Co-reporter:Dongwei Kang, Xiao Ding, Gaochan Wu, Zhipeng Huo, Zhongxia Zhou, Tong Zhao, Da Feng, Zhao Wang, Ye Tian, Dirk Daelemans, Erik De Clercq, Christophe Pannecouque, Peng Zhan, and Xinyong Liu
ACS Medicinal Chemistry Letters November 9, 2017 Volume 8(Issue 11) pp:1188-1188
Publication Date(Web):October 19, 2017
DOI:10.1021/acsmedchemlett.7b00361
Our previous studies led us to conclude that thiophene[3,2-d]pyrimidine is a promising scaffold for diarylpyrimidine (DAPY)-type anti-HIV agents with potent activity against resistance-associated human immunodeficiency virus (HIV) variants (J. Med. Chem. 2016, 59, 7991–8007; J. Med. Chem. 2017, 60, 4424–4443). In the present study, we designed and synthesized a series of thiophenepyrimidine derivatives with various substituents in the right wing region of the structure with the aim of developing new interactions with the tolerant region I of the binding pocket of the HIV-1 non-nucleoside reverse transcriptase (NNRTI), and we evaluated their activity against a panel of mutant HIV-1 strains. All the derivatives exhibited moderate to excellent potency against wild-type (WT) HIV-1 in MT-4 cells. Among them, sulfonamide compounds 9b and 9d were single-figure-nanomolar inhibitors with EC50 values of 9.2 and 7.1 nM, respectively. Indeed, 9a and 9d were effective against the whole viral panel except RES056. Notably, both compounds showed potent antiviral activity against K103N (EC50 = 0.032 and 0.070 μM) and E138K (EC50 = 0.035 and 0.045 μM, respectively). Furthermore, 9a and 9d exhibited high affinity for WT HIV-1 RT (IC50 = 1.041 and 1.138 μM, respectively) and acted as classical NNRT inhibitors (NNRTIs). These results are expected to be helpful in the design of thiophenepyrimidine-based NNRTIs with more potent activity against HIV strains with RT mutations.Keywords: drug design; HIV-1; NNRTIs; thiophene[3,2-d]pyrimidine; tolerant region I;
Co-reporter:Dongwei Kang, Zengjun Fang, Boshi Huang, Xueyi Lu, Heng Zhang, Haoran Xu, Zhipeng Huo, Zhongxia Zhou, Zhao Yu, Qing Meng, Gaochan Wu, Xiao Ding, Ye Tian, Dirk Daelemans, Erik De Clercq, Christophe Pannecouque, Peng Zhan, and Xinyong Liu
Journal of Medicinal Chemistry May 25, 2017 Volume 60(Issue 10) pp:4424-4424
Publication Date(Web):May 8, 2017
DOI:10.1021/acs.jmedchem.7b00332
This work follows on from our initial discovery of a series of piperidine-substituted thiophene[3,2-d]pyrimidine HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTI) ( J. Med. Chem. 2016, 59, 7991−8007). In the present study, we designed, synthesized, and biologically tested several series of new derivatives in order to investigate previously unexplored chemical space. Some of the synthesized compounds displayed single-digit nanomolar anti-HIV potencies against wild-type (WT) virus and a panel of NNRTI-resistant mutant viruses in MT-4 cells. Compound 25a was exceptionally potent against the whole viral panel, affording 3-4-fold enhancement of in vitro antiviral potency against WT, L100I, K103N, Y181C, Y188L, E138K, and K103N+Y181C and 10-fold enhancement against F227L+V106A relative to the reference drug etravirine (ETV) in the same cellular assay. The structure–activity relationships, pharmacokinetics, acute toxicity, and cardiotoxicity were also examined. Overall, the results indicate that 25a is a promising new drug candidate for treatment of HIV-1 infection.
Co-reporter:Han Ju, Jian Zhang, Boshi Huang, Dongwei Kang, Bing Huang, Xinyong Liu, and Peng Zhan
Journal of Medicinal Chemistry May 11, 2017 Volume 60(Issue 9) pp:3533-3533
Publication Date(Web):January 24, 2017
DOI:10.1021/acs.jmedchem.6b01227
Influenza virus (IFV) causes periodic global influenza pandemics, resulting in substantial socioeconomic loss and burden on medical facilities. Yearly variation in the effectiveness of vaccines, slow responsiveness to vaccination in cases of pandemic IFV, and emerging resistance to available drugs highlight the need to develop additional small-molecular inhibitors that act on IFV proteins. One promising target is polymerase acidic (PA) endonuclease, which is a bridged dinuclear metalloenzyme that plays a crucial role in initiating IFV replication. During the past decade, intensive efforts have been made to develop small-molecular inhibitors of this endonuclease as candidate agents for treatment of IFV infection. Here, we review the current status of development of PA endonuclease inhibitors and we discuss the applicability of newer medicinal-chemistry strategies for the discovery more potent, selective, and safer inhibitors.
Co-reporter:Boshi Huang, Xueshun Wang, Xinhao Liu, Zihui Chen, Wanzhuo Li, Songkai Sun, Huiqing Liu, Dirk Daelemans, Erik De Clercq, Christophe Pannecouque, Peng Zhan, Xinyong Liu
Bioorganic & Medicinal Chemistry 2017 Volume 25, Issue 16(Issue 16) pp:
Publication Date(Web):15 August 2017
DOI:10.1016/j.bmc.2017.06.022
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 1.48 μM and 1.61 μM, respectively. They were much potent than the reference drug ddI (EC50 = 76.0 μM) and comparable to 3TC (EC50 = 2.54 μM). 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.A novel series of DAPY-IAS hybrid derivatives were identified as newer HIV-1 NNRTIs using structure-based molecular hybridization.Download high-res image (159KB)Download full-size image
Co-reporter:Zhaoqiang Liu, Ye Tian, Jinghan Liu, Boshi Huang, Dongwei Kang, Erik De Clercq, Dirk Daelemans, Christophe Pannecouque, Peng Zhan, Xinyong Liu
European Journal of Medicinal Chemistry 2017 Volume 140(Volume 140) pp:
Publication Date(Web):10 November 2017
DOI:10.1016/j.ejmech.2017.07.012
•Twenty-one 3,5-diaryl-pyridine derivatives were designed, synthesized and evaluated for their anti-HIV activities.•5b2 (EC50 = 0.04 μM, SI = 3963) was the most potent inhibitor.•The 2-NH2 pyridine derivatives showed better anti-HIV-1 activity than the corresponding 2-NO2 counterparts.As a continuation of our efforts to discover and develop “me-better” drugs of DAPYs, novel diarylpyridine derivatives were designed, synthesized and evaluated for their anti-HIV activities in MT-4 cells. The majority of these compounds showed high activity against wild-type HIV-1 strain (IIIB) with EC50 values in the range of 0.04–4.41 μM. Among them, compound 5b2 (EC50 = 0.04 μM, SI = 3963) was the most potent. This compound showed anti-HIV-1IIIB activity superior than of Nevirapine but still inferior than of Etravirine. Selected compounds were also evaluated for the activity against reverse transcriptase (RT), and most of the compounds exhibited submicromolar IC50 values indicating they are specific RT inhibitors. Preliminary structure-activity relationships and modeling studies of these new analogues provide valuable avenues for future molecular optimization.Download high-res image (361KB)Download full-size image
Co-reporter:Xiao Li, Ping Gao, Boshi Huang, Zhongxia Zhou, Zhao Yu, Zheng Yuan, Huiqing Liu, Christophe Pannecouque, Dirk Daelemans, Erik De Clercq, Peng Zhan, Xinyong Liu
European Journal of Medicinal Chemistry 2017 Volume 126(Volume 126) pp:
Publication Date(Web):27 January 2017
DOI:10.1016/j.ejmech.2016.10.009
•Novel IASs bearing N-substituted piperidine at indole-2-carboxamide were designed.•New IASs have EC50 values ranging from 0.62 μM to 0.006 μM against WT HIV-1.•Compounds 8 (EC50 = 6 nM) and 18 (EC50 = 9 nM) were the most active derivatives.•Compounds 8 and 18 also displayed outstanding potency against some HIV-1 mutants.•SARs and molecular modeling studies were discussed in detail.To further explore the chemical space around the entrance channel of HIV-1 reverse transcriptase (RT), a series of novel indolylarylsulfones (IASs) bearing N-substituted piperidine at indole-2-carboxamide were identified as potent HIV NNRTIs by structure-guided scaffold morphing and fragment rearrangement. All the IASs exhibited moderate to excellent potency against wild-type HIV-1 with EC50 values ranging from 0.62 μM to 0.006 μM 8 (EC50 = 6 nM) and 18 (EC50 = 9 nM) were identified as the most potent compounds, which were more active than NVP and DLV, and reached the same order of EFV and ETV. Furthermore, most compounds maintained high activity agaist various single HIV-1 mutants (L100I, K103N, E138K, Y181C) as well as one double mutant (F227L/V106A) with EC50 values in low-micromolar to double-digit nanomolar concentration ranges. Especially, 8 displayed outstanding potency against L100I (EC50 = 17 nM with a 2.8-fold resistance ratio) and 18 was relatively more potent to E138K mutant (EC50 = 43 nM with a 4.7-fold resistance ratio). Preliminary SARs and molecular modeling studies were also discussed in detail, which may provide valuable insights for further optimization.A series of novel indolylarylsulfones (IASs) bearing N-substituted piperidine at indole-2-carboxamide were identified as potent HIV NNRTIs by structure-guided scaffold morphing and fragment rearrangement.Download high-res image (190KB)Download full-size image
Co-reporter:Heng Zhang, Ye Tian, Dongwei Kang, Zhipeng Huo, Zhongxia Zhou, Huiqing Liu, Erik De Clercq, Christophe Pannecouque, Peng Zhan, Xinyong Liu
European Journal of Medicinal Chemistry 2017 Volume 130(Volume 130) pp:
Publication Date(Web):21 April 2017
DOI:10.1016/j.ejmech.2017.02.047
•Novel uracil-bearing DAPYs derivatives were identified.•16d exhibited best activity with EC50 values of 5.6 nM (wt) and 34.2 nM (E138K).•LogP and water solubility of representative compounds were measured.•Preliminary SARs and molecular simulation of these new analogues were detailed.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.By structure-based molecular hybridization, a new HIV-1 NNRTI 16d was discovered with excellent activity and high selectivity.Download high-res image (164KB)Download full-size image
Co-reporter:Dongwei Kang, Zengjun Fang, Zhenyu Li, Boshi Huang, Heng Zhang, Xueyi Lu, Haoran Xu, Zhongxia Zhou, Xiao Ding, Dirk Daelemans, Erik De Clercq, Christophe Pannecouque, Peng Zhan, and Xinyong Liu
Journal of Medicinal Chemistry 2016 Volume 59(Issue 17) pp:7991-8007
Publication Date(Web):August 19, 2016
DOI:10.1021/acs.jmedchem.6b00738
We designed and synthesized a series of human immunodeficiency virus type 1 (HIV-1) non-nucleoside reverse transcriptase inhibitors (NNRTIs) with a piperidine-substituted thiophene[3,2-d]pyrimidine scaffold, employing a strategy of structure-based molecular hybridization and substituent decorating. Most of the synthesized compounds exhibited broad-spectrum activity with low (single-digit) nanomolar EC50 values toward a panel of wild-type (WT), single-mutant, and double-mutant HIV-1 strains. Compound 27 was the most potent; compared with ETV, its antiviral efficacy was 3-fold greater against WT, 5–7-fold greater against Y181C, Y188L, E138K, and F227L+V106A, and nearly equipotent against L100I and K103N, though somewhat weaker against K103N+Y181C. Importantly, 27 has lower cytotoxicity (CC50 > 227 μM) and a huge selectivity index (SI) value (ratio of CC50/EC50) of >159101. 27 also showed favorable, drug-like pharmacokinetic and safety properties in rats in vivo. Molecular docking studies and the structure–activity relationships provide important clues for further molecular elaboration.
Co-reporter:Jiapei Yang, Wenmin Chen, Dongwei Kang, Xueyi Lu, Xiao Li, Zhaoqiang Liu, Boshi Huang, Dirk Daelemans, Christophe Pannecouque, Erik De Clercq, Peng Zhan, Xinyong Liu
European Journal of Medicinal Chemistry 2016 Volume 109() pp:294-304
Publication Date(Web):15 February 2016
DOI:10.1016/j.ejmech.2015.11.039
•Novel 6-substituted diarylpyridine derivatives were identified as HIV-1 inhibitors.•If, Ia and IIa exhibited anti-HIV-1 (IIIB) activity with EC50 values of 35 nM, 43 nM and 41 nM, respectively.•IIb inhibited the K103N mutation with an EC50 value of 49 nM.•Preliminary SARs and molecular simulation of these new analogues were detailed.The development of novel NNRTIs with activity against variants of HIV-1RT is crucial for overcoming treatment failure. In the present study, a series of novel 6-substituted diarylpyridine derivatives targeting the entrance channel of the NNIBP of RT were designed through a molecular hybridization strategy. Encouragingly, these new diarylpyridine derivatives were found to be active against wild-type (WT) HIV-1 with an EC50 values ranging from 0.035 μM to 1.99 μM. Nearly half of them exhibited more potent inhibitory activities in cellular assays than the control drug nevirapine (NVP). Notably, three most promising compounds If (EC50 = 35 nM), Ia (EC50 = 43 nM) and IIa (EC50 = 41 nM) showed high potency against WT and were comparable to the reference drug delavirdine (DLV) (EC50 = 33 nM). Moreover, compounds Ib, IIb and IIh displayed effective activity against the most common clinically observed single and double-mutated HIV-1 strains in micromolar concentrations. In particular, the inhibition of IIb against the K103N mutation (EC50 = 49 nM), which confers resistance to a wide variety of NNRTIs, was about 140 times more effective than NVP (EC50 = 6.78 μM), 50 times more than DLV (EC50 = 2.48 μM) and about 3 times more than EFV (EC50 = 0.12 μM), indicating that the newly designed compounds have great potential to be further developed as new anti-HIV-1 agents. Preliminary structure-activity relationships (SARs) and molecular modeling of the new diarylpyridine derivatives were discussed in detail.Through structure-based boisosteric replacement and molecular hybridization, a series of novel 6-substituted diarylpyridine derivatives were designed, synthesized and identified as inhibitors of wild-type HIV-1 strain and mutant strains in this paper.
Co-reporter:Heng Zhang, Dongwei Kang, Boshi Huang, Na Liu, Fabao Zhao, Peng Zhan, Xinyong Liu
European Journal of Medicinal Chemistry 2016 Volume 114() pp:65-78
Publication Date(Web):23 May 2016
DOI:10.1016/j.ejmech.2016.02.051
•We reviewed recent advances on small molecular CXCR4 antagonists.•We focused on the evolution of CXCR4 and structure-activity relationships of representative CXCR4 antagonists.•We introduced the medicinal chemistry strategies and novel methodologies.CXCR4 plays vital roles in HIV-1 life cycle for it's essential in mediating the interaction of host and virus and completing the entry process in the lifecycle of HIV-1 infection. Compared with some traditional targets, CXCR4 provides a novel and less mutated drug target in the battle against AIDS. Its antagonists have no cross resistance with other antagonists. Great achievements have been made recent years and a number of small molecular CXCR4 antagonists with diversity scaffolds have been discovered. In this review, recent advances in the discovery of CXCR4 antagonists with special attentions on their evolution and structure-activity relationships of representative CXCR4 antagonists are described. Moreover, some classical medicinal chemistry strategies and novel methodologies are also introduced.Recent advances in the discovery of CXCR4 antagonists with special attentions on their evolution and structure-activity relationships of representative CXCR4 antagonists.
Co-reporter:Xueyi Lu, Xiao Li, Jiapei Yang, Boshi Huang, Dongwei Kang, Fabao Zhao, Zhongxia Zhou, Erik De Clercq, Dirk Daelemans, Christophe Pannecouque, Peng Zhan, Xinyong Liu
Bioorganic & Medicinal Chemistry 2016 Volume 24(Issue 18) pp:4424-4433
Publication Date(Web):15 September 2016
DOI:10.1016/j.bmc.2016.07.041
•A series of novel purinylthioacetanilide derivatives were identified as potential HIV-1 NNRTIs.•LAD-8 displayed anti-HIV activity with an EC50 value of 0.78 μM.•LBD-6 showed moderate activity against L100I mutant and double mutant strain RES056.•Preliminary SARs of these new analogues were discussed in detail.By means of structure-based bioisosterism approach, a series of novel purinylthioacetanilide derivatives were designed, synthesized and evaluated as potent HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs). Some of the tested compounds were found to be active against wild-type (WT) HIV-1(IIIB) with EC50 in the range of 0.78–4.46 μM. Among them, LAD-8 displayed the most potent anti-HIV activity (EC50 = 0.78 μM, SI = 24). In addition, LBD-6 showed moderate activity against L100I mutant (EC50 = 5.64 μM) and double mutant strain RES056 (EC50 = 22.24 μM). Preliminary structure–activity relationships (SARs) were discussed in detail. Molecular modeling study was used to predict the optimal conformation in the NNRTI binding site, which may play a guiding role in further rational optimization.
Co-reporter:Wenxin Li;Boshi Huang;Dongwei Kang;Erik De Clercq;Dirk Daelemans;Christophe Pannecouque;Xinyong Liu
Chemical Biology & Drug Design 2016 Volume 88( Issue 3) pp:380-385
Publication Date(Web):
DOI:10.1111/cbdd.12765
A series of novel 5-alkyl-6-Adamantylmethylpyrimidin-4(3H)-ones bearing various substituents at the C-2 position of the pyrimidinone ring were synthesized using a facile route and evaluated for their anti-HIV activity in MT-4 cells. The biological results demonstrated that the majority of the newly designed compounds possessed moderate efficiency in inhibiting the replication of the wild-type (WT) HIV-1 strain (IIIB) with EC50 values in the range from 0.10 to 5.39 μm. Among them, 5b1 and 5b3 proved to be the two most active inhibitors against WT HIV-1 with EC50 values of 0.10 and 0.12 μm, respectively, which were more active than nevirapine (NVP) in the same assay. In addition, HIV-1 reverse-transcriptase (RT) inhibition assay indicated that the representative compound 5b1 showed affinity to WT HIV-1 RT, and inhibited the activity of RT with an IC50 value superior to the reference drug NVP. Moreover, the preliminary structure–activity relationship (SAR) and the molecular modeling analysis of these new derivatives are also discussed.
Co-reporter:Xiao Li;Boshi Huang;Zhongxia Zhou;Ping Gao;Christophe Pannecouque;Dirk Daelemans;Erik De Clercq;Xinyong Liu
Chemical Biology & Drug Design 2016 Volume 88( Issue 2) pp:241-253
Publication Date(Web):
DOI:10.1111/cbdd.12751
With the continuation of our unremitting efforts toward the discovery of potent HIV-1 NNRTIs, a series of novel imidazo[4,5-b]pyridin-2-ylthioacetanilides were designed, synthesized, and evaluated for their antiviral activities through combining bioisosteric replacement and structure-based drug design. Almost all of the title compounds displayed moderate to good activities against wild-type (wt) HIV-1 strain with EC50 values ranging from 0.059 to 1.41 μm in a cell-based antiviral assay. Thereinto, compounds 12 and 13 were the most active two analogues possessing an EC50 value of 0.059 and 0.073 μm against wt HIV-1, respectively, which was much more effective than the control drug nevirapine (EC50 = 0.26 μm) and comparable to delavirdine (EC50 = 0.038 μm). In addition, one selected compound showed a remarkable reverse transcriptase inhibitory activity compared to nevirapine and etravirine. In the end of this manuscript, preliminary structure–activity relationships (SARs) and molecular modeling studies were detailedly discussed, which may provide valuable insights for further optimization.
Co-reporter:Boshi Huang;Xiao Li;Erik De Clercq;Dirk Daelemans;Christophe Pannecouque;Xinyong Liu
Chemical Biology & Drug Design 2016 Volume 87( Issue 2) pp:283-289
Publication Date(Web):
DOI:10.1111/cbdd.12657
Through a structure-based molecular hybridization and bioisosterism approach, a series of novel 2-(pyridin-3-yloxy)acetamide derivatives were designed, synthesized, and evaluated for their anti-HIV activities in MT-4 cell cultures. Biological results showed that three compounds (Ia, Ih, and Ij) exhibited moderate inhibitory activities against wild-type (wt) HIV-1 strain (IIIB) with EC50 values ranging from 8.18 μm to 41.52 μm. Among them, Ij was the most active analogue possessing an EC50 value of 8.18 μm. To further confirm the binding target, four compounds were selected to implement an HIV-1 RT inhibitory assay. In addition, preliminary structure–activity relationship (SAR) analysis and some predicted physicochemical properties of three active compounds Ia, Ih, and Ij were discussed in detail. Molecular docking studies were also carried out to investigate the binding modes of Ij and the lead compound GW678248 in the binding pocket of RT, which provided beneficial information for further rational design of non-nucleoside reverse transcriptase inhibitors.
Co-reporter:Dongwei Kang, Heng Zhang, Zhongxia Zhou, Boshi Huang, Lieve Naesens, Peng Zhan, Xinyong Liu
Bioorganic & Medicinal Chemistry Letters 2016 Volume 26(Issue 21) pp:5182-5186
Publication Date(Web):1 November 2016
DOI:10.1016/j.bmcl.2016.09.071
•First discovery of novel 3-hydroxy-quinazoline-2,4(1H,3H)-diones as specific anti-vaccinia and adenovirus agents.•24b11 displayed the most potent inhibitory activity against vaccinia with an EC50 value of 1.7 μM.•24b13 was the most potent compound against adenovirus-2 with an EC50 value of 6.2 μM.•Preliminary SARs of these novel analogues were detailed.A series of 1,2,3-triazolyl 3-hydroxy-quinazoline-2,4(1H,3H)-diones was constructed utilizing Cu(I)-catalyzed azide-alkyne 1,3-dipolar cycloaddition (CuAAC) method. The biological significance of the novel synthesized quinazolines was highlighted by evaluating them in vitro for antiviral activity, wherein several compounds exhibited excellent activity specifically against vaccinia and adenovirus. Especially, 24b11 displayed the most potent inhibitory activity against vaccinia with an EC50 value of 1.7 μM, which was 15 fold than that of the reference drug Cidofovir (EC50 = 25 μM). 24b13 was the most potent compound against adenovirus-2 with an EC50 value of 6.2 μM, which proved lower than all the reference drugs. Preliminary structure–activity relationships were also discussed. To the best of our knowledge, no data are present in the literature on antiviral activity of 3-hydroxy-quinazoline-2,4(1H,3H)-diones against DNA-viruses. Thus, these findings warrant further investigations (library expansion and compound refinement) on this novel class of antiviral agents.Download high-res image (189KB)Download full-size image
Co-reporter:Peng Zhan; Yukihiro Itoh; Takayoshi Suzuki;Xinyong Liu
Journal of Medicinal Chemistry 2015 Volume 58(Issue 19) pp:7611-7633
Publication Date(Web):June 18, 2015
DOI:10.1021/acs.jmedchem.5b00229
Currently, the creation of class- and isoform-selective modulators of biologically important targets is a particularly challenging problem because different isoforms within a protein family often show striking similarity in spatial quaternary structure, especially at the catalytic sites or binding pockets. Therefore, an understanding of both the precise three-dimensional structure of the target protein and the mechanisms of action of modulators is important for developing more effective and selective agents. In this Perspective, we discuss currently available rational design strategies for obtaining class- and isoform-selective inhibitors and we illustrate these strategies with the aid of specific examples from the recent literature. The strategies covered include: (1) target-derived (-dependent) de novo drug discovery methodologies, and (2) follow-on derivatization approaches from initially identified active molecules (hit-to-lead and lead-to-candidate efforts). We also comment on prospects for further development and integration of strategies to achieve target-specific or isoform-selective inhibition.
Co-reporter:Wenxin Li, Xiao Li, Erik De Clercq, Peng Zhan, Xinyong Liu
European Journal of Medicinal Chemistry 2015 Volume 102() pp:167-179
Publication Date(Web):18 September 2015
DOI:10.1016/j.ejmech.2015.07.043
•Arylthioacetanilide family proved to be highly active HIV-1 NNRTIs.•The discovery and development of the arylthioacetanilides were reviewed.•Crystal structure analyses and SARs of arylthioacetanilides were detailed.•The strategies to overcome drug resistance in arylthioacetanilides were described.The poor pharmacokinetics, side effects and particularly the rapid emergence of drug resistance compromise the efficiency of the clinically used anti-HIV drugs. Therefore, the discovery of novel and effective NNRTIs is still an extremely primary mission. Arylthioacetanilide family is one of the highly active HIV-1 NNRTIs against wide-type (WT) HIV-1 and a wide range of drug-resistant mutant strains. Especially, VRX-480773 and RDEA806 have been chosen as candidates for further clinical studies. In this article, we review the discovery and development of the arylthioacetanilides, and, especially, pay much attention to the structural modifications, SARs conclusions and molecular modeling. Moreover, several medicinal chemistry strategies to overcome drug resistance involved in the optimization process of arylthioacetanilides are highlighted, providing valuable clues for further investigations.Discovery and development of the arylthioacetanilide derivatives as HIV-1 non-nucleoside reverse transcriptase inhibitors were reviewed.
Co-reporter:Fabao Zhao, Na Liu, Peng Zhan, Xuemei Jiang, Xinyong Liu
European Journal of Medicinal Chemistry 2015 Volume 94() pp:218-228
Publication Date(Web):13 April 2015
DOI:10.1016/j.ejmech.2015.03.012
•Thumb site I is an especially attractive target, as compounds targeting this site enable a broad genotypic coverage.•Discovery and development of indole analogues as thumb site I inhibitors were reviewed.•Crystal structure analyses of indole analogues with thumb site I were described.•The SARs and drug-like profiles of indole analogues as thumb site I inhibitors were reviewed.Hepatitis C virus (HCV) NS5B RNA-depended-RNA-polymerase (RdRp) is an essential enzyme in HCV viral replication and has no functional equivalent in mammalian cells. Several classes of nucleoside and non-nucleoside inhibitors, targeting the different allosteric sites, have demonstrated efficacy in clinical trials. Compared to other allosteric sites, thumb site I is a more compelling allosteric target with a significant number of inhibitors in clinical trials. Among them, indole analogues are the most important series of NS5B thumb site I inhibitors with considerable antiviral activity. This review focuses on the discovery and development of indole inhibitors targeting on NS5B thumb site I. Five fundamental principles, the general structure–activity relationships (SARs) model of indole scaffold, were summarized, which could pave the way for further structural optimization of indole-based anti-HCV agents.Discovery and development of indole analogues as HCV NS5B thumb site I inhibitors were reviewed.
Co-reporter:Boshi Huang, Cuicui Li, Wenmin Chen, Tao Liu, Mingyan Yu, Lu Fu, Yueyue Sun, Huiqing Liu, Erik De Clercq, Christophe Pannecouque, Jan Balzarini, Peng Zhan, Xinyong Liu
European Journal of Medicinal Chemistry 2015 Volume 92() pp:754-765
Publication Date(Web):6 March 2015
DOI:10.1016/j.ejmech.2015.01.042
•Novel [1,2,4]triazolo[1,5-a]pyrimidines were identified as potent HIV-1 inhibitors.•7d exhibited anti-HIV-1 activity with EC50 values of 8.1 nM (wt) and 13 μM (RES056).•Log P and water solubility of 7d were measured.•Preliminary SARs and molecular simulation of these new analogs were detailed.In our arduous efforts to develop new potent HIV-1 non-nucleoside reverse transcriptase (RT) inhibitors (NNRTIs), novel piperidine-linked [1,2,4]triazolo[1,5-a]pyrimidine derivatives were designed, synthesized and evaluated for their antiviral activities in MT-4 cell cultures. Biological results showed that all of the title compounds displayed moderate to excellent activities against wild-type (wt) HIV-1 strain (IIIB) with EC50 values ranging from 8.1 nM to 2284 nM in a cell-based assay. Among them, the most promising analog 7d possessed an EC50 value of 8.1 nM against wt HIV-1, which was much more potent than the reference drugs DDI, 3 TC, NVP and DLV. Additionally, 7d demonstrated weak activity against the double mutant HIV-1 strain (K103N + Y181C), and was more efficient than NVP in a RT inhibition assay. Besides, some measured and calculated physicochemical properties of 7d, like log P and water solubility, as well as the structure–activity relationships (SARs) analysis have been discussed in detail. Furthermore, the binding mode of the active compound 7d was rationalized by molecular simulation studies.A series of novel piperidine-linked [1,2,4]triazolo[1,5-a]pyrimidine derivatives were synthesized and identified as inhibitors of HIV-1 wild-type and K103N + Y181C double mutant strains in this paper.
Co-reporter:Boshi Huang, Xin Liang, Cuicui Li, Wenmin Chen, Tao Liu, Xiao Li, Yueyue Sun, Lu Fu, Huiqing Liu, Erik De Clercq, Christophe Pannecouque, Peng Zhan, Xinyong Liu
European Journal of Medicinal Chemistry 2015 Volume 93() pp:330-337
Publication Date(Web):26 March 2015
DOI:10.1016/j.ejmech.2015.02.022
•Novel imidazo[1,2-a]pyrazines were identified as HIV-1 inhibitors.•4a and 5a exhibited anti-HIV-1 (IIIB) activity with EC50 values of 0.26 μM and 0.32 μM respectively.•Some drug-like properties of 4a and 5a were predicted.•Preliminary SARs and molecular simulation of these new analogues were detailed.Through a structure-guided core-refining approach, a series of novel imidazo[1,2-a]pyrazine derivatives were designed, synthesized and evaluated as HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs). Biological results of antiviral assay in MT-4 cell cultures showed that 12 target compounds displayed moderate activities against wild-type (wt) HIV-1 strain (IIIB) with EC50 values ranging from 0.26 μM to 19 μM. Among them, 4a and 5a were found to be the two most active analogues possessing EC50 values of 0.26 μM and 0.32 μM respectively, comparable to delavirdine (DLV, EC50 = 0.54 μM) and nevirapine (NVP, EC50 = 0.31 μM) in a cell-based assay. Additionally, 9 compounds showed RT inhibitory activity superior to that of NVP. Moreover, some predicted drug-like properties of representative compounds 4a and 5a, as well as the structure-activity relationship (SAR) analysis were discussed in detail. The binding mode of compound 4a was investigated by molecular simulation studies.Through a structure-guided core-refining approach, a series of novel imidazo[1,2-a]pyrazine derivatives were designed, synthesized and identified as inhibitors of wild-type HIV-1 strain in this paper.
Co-reporter:Na Liu, Fabao Zhao, Haiyong Jia, Diwakar Rai, Peng Zhan, Xuemei Jiang and Xinyong Liu
MedChemComm 2015 vol. 6(Issue 4) pp:521-535
Publication Date(Web):16 Dec 2014
DOI:10.1039/C4MD00521J
Hepatitis B is an infectious inflammatory disease of the liver, which is caused by the hepatitis B virus (HBV). Nowadays, the dramatic development of new HBV inhibitors is focused on discovering diverse non-nucleoside compounds with either novel structures or new mechanisms of action. In this review, we focus on the recent advances in discovery, structural modifications and biological activities studies of several distinct classes of synthetic non-nucleoside small molecular compounds with new mechanisms.
Co-reporter:Liu Wang, Ye Tian, Wenmin Chen, Hong Liu, Peng Zhan, Dongyue Li, Huiqing Liu, Erik De Clercq, Christophe Pannecouque, Xinyong Liu
European Journal of Medicinal Chemistry 2014 Volume 85() pp:293-303
Publication Date(Web):6 October 2014
DOI:10.1016/j.ejmech.2014.07.104
•[1,2,4]Triazolo[1,5-a]pyrimidines were identified as effective HIV-1 inhibitors.•7n show anti-HIV-1 activity with EC50 of 0.02 μM (wt) and 7.6 μM (RES056).•Preliminary SARs and molecular modeling of these new analogues were detailed.Guided by crystal structures of HIV-1 RT/DAPY complex and molecular modeling studies, a series of novel [1,2,4]triazolo[1,5-a]pyrimidine derivatives were rationally designed via structure-based core refining approach, synthesized through the readily accessible synthetic methods and evaluated for their anti-HIV activities in MT-4 cells. Preliminary biological evaluation indicated that most of the compounds exhibited marked inhibitory activity against the wild-type HIV-1 IIIB. Particularly, compound 7n was the most potent inhibitor against wild-type and K103N/Y181C double resistant mutant strain of HIV-1, possessing EC50 values of 0.02 μM and 7.6 μM, respectively, which were much better than or similar to nevirapine (NVP, EC50 = 0.15 μM, 2.9 μM) and delavirdine (DLV, EC50 = 0.07 μM, >36 μM). Besides, some other compounds, 5b, 7c, 7e, 7f, and 7m, were also endowed with favorable anti-HIV-1 potency (EC50 = 0.07, 0.05, 0.05, 0.07, and 0.05 μM, respectively), which were better than or similar to those of NVP and DLV, suggesting a high potential to further develop this type of bridgehead nitrogen heterocycle as a novel class of NNRTIs with improved antiviral efficacy and resistance profile. The selected compound, 7i, was found moderately inhibitory towards RT (IC50 = 0.39 μM), which was higher than for ETV (IC50 = 0.56 μM). Preliminary structure–activity relationships (SARs) and molecular modeling of these new analogues were detailed in this manuscript.A series of novel [1,2,4]triazolo[1,5-a]pyrimidine derivatives were synthesized and evaluated as inhibitors of the HIV-1 wild-type and double mutant (K103N + Y181C) RES056 strains in this article.
Co-reporter:Jun Wang, Peng Zhan, Zhenyu Li, Huiqing Liu, Erik De Clercq, Christophe Pannecouque, Xinyong Liu
European Journal of Medicinal Chemistry 2014 Volume 76() pp:531-538
Publication Date(Web):9 April 2014
DOI:10.1016/j.ejmech.2014.02.047
•Synthesize a series of substituted nitropyridine derivatives as NNRTIs.•The proposed binding mode was investigated by molecular docking.•A preliminary structure–activity relationship was discussed.As a continuation of our efforts to discover and develop back-up analogs of DAPYs, novel substituted nitropyridine derivatives were designed via a structure-based core refining approach, synthesized and evaluated for their in vitro HIV-1 activity in MT-4 cells. Preliminary biological evaluation indicated that most of the compounds exhibited marked inhibitory activity against wild-type HIV-1 IIIB. Most notably, the compound 7b was identified as the most promising candidate in inhibiting HIV-1 replication with an EC50 value of 0.056 μM and a selective index (SI) of 1251, which were much better than those of NVP (EC50 = 0.23 μM) and DLV (EC50 = 0.51 μM). Some other compounds, 7k, 7c, 7j and 7e, were also endowed with a favorable anti-HIV-1 potency (EC50 = 0.034, 0.11, 0.11 and 0.16 μM, respectively). Some antivirally active compounds also showed moderate inhibitory activity against RT. Preliminary structure–activity relationships (SARs) and molecular modeling of these new analogs provide valuable avenues for future molecular optimization.A series of substituted nitropyridine derivatives were identified as potent HIV NNRTIs via a structure-based core refining approach.
Co-reporter:Zhaoqiang Liu, Wenmin Chen, Peng Zhan, Erik De Clercq, Christophe Pannecouque, Xinyong Liu
European Journal of Medicinal Chemistry 2014 Volume 87() pp:52-62
Publication Date(Web):24 November 2014
DOI:10.1016/j.ejmech.2014.09.054
•Novel DANAs derivatives were designed by a molecular hybridization approach.•The DANAs were designed to target the entrance channel of HIV-1 NNIBP.•6b11 has EC50 value of 27 nM against WT HIV-1 and SI > 12518.•6b5 has EC50 values of 29 nM and 6.1 μM against WT and mutant HIV-1 strains.•SARs were discussed in detail.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.A novel series of diarylnicotinamide derivatives (DANAs) were rationally designed synthesized and evaluated as inhibitors of HIV-1 wild-type and double mutant (K103N + Y181C) RES056 strains.
Co-reporter:Ye Tian, Deping Du, Diwakar Rai, Liu Wang, Huiqing Liu, Peng Zhan, Erik De Clercq, Christophe Pannecouque, Xinyong Liu
Bioorganic & Medicinal Chemistry 2014 Volume 22(Issue 7) pp:2052-2059
Publication Date(Web):1 April 2014
DOI:10.1016/j.bmc.2014.02.029
In our continuous efforts to identify novel potent HIV-1 NNRTIs, a novel class of 5,7-disubstituted pyrazolo[1,5-a]pyrimidine derivatives were rationally designed, synthesized and evaluated for their anti-HIV activities in MT4 cell cultures. Biological results showed that most of the tested compounds displayed excellent activity against wild-type HIV-1 with a wide range of EC50 values from 5.98 to 0.07 μM. Among the active compounds, 5a was found to be the most promising analogue with an EC50 of 0.07 μM against wild-type HIV-1 and very high selectivity index (SI, 3999). Compound 5a was more effective than the reference drugs nevirapine (by 2-fold) and delavirdine (by 2-fold). In order to further confirm their binding target, an HIV-1 RT inhibitory assay was also performed. Furthermore, SAR analysis among the newly synthesized compounds was discussed and the binding mode of the active compound 5a was rationalized by molecular modeling studies.A novel class of 5,7-disubstituted pyrazolo[1,5-a]pyrimidine derivatives were rationally designed, synthesized and evaluated for their anti-HIV activities in MT4 cell cultures.
Co-reporter:Peng Zhan, Yu'ning Song, Yukihiro Itoh, Takayoshi Suzuki and Xinyong Liu
Molecular BioSystems 2014 vol. 10(Issue 11) pp:2783-2799
Publication Date(Web):28 Aug 2014
DOI:10.1039/C4MB00385C
Human tankyrases 1 and 2 (TNKS1/2) are attractive pharmacological biotargets, especially for the treatment of specific types of cancer. This article provides a fairly comprehensive overview of the structural biology of the TNKS–inhibitor complex and the current medicinal chemistry strategies being used in the structure-based rational design of tankyrase-specific inhibitors.
Co-reporter:Xiao Li, Xueyi Lu, Wenmin Chen, Huiqing Liu, Peng Zhan, Christophe Pannecouque, Jan Balzarini, Erik De Clercq, Xinyong Liu
Bioorganic & Medicinal Chemistry 2014 22(19) pp: 5290-5297
Publication Date(Web):
DOI:10.1016/j.bmc.2014.08.001
Co-reporter:Xiao Li, Wenmin Chen, Ye Tian, Huiqing Liu, Peng Zhan, Erik De Clercq, Christophe Pannecouque, Jan Balzarini, Xinyong Liu
European Journal of Medicinal Chemistry 2014 80() pp: 112-121
Publication Date(Web):
DOI:10.1016/j.ejmech.2014.04.036
Co-reporter:Xueshun Wang, Boshi Huang, Xinyong Liu, Peng Zhan
Drug Discovery Today (January 2016) Volume 21(Issue 1) pp:118-132
Publication Date(Web):1 January 2016
DOI:10.1016/j.drudis.2015.08.004
•Advances in the combination of the CuAAC reaction with direct screening.•Before library assembly, the bioisosteric potential of 1,2,3-triazole should be confirmed.•The degree of diversity and drug-like properties are important to a 1,2,3-triazole library.•The potential undesirable influence of the crude samples in bioassay should be considered.•Other robust reactions suitable for rapid synthesis of diverse libraries will be exploited.The rapid assembly and in situ screening of focused combinatorial fragment libraries using CuAAC click chemistry is a highly robust and efficient strategy for establishing SAR and for discovering bioactive molecules. This review outlines the current status of this methodology in drug discovery application. The inherent limitations, challenges and prospects are critically discussed.
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