Hybrid chemistry. Part 4: Discovery of etravirine–VRX-480773 hybrids as potent HIV-1 non-nucleoside reverse transcriptase inhibitors
Graphical abstract
Introduction
The discovery of etravirine 1 (TMC125, Fig. 1) is a comprehensive result of the coordinated multidisciplinary endeavor lasting for more than 20 years of research on non-nucleoside reverse transcriptase inhibitors (NNRTIs).1 This promising NNRTI was approved by the FDA in 2008 for AIDS therapy owing to potency against both wild-type (WT) and mutant virus strains. Another clinical candidate NNRTI, VRX-480773 22 (Fig. 1) originated from high-throughput screening (HTS) of compound libraries as a second generation NNRTI, showed resilience to most NNRTI-resistant clinical HIV-1 isolates. However, there is still a great need for additional new chemical entities with improved affinity and efficacy profiles and higher genetic barriers to resistance.
The present work is an extension of our ongoing efforts toward developing effective NNRTIs through a hybrid pharmacophore approach3, 4, 5, and one that uses etravirine and VRX-480773 as a starting point. Our docking model of overlaying the lower-energy conformations of etravirine and VRX-480773 templates within the NNRTIs binding sites (NNIBS) reveals that most fragments in the structures can superpose well with each other (Fig. 2). They exhibit similar binding patterns with HIV-1 RT (Fig. 2). In this paper, a series of etravirine–VRX-480773 hybrids 3 (Fig. 3), characterized by a 2,6-dimethyl-4-cyanophenoxyl group, a central pyrimidine ring and thioacetanilide moieties, were synthesized and evaluated as novel NNRTIs. Preliminary structure-activity relationships (SARs) and molecular modeling for these hybrids are also discussed.
Section snippets
Chemistry
The synthetic route for the target compounds 3a–u is depicted in Scheme 1. Biaryl ether 5 was obtained by regioselective coupling of 2,6-dimethyl-4-cyanophenol to the 4-position of 2,4-dichloropyrimidine (4).6 Treatment of 2-chloropyrimidine 5 with thiourea yielded 2-mercaptopyrimidine 6.7 Further condensation with known intermediates α-bromoacetamide 7a–u8 created the desired target compounds with yields of 48–86%.
Biological activity
The newly synthesized etravirine–VRX-480773 hybrids were evaluated for their anti-HIV activity in MT-4 cell cultures infected with a WT HIV-1 strain (IIIB), a double mutant HIV-1 strain RES056 (K103N + Y181C) or an HIV-2 strain (ROD). The results were expressed as cytotoxicity (CC50), anti-HIV activity (EC50) and selective index (SI = CC50/EC50). The SI indicates the specificity of the antiviral effect. The results are illustrated in Table 1, and include those of the two FDA approved drugs,
Conclusion
Based on a structure-guided molecular hybridization approach, we designed and synthesized a novel series of etravirine–VRX-480773 hybrids as potent HIV-1 NNRTIs. These hybrids were assessed for their anti-HIV-1 activity in MT-4 cell cultures. Most compounds (except for compound 3a) exhibited significant potency against WT HIV-1 strain (IIIB) at micromolar concentrations (EC50 = 0.24–41 μM). Among them, compound 3d displayed the highest activity with an EC50 value of 0.24 μM and SI >1225. Taking full
Chemistry
Chemical reagents and solvents, purchased from commercial sources, were of analytical grade and were used without further purification. All air-sensitive reactions were run under a nitrogen atmosphere. All the reactions were monitored by TLC on pre-coated silica gel G plates at 254 nm under a UV lamp using ethyl acetate/hexane as eluent. Column chromatography separations were performed with silica gel (300–400 mesh). Melting points were measured on a SGW X-1 microscopic melting point apparatus. 1
Acknowledgements
This research was financially supported by National Natural Science Foundation of China under Grant No. 81172918, Shanghai Municipal Natural Science Foundation under Grant No. 13ZR1402200, Chinese National Science and Technology Major Project under Grant No. 2012ZX09103101-068 and Open Foundation of Key Laboratory of Natural Resources of Changbai Mountain & Functional Molecules (Yanbian University), Ministry of Education.
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