Publicaties

With our previously identified potent NNRTIs 25a and HBS-11c as leads, series of novel thiophene[3,2-d]pyrimidine and thiophene[2,3-d]pyrimidine derivatives were designed via molecular hybridization strategy. All the target compounds were evaluated for their anti-HIV-1 activity and cytotoxicity in MT-4 cells. Compounds 16a1 and 16b1 turned out to be the most potent inhibitors against WT and mutant HIV-1 strains (L100I, K103N, and E138K), with ...

Structural modifications at position 3 of the isothiazolo[4,3-b]pyridine scaffold afforded a new series of cyclin G-associated kinase (GAK) inhibitors. It was shown that the insertion of a carboxamide residue at position 3 of a phenyl or piperidinyl moiety generated potent GAK inhibitors with IC50 values in a low nanomolar range. This potent GAK binding affinity was rationalized by molecular modelling demonstrating that the carboxamide moiety ...

To yield potent HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs) with favorable drug-like properties, a series of novel diarylpyrimidine derivatives targeting the tolerant region I of the NNRTI binding pocket were designed, synthesized and biologically evaluated. The most active inhibitor 10c exhibited outstanding antiviral activity against most of the viral panel, being about 2-fold (wild-type, EC50 = 0.0021 μM), 1.7-fold (K103N, ...

Leucyl-tRNA synthetase (LeuRS) is a clinically validated target for the development of antimicrobials. This enzyme catalyzes the formation of charged tRNALeu molecules, an essential substrate for protein translation. In the first step of catalysis LeuRS activates leucine using ATP, forming a leucyl-adenylate intermediate. Bi-substrate inhibitors that mimic this chemically labile phosphoanhydride-linked nucleoside have proven to be potent ...

We present the design, synthesis and biological activity of novel N-substituted benzimidazole based acrylonitriles as potential tubulin polymerization inhibitors. Their synthesis was achieved using classical linear organic and microwave assisted techniques, starting from aromatic aldehydes and N-substituted-2-cyanomethylbenzimidazoles. All newly prepared compounds were tested for their antiproliferative activity in vitro on eight human cancer ...

Inspired by our previous efforts to improve the drug-resistance profiles of HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs), a novel series of “dual-site” binding diarylpyrimidine (DAPY) derivatives targeting both the NNRTI adjacent site and NNRTIs binding pocket (NNIBP) were designed, synthesized, and evaluated for their anti-HIV potency in TZM-bl and MT-4 cells. Eight compounds exhibited moderate to excellent potencies in ...

The naphthalene sulfonamide scaffold is known to possess CCR8 antagonistic properties. In order to expand the structure-activity relationship study of this compound class, a variety of palladium-catalyzed cross-coupling reactions was performed on a bromo-naphthalene precursor yielding a diverse library. These compounds displayed CCR8 antagonistic properties in binding and calcium mobilization assays, with IC50 values in the 0.2 - 10 µM range. ...

Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are widely used in combination therapies against HIV-1. However, emergent and transmitted drug resistance compromise their efficacy in the clinical setting. Y181C is selected in patients receiving nevirapine, etravirine and rilpivirine, and together with K103N is the most prevalent NNRTI-associated mutation in HIV-infected patients. Herein, we report on the design, synthesis and biological ...

In addition to its therapeutic value as a chemotherapy drug, gemcitabine is of ongoing interest to the scientific community for its broad-spectrum antiviral activity. Herein the synthesis of 4'-methoxy- and 4'-fluoro-substituted gemcitabine analogues along with their phosphoramidate prodrugs is described. Among these derivatives, 4'-fluorogemcitabine proved to be active against varicella zoster virus (VZV, TK+ strain) with an EC50 of 0.042 μM ...