The Experts below are selected from a list of 219 Experts worldwide ranked by ideXlab platform
Christophe Pannecouque - One of the best experts on this subject based on the ideXlab platform.
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Molecular Hybridization inspired optimization of diarylbenzopyrimidines as hiv 1 nonnucleoside reverse transcriptase inhibitors with improved activity against k103n and e138k mutants and pharmacokinetic profiles
ACS Infectious Diseases, 2020Co-Authors: Sheng Han, Erik De Clercq, Christophe Pannecouque, Chunlin Zhuang, Yali Sang, Yuan Tao, Fener ChenAbstract:Molecular Hybridization is a powerful strategy in drug discovery. A series of novel diarylbenzopyrimidine (DABP) analogues were developed by the Hybridization of FDA-approved drugs etravirine (ETR) and efavirenz (EFV) as potential HIV-1 nonnucleoside reverse transcriptase inhibitors (NNRTIs). Substituent modifications resulted in the identification of new DABPs with the combination of the strengths of the two drugs, especially compound 12d, which showed promising activity toward the EFV-resistant K103N mutant. 12d also had a favorable pharmacokinetic (PK) profile with liver microsome clearances of 14.4 μL/min/mg (human) and 33.2 μL/min/mg (rat) and an oral bioavailability of 15.5% in rat. However, its activity against the E138K mutant was still unsatisfactory; E138K is the most prevalent NNRTI resistance-associated mutant in ETR treatment. Further optimizations resulted in a highly potent compound (12z) with no substituents on the phenyl ring and a 2-methyl-6-nitro substitution pattern on the 4-cyanovinyl-2,6-disubstitued phenyl motif. The antiviral activity of this compound was much higher than those of ETR and EFV against the WT, E138K, and K103N variants (EC50 = 3.4, 4.3, and 3.6 nM, respectively), and the cytotoxicity was decreased while the selectivity index (SI) was increased. In particular, this compound exhibited acceptable intrinsic liver microsome stability (human, 34.5 μL/min/mg; rat, 33.2 μL/min/mg) and maintained the good PK profile of its parent compound EFV and showed an oral bioavailability of 16.5% in rat. Molecular docking and structure-activity relationship (SAR) analysis provided further insights into the binding of the DABPs with HIV-1 reverse transcriptase and provided a deeper understanding of the key structural features responsible for their interactions.
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design of biphenyl substituted diarylpyrimidines with a cyanomethyl linker as hiv 1 nnrtis via a Molecular Hybridization strategy
Molecules, 2020Co-Authors: Yuan Lei, Erik De Clercq, Christophe Pannecouque, Sheng Han, Yang Yang, Chunlin Zhuang, Fener ChenAbstract:The key problems of human immunodeficiency virus (HIV) therapy are the rapid emergence of drug-resistant mutant strains and significant cumulative drug toxicities. Therefore, there is an urgent demand for new anti-HIV agents with low toxicity and broad-spectrum antiviral potency. A series of biphenyl-substituted diarylpyrimidines with a cyanomethyl linker were designed using a Molecular Hybridization strategy. The cell-based anti-HIV assay showed that most of the compounds exhibited moderate to good activities against wild-type HIV-1 and clinically relevant mutant strains with a more favorable toxicity, and the enzymatic assay showed they had nanomolar activity against reverse transcriptase (RT). Compound 10p exhibited the best activity against wild-type HIV-1 with an EC50 (50% HIV-1 replication inhibitory concentration) value of 0.027 µM, an acceptable CC50 (50% cytotoxic concentration) value of 36.4 µM, and selectivity index of 1361, with moderate activities against the single mutants (EC50: E138K, 0.17 µM; Y181C, 0.87 µM; K103N, 0.9 µM; L100I, 1.21 µM, respectively), and an IC50 value of 0.059 µM against the RT enzyme, which was six-fold higher than nevirapine (NVP). The preliminary structure-activity relationship (SAR) of these new compounds was concluded. The Molecular modeling predicted the binding modes of the new compounds with RT, providing Molecular insight for further drug design.
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discovery of novel dapy ias hybrid derivatives as potential hiv 1 inhibitors using Molecular Hybridization based on crystallographic overlays
Bioorganic & Medicinal Chemistry, 2017Co-Authors: Boshi Huang, Erik De Clercq, Christophe Pannecouque, Huiqing Liu, Xueshun Wang, Xinhao Liu, Zihui Chen, Songkai Sun, Dirk Daelemans, Peng ZhanAbstract:Crystallographic overlap studies and pharmacophoric analysis indicated that diarylpyrimidine (DAPY)-based HIV-1 NNRTIs showed a similar binding mode and pharmacophoric features as indolylarylsulfones (IASs), another class of potent NNRTIs. Thus, a novel series of DAPY-IAS hybrid derivatives were identified as newer NNRTIs using structure-based Molecular Hybridization. Some target compounds exhibited moderate activities against HIV-1 IIIB strain, among which the two most potent inhibitors possessed EC50 values of 1.48μM and 1.61μM, respectively. They were much potent than the reference drug ddI (EC50=76.0μM) and comparable to 3TC (EC50=2.54μM). Compound 7a also exhibited the favorable selectivity index (SI=80). Preliminary structure-activity relationships (SARs), structure-cytotoxicity relationships, Molecular modeling studies, and in silico calculation of physicochemical properties of these new inhibitors were also discussed.
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discovery of uracil bearing dapys derivatives as novel hiv 1 nnrtis via crystallographic overlay based Molecular Hybridization
European Journal of Medicinal Chemistry, 2017Co-Authors: Heng Zhang, Peng Zhan, Erik De Clercq, Christophe Pannecouque, Zhongxia Zhou, Huiqing Liu, Ye Tian, Dongwei Kang, Zhipeng Huo, Xinyong LiuAbstract:A novel series of uracil-bearing DAPYs derivatives were designed and synthesized via structure-based Molecular Hybridization to discover compounds with improved anti-resistance profiles. Anti-HIV activity of the designed compounds was tested in MT-4 cell cultures. The most promising compound 16d showed excellent activity with EC50 value of 5.6 nM against wide-type HIV-1 and low cytotoxicity (SI > 50000). Activity against the clinic prevalent mutant strains was also tested, suggesting that 16d was sensitive to E138K (EC50 = 34.2 nM). Primary drug-like properties, such as water solubility and logP, were evaluated by experiment or calculation, which indicated that introducing an uracil can improve solubility. The Molecular modeling accompanied with the preliminary SAR correlations paved the way for the next round of rational design of potent anti-HIV agents.
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hybrid chemistry part 4 discovery of etravirine vrx 480773 hybrids as potent hiv 1 non nucleoside reverse transcriptase inhibitors
Bioorganic & Medicinal Chemistry, 2015Co-Authors: Yafeng Wang, Erik De Clercq, Dirk Daelemans, Fener Chen, Huri Piao, Christophe PannecouqueAbstract:Abstract A novel series of etravirine–VRX-480773 hybrids were designed using structure-guided Molecular Hybridization strategy and fusing the pharmacophore templates of etravirine and VRX-480773. The anti-HIV-1 activity and cytotoxicity was evaluated in MT-4 cell cultures. The most active hybrid compound in this series, N-(2-chlorophenyl)-2-((4-(4-cyano-2,6-dimethylphenoxy)pyrimidin-2-yl)thio)acetamide 3d (EC50 = 0.24 , SI >1225), was more potent than delavirdine (EC50 = 0.66 μM, SI >67) in the anti-HIV-1 in vitro cellular assay. Studies of structure-activity relationships established a correlation between anti-HIV activity and the substitution pattern of the acetanilide group.
Erik De Clercq - One of the best experts on this subject based on the ideXlab platform.
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Molecular Hybridization inspired optimization of diarylbenzopyrimidines as hiv 1 nonnucleoside reverse transcriptase inhibitors with improved activity against k103n and e138k mutants and pharmacokinetic profiles
ACS Infectious Diseases, 2020Co-Authors: Sheng Han, Erik De Clercq, Christophe Pannecouque, Chunlin Zhuang, Yali Sang, Yuan Tao, Fener ChenAbstract:Molecular Hybridization is a powerful strategy in drug discovery. A series of novel diarylbenzopyrimidine (DABP) analogues were developed by the Hybridization of FDA-approved drugs etravirine (ETR) and efavirenz (EFV) as potential HIV-1 nonnucleoside reverse transcriptase inhibitors (NNRTIs). Substituent modifications resulted in the identification of new DABPs with the combination of the strengths of the two drugs, especially compound 12d, which showed promising activity toward the EFV-resistant K103N mutant. 12d also had a favorable pharmacokinetic (PK) profile with liver microsome clearances of 14.4 μL/min/mg (human) and 33.2 μL/min/mg (rat) and an oral bioavailability of 15.5% in rat. However, its activity against the E138K mutant was still unsatisfactory; E138K is the most prevalent NNRTI resistance-associated mutant in ETR treatment. Further optimizations resulted in a highly potent compound (12z) with no substituents on the phenyl ring and a 2-methyl-6-nitro substitution pattern on the 4-cyanovinyl-2,6-disubstitued phenyl motif. The antiviral activity of this compound was much higher than those of ETR and EFV against the WT, E138K, and K103N variants (EC50 = 3.4, 4.3, and 3.6 nM, respectively), and the cytotoxicity was decreased while the selectivity index (SI) was increased. In particular, this compound exhibited acceptable intrinsic liver microsome stability (human, 34.5 μL/min/mg; rat, 33.2 μL/min/mg) and maintained the good PK profile of its parent compound EFV and showed an oral bioavailability of 16.5% in rat. Molecular docking and structure-activity relationship (SAR) analysis provided further insights into the binding of the DABPs with HIV-1 reverse transcriptase and provided a deeper understanding of the key structural features responsible for their interactions.
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design of biphenyl substituted diarylpyrimidines with a cyanomethyl linker as hiv 1 nnrtis via a Molecular Hybridization strategy
Molecules, 2020Co-Authors: Yuan Lei, Erik De Clercq, Christophe Pannecouque, Sheng Han, Yang Yang, Chunlin Zhuang, Fener ChenAbstract:The key problems of human immunodeficiency virus (HIV) therapy are the rapid emergence of drug-resistant mutant strains and significant cumulative drug toxicities. Therefore, there is an urgent demand for new anti-HIV agents with low toxicity and broad-spectrum antiviral potency. A series of biphenyl-substituted diarylpyrimidines with a cyanomethyl linker were designed using a Molecular Hybridization strategy. The cell-based anti-HIV assay showed that most of the compounds exhibited moderate to good activities against wild-type HIV-1 and clinically relevant mutant strains with a more favorable toxicity, and the enzymatic assay showed they had nanomolar activity against reverse transcriptase (RT). Compound 10p exhibited the best activity against wild-type HIV-1 with an EC50 (50% HIV-1 replication inhibitory concentration) value of 0.027 µM, an acceptable CC50 (50% cytotoxic concentration) value of 36.4 µM, and selectivity index of 1361, with moderate activities against the single mutants (EC50: E138K, 0.17 µM; Y181C, 0.87 µM; K103N, 0.9 µM; L100I, 1.21 µM, respectively), and an IC50 value of 0.059 µM against the RT enzyme, which was six-fold higher than nevirapine (NVP). The preliminary structure-activity relationship (SAR) of these new compounds was concluded. The Molecular modeling predicted the binding modes of the new compounds with RT, providing Molecular insight for further drug design.
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discovery of novel dapy ias hybrid derivatives as potential hiv 1 inhibitors using Molecular Hybridization based on crystallographic overlays
Bioorganic & Medicinal Chemistry, 2017Co-Authors: Boshi Huang, Erik De Clercq, Christophe Pannecouque, Huiqing Liu, Xueshun Wang, Xinhao Liu, Zihui Chen, Songkai Sun, Dirk Daelemans, Peng ZhanAbstract:Crystallographic overlap studies and pharmacophoric analysis indicated that diarylpyrimidine (DAPY)-based HIV-1 NNRTIs showed a similar binding mode and pharmacophoric features as indolylarylsulfones (IASs), another class of potent NNRTIs. Thus, a novel series of DAPY-IAS hybrid derivatives were identified as newer NNRTIs using structure-based Molecular Hybridization. Some target compounds exhibited moderate activities against HIV-1 IIIB strain, among which the two most potent inhibitors possessed EC50 values of 1.48μM and 1.61μM, respectively. They were much potent than the reference drug ddI (EC50=76.0μM) and comparable to 3TC (EC50=2.54μM). Compound 7a also exhibited the favorable selectivity index (SI=80). Preliminary structure-activity relationships (SARs), structure-cytotoxicity relationships, Molecular modeling studies, and in silico calculation of physicochemical properties of these new inhibitors were also discussed.
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discovery of uracil bearing dapys derivatives as novel hiv 1 nnrtis via crystallographic overlay based Molecular Hybridization
European Journal of Medicinal Chemistry, 2017Co-Authors: Heng Zhang, Peng Zhan, Erik De Clercq, Christophe Pannecouque, Zhongxia Zhou, Huiqing Liu, Ye Tian, Dongwei Kang, Zhipeng Huo, Xinyong LiuAbstract:A novel series of uracil-bearing DAPYs derivatives were designed and synthesized via structure-based Molecular Hybridization to discover compounds with improved anti-resistance profiles. Anti-HIV activity of the designed compounds was tested in MT-4 cell cultures. The most promising compound 16d showed excellent activity with EC50 value of 5.6 nM against wide-type HIV-1 and low cytotoxicity (SI > 50000). Activity against the clinic prevalent mutant strains was also tested, suggesting that 16d was sensitive to E138K (EC50 = 34.2 nM). Primary drug-like properties, such as water solubility and logP, were evaluated by experiment or calculation, which indicated that introducing an uracil can improve solubility. The Molecular modeling accompanied with the preliminary SAR correlations paved the way for the next round of rational design of potent anti-HIV agents.
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hybrid chemistry part 4 discovery of etravirine vrx 480773 hybrids as potent hiv 1 non nucleoside reverse transcriptase inhibitors
Bioorganic & Medicinal Chemistry, 2015Co-Authors: Yafeng Wang, Erik De Clercq, Dirk Daelemans, Fener Chen, Huri Piao, Christophe PannecouqueAbstract:Abstract A novel series of etravirine–VRX-480773 hybrids were designed using structure-guided Molecular Hybridization strategy and fusing the pharmacophore templates of etravirine and VRX-480773. The anti-HIV-1 activity and cytotoxicity was evaluated in MT-4 cell cultures. The most active hybrid compound in this series, N-(2-chlorophenyl)-2-((4-(4-cyano-2,6-dimethylphenoxy)pyrimidin-2-yl)thio)acetamide 3d (EC50 = 0.24 , SI >1225), was more potent than delavirdine (EC50 = 0.66 μM, SI >67) in the anti-HIV-1 in vitro cellular assay. Studies of structure-activity relationships established a correlation between anti-HIV activity and the substitution pattern of the acetanilide group.
Xinyong Liu - One of the best experts on this subject based on the ideXlab platform.
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discovery of uracil bearing dapys derivatives as novel hiv 1 nnrtis via crystallographic overlay based Molecular Hybridization
European Journal of Medicinal Chemistry, 2017Co-Authors: Heng Zhang, Peng Zhan, Erik De Clercq, Christophe Pannecouque, Zhongxia Zhou, Huiqing Liu, Ye Tian, Dongwei Kang, Zhipeng Huo, Xinyong LiuAbstract:A novel series of uracil-bearing DAPYs derivatives were designed and synthesized via structure-based Molecular Hybridization to discover compounds with improved anti-resistance profiles. Anti-HIV activity of the designed compounds was tested in MT-4 cell cultures. The most promising compound 16d showed excellent activity with EC50 value of 5.6 nM against wide-type HIV-1 and low cytotoxicity (SI > 50000). Activity against the clinic prevalent mutant strains was also tested, suggesting that 16d was sensitive to E138K (EC50 = 34.2 nM). Primary drug-like properties, such as water solubility and logP, were evaluated by experiment or calculation, which indicated that introducing an uracil can improve solubility. The Molecular modeling accompanied with the preliminary SAR correlations paved the way for the next round of rational design of potent anti-HIV agents.
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design synthesis and anti hiv evaluation of novel diarylnicotinamide derivatives danas targeting the entrance channel of the nnrti binding pocket through structure guided Molecular Hybridization
European Journal of Medicinal Chemistry, 2014Co-Authors: Zhaoqiang Liu, Wenmin Chen, Peng Zhan, Erik De Clercq, Christophe Pannecouque, Xinyong LiuAbstract:Through a structure-based Molecular Hybridization approach, a novel series of diarylnicotinamide derivatives (DANAs) targeting the entrance channel of HIV-1 NNRTIs binding pocket (NNIBP) were rationally designed, synthesized and evaluated for their anti-HIV activities in MT-4 cells together with the inhibition against the reverse transcriptase (RT) in an enzymatic assay. Encouragingly, most of the new DANAs were found to be active against wild-type HIV-1 with an EC50 in the range of 0.027-4.54 μM. Among them, compound 6b11 (EC50 = 0.027 μM, SI > 12518) and 6b5 (EC50 = 0.029 μM, SI = 2471) were identified as the most potent inhibitors, which were more potent than the reference drugs nevirapine (EC50 = 0.31 μM) and delavirdine (EC50 = 0.66 μM). Some DANAs were also active at micromolar concentrations against the K103N + Y181C resistant mutant. Compound 6b11 exhibited the highest enzymatic inhibition activity (IC50 = 20 nM), which is equal to that of efavirenz (EC50 = 20 nM) and 31 times higher than that of nevirapine (EC50 = 0.62 μM). Preliminary structure-activity relationships (SARs) and Molecular modeling of these new DANAs have been discussed.
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Discovery of 2-pyridone derivatives as potent HIV-1 NNRTIs using Molecular Hybridization based on crystallographic overlays
Bioorganic & medicinal chemistry, 2014Co-Authors: Wenmin Chen, Peng Zhan, Diwakar Rai, Erik De Clercq, Christophe Pannecouque, Jan Balzarini, Zhongxia Zhou, Huiqing Liu, Xinyong LiuAbstract:Abstract Based on crystallographic overlays of the known inhibitors TMC125 and R221239 complexed in RT, we designed a novel series of 4-phenoxy-6-(phenylamino)pyridin-2(1H)-one derivatives as HIV NNRTIs by Molecular Hybridization approach. The biological testing results indicated that 2-pyridone scaffold of these inhibitors was indispensable for their anti-HIV-1 activity, and substitution of halogen at the 3-position of the 2-pyridone ring would decrease the anti-HIV activity. Four most potent compounds had anti-HIV-1 IIIB activities at low micromolar concentrations (EC50 = 0.15–0.84 μM), comparable to that of nevirapine and delavidine. Some compounds were selected to test their anti-HIV-1 RT inhibitory action and to perform Molecular modeling studies to predict the binding mode of these 2-pyridone derivatives.
Peng Zhan - One of the best experts on this subject based on the ideXlab platform.
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discovery of novel dapy ias hybrid derivatives as potential hiv 1 inhibitors using Molecular Hybridization based on crystallographic overlays
Bioorganic & Medicinal Chemistry, 2017Co-Authors: Boshi Huang, Erik De Clercq, Christophe Pannecouque, Huiqing Liu, Xueshun Wang, Xinhao Liu, Zihui Chen, Songkai Sun, Dirk Daelemans, Peng ZhanAbstract:Crystallographic overlap studies and pharmacophoric analysis indicated that diarylpyrimidine (DAPY)-based HIV-1 NNRTIs showed a similar binding mode and pharmacophoric features as indolylarylsulfones (IASs), another class of potent NNRTIs. Thus, a novel series of DAPY-IAS hybrid derivatives were identified as newer NNRTIs using structure-based Molecular Hybridization. Some target compounds exhibited moderate activities against HIV-1 IIIB strain, among which the two most potent inhibitors possessed EC50 values of 1.48μM and 1.61μM, respectively. They were much potent than the reference drug ddI (EC50=76.0μM) and comparable to 3TC (EC50=2.54μM). Compound 7a also exhibited the favorable selectivity index (SI=80). Preliminary structure-activity relationships (SARs), structure-cytotoxicity relationships, Molecular modeling studies, and in silico calculation of physicochemical properties of these new inhibitors were also discussed.
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discovery of uracil bearing dapys derivatives as novel hiv 1 nnrtis via crystallographic overlay based Molecular Hybridization
European Journal of Medicinal Chemistry, 2017Co-Authors: Heng Zhang, Peng Zhan, Erik De Clercq, Christophe Pannecouque, Zhongxia Zhou, Huiqing Liu, Ye Tian, Dongwei Kang, Zhipeng Huo, Xinyong LiuAbstract:A novel series of uracil-bearing DAPYs derivatives were designed and synthesized via structure-based Molecular Hybridization to discover compounds with improved anti-resistance profiles. Anti-HIV activity of the designed compounds was tested in MT-4 cell cultures. The most promising compound 16d showed excellent activity with EC50 value of 5.6 nM against wide-type HIV-1 and low cytotoxicity (SI > 50000). Activity against the clinic prevalent mutant strains was also tested, suggesting that 16d was sensitive to E138K (EC50 = 34.2 nM). Primary drug-like properties, such as water solubility and logP, were evaluated by experiment or calculation, which indicated that introducing an uracil can improve solubility. The Molecular modeling accompanied with the preliminary SAR correlations paved the way for the next round of rational design of potent anti-HIV agents.
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design synthesis and anti hiv evaluation of novel diarylnicotinamide derivatives danas targeting the entrance channel of the nnrti binding pocket through structure guided Molecular Hybridization
European Journal of Medicinal Chemistry, 2014Co-Authors: Zhaoqiang Liu, Wenmin Chen, Peng Zhan, Erik De Clercq, Christophe Pannecouque, Xinyong LiuAbstract:Through a structure-based Molecular Hybridization approach, a novel series of diarylnicotinamide derivatives (DANAs) targeting the entrance channel of HIV-1 NNRTIs binding pocket (NNIBP) were rationally designed, synthesized and evaluated for their anti-HIV activities in MT-4 cells together with the inhibition against the reverse transcriptase (RT) in an enzymatic assay. Encouragingly, most of the new DANAs were found to be active against wild-type HIV-1 with an EC50 in the range of 0.027-4.54 μM. Among them, compound 6b11 (EC50 = 0.027 μM, SI > 12518) and 6b5 (EC50 = 0.029 μM, SI = 2471) were identified as the most potent inhibitors, which were more potent than the reference drugs nevirapine (EC50 = 0.31 μM) and delavirdine (EC50 = 0.66 μM). Some DANAs were also active at micromolar concentrations against the K103N + Y181C resistant mutant. Compound 6b11 exhibited the highest enzymatic inhibition activity (IC50 = 20 nM), which is equal to that of efavirenz (EC50 = 20 nM) and 31 times higher than that of nevirapine (EC50 = 0.62 μM). Preliminary structure-activity relationships (SARs) and Molecular modeling of these new DANAs have been discussed.
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Discovery of 2-pyridone derivatives as potent HIV-1 NNRTIs using Molecular Hybridization based on crystallographic overlays
Bioorganic & medicinal chemistry, 2014Co-Authors: Wenmin Chen, Peng Zhan, Diwakar Rai, Erik De Clercq, Christophe Pannecouque, Jan Balzarini, Zhongxia Zhou, Huiqing Liu, Xinyong LiuAbstract:Abstract Based on crystallographic overlays of the known inhibitors TMC125 and R221239 complexed in RT, we designed a novel series of 4-phenoxy-6-(phenylamino)pyridin-2(1H)-one derivatives as HIV NNRTIs by Molecular Hybridization approach. The biological testing results indicated that 2-pyridone scaffold of these inhibitors was indispensable for their anti-HIV-1 activity, and substitution of halogen at the 3-position of the 2-pyridone ring would decrease the anti-HIV activity. Four most potent compounds had anti-HIV-1 IIIB activities at low micromolar concentrations (EC50 = 0.15–0.84 μM), comparable to that of nevirapine and delavidine. Some compounds were selected to test their anti-HIV-1 RT inhibitory action and to perform Molecular modeling studies to predict the binding mode of these 2-pyridone derivatives.
Fener Chen - One of the best experts on this subject based on the ideXlab platform.
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Molecular Hybridization inspired optimization of diarylbenzopyrimidines as hiv 1 nonnucleoside reverse transcriptase inhibitors with improved activity against k103n and e138k mutants and pharmacokinetic profiles
ACS Infectious Diseases, 2020Co-Authors: Sheng Han, Erik De Clercq, Christophe Pannecouque, Chunlin Zhuang, Yali Sang, Yuan Tao, Fener ChenAbstract:Molecular Hybridization is a powerful strategy in drug discovery. A series of novel diarylbenzopyrimidine (DABP) analogues were developed by the Hybridization of FDA-approved drugs etravirine (ETR) and efavirenz (EFV) as potential HIV-1 nonnucleoside reverse transcriptase inhibitors (NNRTIs). Substituent modifications resulted in the identification of new DABPs with the combination of the strengths of the two drugs, especially compound 12d, which showed promising activity toward the EFV-resistant K103N mutant. 12d also had a favorable pharmacokinetic (PK) profile with liver microsome clearances of 14.4 μL/min/mg (human) and 33.2 μL/min/mg (rat) and an oral bioavailability of 15.5% in rat. However, its activity against the E138K mutant was still unsatisfactory; E138K is the most prevalent NNRTI resistance-associated mutant in ETR treatment. Further optimizations resulted in a highly potent compound (12z) with no substituents on the phenyl ring and a 2-methyl-6-nitro substitution pattern on the 4-cyanovinyl-2,6-disubstitued phenyl motif. The antiviral activity of this compound was much higher than those of ETR and EFV against the WT, E138K, and K103N variants (EC50 = 3.4, 4.3, and 3.6 nM, respectively), and the cytotoxicity was decreased while the selectivity index (SI) was increased. In particular, this compound exhibited acceptable intrinsic liver microsome stability (human, 34.5 μL/min/mg; rat, 33.2 μL/min/mg) and maintained the good PK profile of its parent compound EFV and showed an oral bioavailability of 16.5% in rat. Molecular docking and structure-activity relationship (SAR) analysis provided further insights into the binding of the DABPs with HIV-1 reverse transcriptase and provided a deeper understanding of the key structural features responsible for their interactions.
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design of biphenyl substituted diarylpyrimidines with a cyanomethyl linker as hiv 1 nnrtis via a Molecular Hybridization strategy
Molecules, 2020Co-Authors: Yuan Lei, Erik De Clercq, Christophe Pannecouque, Sheng Han, Yang Yang, Chunlin Zhuang, Fener ChenAbstract:The key problems of human immunodeficiency virus (HIV) therapy are the rapid emergence of drug-resistant mutant strains and significant cumulative drug toxicities. Therefore, there is an urgent demand for new anti-HIV agents with low toxicity and broad-spectrum antiviral potency. A series of biphenyl-substituted diarylpyrimidines with a cyanomethyl linker were designed using a Molecular Hybridization strategy. The cell-based anti-HIV assay showed that most of the compounds exhibited moderate to good activities against wild-type HIV-1 and clinically relevant mutant strains with a more favorable toxicity, and the enzymatic assay showed they had nanomolar activity against reverse transcriptase (RT). Compound 10p exhibited the best activity against wild-type HIV-1 with an EC50 (50% HIV-1 replication inhibitory concentration) value of 0.027 µM, an acceptable CC50 (50% cytotoxic concentration) value of 36.4 µM, and selectivity index of 1361, with moderate activities against the single mutants (EC50: E138K, 0.17 µM; Y181C, 0.87 µM; K103N, 0.9 µM; L100I, 1.21 µM, respectively), and an IC50 value of 0.059 µM against the RT enzyme, which was six-fold higher than nevirapine (NVP). The preliminary structure-activity relationship (SAR) of these new compounds was concluded. The Molecular modeling predicted the binding modes of the new compounds with RT, providing Molecular insight for further drug design.
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hybrid chemistry part 4 discovery of etravirine vrx 480773 hybrids as potent hiv 1 non nucleoside reverse transcriptase inhibitors
Bioorganic & Medicinal Chemistry, 2015Co-Authors: Yafeng Wang, Erik De Clercq, Dirk Daelemans, Fener Chen, Huri Piao, Christophe PannecouqueAbstract:Abstract A novel series of etravirine–VRX-480773 hybrids were designed using structure-guided Molecular Hybridization strategy and fusing the pharmacophore templates of etravirine and VRX-480773. The anti-HIV-1 activity and cytotoxicity was evaluated in MT-4 cell cultures. The most active hybrid compound in this series, N-(2-chlorophenyl)-2-((4-(4-cyano-2,6-dimethylphenoxy)pyrimidin-2-yl)thio)acetamide 3d (EC50 = 0.24 , SI >1225), was more potent than delavirdine (EC50 = 0.66 μM, SI >67) in the anti-HIV-1 in vitro cellular assay. Studies of structure-activity relationships established a correlation between anti-HIV activity and the substitution pattern of the acetanilide group.