylate and catechol groups

• Published in: Bioorganic & medicinal chemistry Vol. 19; no. 16; pp. 4935 - 4952
• Main Authors: Fan, Xing, Zhang, Feng-Hua, Al-Safi, Rasha I., Zeng, Li-Fan, Shabaik, Yumna, Debnath, Bikash, Sanchez, Tino W., Odde, Srinivas, Neamati, Nouri, Long, Ya-Qiu
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 15.08.2011; Elsevier
• Subjects: 2,3-Dihydroxybenzamide; 3′-Process; active sites; Adaptor Proteins, Signal Transducing - analysis; Adaptor Proteins, Signal Transducing - antagonists & inhibitors; Adaptor Proteins, Signal Transducing - drug effects; Adaptor Proteins, Signal Transducing - metabolism; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; Antiviral Agents - chemistry; Antiviral Agents - pharmacology; binding sites; Biological and medical sciences; Catalytic Domain - drug effects; Catalytic Domain - genetics; Catechol; Catechols - chemical synthesis; Catechols - chemistry; Cell Line, Tumor; Chelation; Cofactors; Drug Design; Drug development; Drug Resistance, Multiple, Viral; Drug Screening Assays, Antitumor; HIV Integrase Inhibitors - chemical synthesis; HIV Integrase Inhibitors - chemistry; HIV Integrase Inhibitors - pharmacology; HIV-1 - drug effects; HIV-1 - genetics; HIV-1 integrase inhibitors; Human immunodeficiency virus 1; Humans; inhibitory concentration 50; Integrase; Integration; Ions; LEDGF/p75; mechanism of action; Medical sciences; metal ions; Metals; Metals - chemistry; Models, Molecular; Molecular modelling; Molecular Structure; Molecular Targeted Therapy; pharmacology; Pharmacology. Drug treatments; pharmacophores; Receptor, Nerve Growth Factor - analysis; Receptor, Nerve Growth Factor - antagonists & inhibitors; Receptor, Nerve Growth Factor - drug effects; Receptor, Nerve Growth Factor - metabolism; Salicylates - chemical synthesis; Salicylates - chemistry; Salicylic acid; scaffolds; Strand transfer; Transcription Factors - analysis; Transcription Factors - antagonists & inhibitors; Transcription Factors - drug effects; Transcription Factors - metabolism; 3′-Process; Chelation; LEDGF/p75; Strand transfer; HIV-1 integrase inhibitors; 2,3-Dihydroxybenzamide; Cyclohexane derivatives; HIV-1 virus; Phenolic acid; Lens epithelium derived growth factor; Molecular interaction; Integrase inhibitor; Structure activity relation; Molecular model; Binding mode; Antiviral; Inhibition; Mechanism of action; Chemical synthesis; Sulfonamide; Enzyme; Transferases; Benzene derivatives; Retroviridae; Enzyme inhibitor; Virus replication cycle; Lentivirus; In vitro; Virus; Biological fixation; Nucleotidyltransferases; Carboxamide; Human immunodeficiency virus; 3'-Process
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2011.06.058

HIV-1 integrase (IN) is a validated therapeutic target for antiviral drug design. However, the emergence of viral strains resistant to clinically studied IN inhibitors demands the discovery of novel inhibitors that are structurally as well mechanistically different. Herein, we describe the design and discovery of novel IN inhibitors targeting the catalytic domain as well as its interaction with LEDGF/p75, which is essential for the HIV-1 integration as an IN cofactor. By merging the pharmacophores of salicylate and catechol, the 2,3-dihydroxybenzamide (5a) was identified as a new scaffold to inhibit the strand transfer reaction efficiently. Further structural modifications on the 2,3-dihydroxybenzamide scaffold revealed that the heteroaromatic functionality attached on the carboxamide portion and the piperidin-1-ylsulfonyl substituted at the phenyl ring are beneficial for the activity, resulting in a low micromolar IN inhibitor (5p, IC50=5μM) with more than 40-fold selectivity for the strand transfer over the 3′-processing reaction. More significantly, this active scaffold remarkably inhibited the interaction between IN and LEDGF/p75 cofactor. The prototype example, N-(cyclohexylmethyl)-2,3-dihydroxy-5-(piperidin-1-ylsulfonyl) benzamide (5u) inhibited the IN-LEDGF/p75 interaction with an IC50 value of 8μM. Using molecular modeling, the mechanism of action was hypothesized to involve the chelation of the divalent metal ions inside the IN active site. Furthermore, the inhibitor of IN-LEDGF/p75 interaction was properly bound to the LEDGF/p75 binding site on IN. This work provides a new and efficient approach to evolve novel HIV-1 IN inhibitors from rational integration and optimization of previously reported inhibitors.