复旦大学：《药物设计学》课程教学资源（教学研究）基于配体结构的药物设计_Rational design of 2-pyrrolinones as inhibitors of HIV-1 integrase

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Author's personal copy Bioorganic Medicinal Chemistry Letters 21(2011)6724-6727 Contents lists available at SciVerse Science Direct Bioorganic Medicinal Chemistry Letters LSEVIER journalhomepagewww.elsevier.com/locate/bmcl Rational design of 2-pyrrolinones as inhibitors of HIV-1 integrase Kaiqing Ma, Penghui Wang a, Wei Fu, Xiaolong Wan, Lu Zhou a, Yong Chua.*, Deyong Ye.* ARTICLE IN FO A BSTRACT Article history HIV-1 integrase is an essential enzyme for viral replication and a validated target for the development of drugs against AIDS. With an aim to discover new potent inhibitors of Hiv-1 integrase, we developed a Accepted 15 September 2011 Available online 20 September 2011 of 2-pyrrolinones fitting all the features of the pharmacophore query were found through the screening of an in-house database. These candidates were successfully synthesized, and three of them showed strand transfer inhibitory activity, in which, one compound showed antiviral activity. Further mapping HIV integras analysis and docking studies affirmed these results. e 2011 Elsevier Ltd. All rights reserved. Structure-activity relationship(SAR) HIV-1 integrase(IN) is an important enzyme involved in medi- diversity have been successfully discovered by this approach. 1, 16-19 ating the full integration of proviral dNa into the human genome In this study, we focus on the development of the pharmacophore hich is essential for retroviral replication. This step consists of model, which was constructed based on the chemical features of fif two reactions with DNA. (1)The first step is referred to as 3 -pro- teen reported potent IN inhibitors. In fact, several Hiv iN pharmaco cessing which includes the endonucleolytic cleavage of the 3-ends phores have already been published. .16, 17 However to the best of of the viral DNA. (2)The second step, called strand transfer, results our knowledge, no attempts to build the model on these potent B- in the ligation of the 3'-processed proviral dNa into host chromo- diketo acid(DKA-like strand-transfer-selective inhibitors have some IN is an attractive target because no known human enzyme been reported. The resulting model can generate the common fea exists with similar activity. 2 Therefore, the addition of an IN inhib- tures of these effective inhibitors, and it is further utilized to predict itor to existing components of antiretroviral therapy is expected to novel bioactive molecules through the virtual screening of an in improve the outcome of therapy by potential synergism without house database. Eight representatives selected from a group of hits exacerbating toxicity have been successfully synthesized for a biological assay, and three The search for HIv-1 IN inhibitors has spanned more than a dec- of them exhibit strand transfer inhibition in vitro ade3-8The B-diketo acids have been identified as strand transfer Fifteen compounds(Fig. 1)for the training set were selected specific IN inhibitors and have been shown to be ' druggable. from literatures, 9-22 which was based on the principles of struc Many bioisosteres of B-diketo acids have been developed for years. tural diversity and certain coverage of activity range. These com- Some of them, such as 12(S1360) 2(L870810). 09(GS-9137). 1 pounds were provided to the HipHop module to generate the 6(GSK-364735) 2 shown in Figure 1 have already entered into common features of the pharmacophore model. The chemical struc- clinical phase. Moreover, Raltegravir, 4(MK-0518)3 has been tures of these drugs/ candidates were sketched using ISIS/Draw recently approved by fda as the first IN inhibitor. However, the(MDL Informations Systems, Inc., San Leandro, CA, USA)as shown inevitable emergence of drug resistant substitutions in IN will in Table 1, and their 3D structures with hydrogens were converted require a constant effort toward the discovery of novel inhibitors by CoRINa (a fast generation of high-quality 3D molecular models, tomaintainatherapeuticadvantageoverthevirusOurlaborato-MolecularNetworks,http://www.molecular-networks.com/prod- ries focus on finding new potent inhibitors of 3 -processing and ucts/corina). Atomic types and bond types of these compounds strand transfer especially the new selective strand transfer were inspected and modified manually, and gasteiger charges were assigned to them. Furthermore, the structures were nized b Pharmacophore modeling is one of the widely used analog-based means of molecular mechanics, using a Tripos force field encoded g getically reasonable conformations were built within the CATALYST (Version 4.0: Accelrys, Inc, 2003 )CatConf module using the Poling E-mail ad Algorithm. The 'Best conformer generation'option was used with see front matter o 2011 Elsevier Ltd. All rights reserved

Author's personal copy Rational design of 2-pyrrolinones as inhibitors of HIV-1 integrase Kaiqing Ma a , Penghui Wang a , Wei Fu a , Xiaolong Wan b , Lu Zhou a , Yong Chu a,⇑ , Deyong Ye a,⇑ aDepartment of Medicinal Chemistry, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 201203, PR China b Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, PR China article info Article history: Received 30 May 2011 Revised 1 September 2011 Accepted 15 September 2011 Available online 20 September 2011 Keywords: HIV integrase Inhibitors Pharmacophore Structure–activity relationship (SAR) abstract HIV-1 integrase is an essential enzyme for viral replication and a validated target for the development of drugs against AIDS. With an aim to discover new potent inhibitors of HIV-1 integrase, we developed a pharmacophore model based on reported inhibitors embodying structural diversity. Eight compounds of 2-pyrrolinones fitting all the features of the pharmacophore query were found through the screening of an in-house database. These candidates were successfully synthesized, and three of them showed strand transfer inhibitory activity, in which, one compound showed antiviral activity. Further mapping analysis and docking studies affirmed these results. 2011 Elsevier Ltd. All rights reserved. HIV-1 integrase (IN) is an important enzyme involved in mediating the full integration of proviral DNA into the human genome, which is essential for retroviral replication.1 This step consists of two reactions with DNA. (1) The first step is referred to as 30 -processing which includes the endonucleolytic cleavage of the 30 -ends of the viral DNA. (2) The second step, called strand transfer, results in the ligation of the 30 -processed proviral DNA into host chromosome. IN is an attractive target because no known human enzyme exists with similar activity.2 Therefore, the addition of an IN inhibitor to existing components of antiretroviral therapy is expected to improve the outcome of therapy by potential synergism without exacerbating toxicity.3 The search for HIV-1 IN inhibitors has spanned more than a decade.3–8 The b-diketo acids have been identified as strand transfer specific IN inhibitors and have been shown to be ‘druggable’.9 Many bioisosteres of b-diketo acids have been developed for years. Some of them, such as 12 (S1360),2 2 (L870810),10 9 (GS-9137),11 6 (GSK-364735)12 shown in Figure 1 have already entered into clinical phase. Moreover, Raltegravir, 4 (MK-0518)13 has been recently approved by FDA as the first IN inhibitor. However, the inevitable emergence of drug resistant substitutions in IN will require a constant effort toward the discovery of novel inhibitors to maintain a therapeutic advantage over the virus. Our laboratories focus on finding new potent inhibitors of 30 -processing and strand transfer especially the new selective strand transfer inhibitor. Pharmacophore modeling is one of the widely used analog-based drug design methods.14,15 Some IN inhibitors with structural diversity have been successfully discovered by this approach.11,16–19 In this study, we focus on the development of the pharmacophore model, which was constructed based on the chemical features of fifteen reported potent IN inhibitors. In fact, several HIV IN pharmacophores have already been published.3,16,17 However, to the best of our knowledge, no attempts to build the model on these potent bdiketo acid (DKA)-like strand-transfer-selective inhibitors have been reported. The resulting model can generate the common features of these effective inhibitors, and it is further utilized to predict novel bioactive molecules through the virtual screening of an inhouse database. Eight representatives selected from a group of hits have been successfully synthesized for a biological assay, and three of them exhibit strand transfer inhibition in vitro. Fifteen compounds (Fig. 1) for the training set were selected from literatures,19–22 which was based on the principles of structural diversity and certain coverage of activity range. These compounds were provided to the HipHop module to generate the common features of the pharmacophore model. The chemical structures of these drugs/candidates were sketched using ISIS/Draw (MDL Informations Systems, Inc., San Leandro, CA, USA) as shown in Table 1, and their 3D structures with hydrogens were converted by CORINA (a fast generation of high-quality 3D molecular models, Molecular Networks, http://www.molecular-networks.com/products/corina). Atomic types and bond types of these compounds were inspected and modified manually, and Gasteiger charges were assigned to them. Furthermore, the structures were optimized by means of molecular mechanics, using a Tripos force field encoded in SYBYL v6.9 (Tripos Associates, St. Louis, MO, USA). A set of energetically reasonable conformations were built within the CATALYST (Version 4.0; Accelrys, Inc., 2003) CatConf module using the Poling Algorithm.23 The ‘Best conformer generation’ option was used with 0960-894X/$ - see front matter 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.bmcl.2011.09.054 ⇑ Corresponding authors. E-mail address: cy110@fudan.edu.cn (Y. Chu). Bioorganic & Medicinal Chemistry Letters 21 (2011) 6724–6727 Contents lists available at SciVerse ScienceDirect Bioorganic & Medicinal Chemistry Letters journal homepage: www.elsevier.com/locate/bmcl

Author's personal copy K Ma et aL/ Bioorg. Med. Chem. Lett. 21(2011)6724-6722 25 aig olG o,20 res of the 15 training set compound Table 1 The iN inhibitory activities and the pharmacophore fit values of the 2-pyrrolinone derivatives Pharmacophore fit value 3-Processing(HM) Strand transfer (uM) 4-NO>-Ph- -(CHzh-Ph-4-0Me 22 3-Cl-Ph -(CHz)-Ph-4-0Me OH-Ph -(CH2上-Ph-4-OMe 4-NOx-Ph- -Me HIV-1 ry activity was measured according to the procedure described in Experimental Values are means of three determinations and deviation from the mean is <10% of the mean value b The overall fit value is 4. a 20 kcal mol energy cut off. Default settings were used for the structure multiconformers, most of which are based on an avail- other parameters. able compound library. The top ranked pharmacophore model (hypol) had the best Virtual screening was carried out in CATALYST after the library predictive power and statistical significance and was characterized compounds were minimized to the closest local minimum. a tota by the lowest total cost value(824009). the highest cost difference of 89 2-pyrrolinone compounds as primary hits were obtained by (100.0801), the lowest RMSD(0.5003), and the best correlation use of abest fit. Among them, compounds 20-27 show pharmaco- coefficient(0.9785). The hypothesis(Hypo1)(shown in Fig. 2A) phore fit values from 2.23 to 2.98 when one feature of the has four features, namely a hydrophobic aromatic feature(HrA) Hypol is allowed to be missing in the mapping process. In order and three H-bond acceptors(HBA). Three excluded volumes wer find more active compounds based on the corrected pharmaco- used to define the entrance of the active site. Compound 6 phore model, several representative hits selected on the basis of (GSK-364735)was mapped onto Hypol with high pharmacophore the pharmacophore fit value were synthesized and tested for their fit values (3.99)between the key chemical features of the com- HIV-1 IN inhibitory activities pound and the pharmacophore features of Hypol( Fig 2B). Synthetic approaches for preparation of the hit compounds are The Hypol model was applied to an in-house database as a depicted in Scheme 1. This strategy is concise with just a two-step query to find the compounds that fitted all the above features. process. Firstly, condensation of acetophenone(16)or 1-(pyridin- Our in-house database is a chemical database with searchable 3D 2-yl)ethanone(17) with diethyl oxalate in the presence of sodium

Author's personal copy a 20 kcal/mol energy cut off. Default settings were used for the other parameters. The top ranked pharmacophore model (Hypo1) had the best predictive power and statistical significance and was characterized by the lowest total cost value (82.4009), the highest cost difference (100.0801), the lowest RMSD (0.5003), and the best correlation coefficient (0.9785). The hypothesis (Hypo1) (shown in Fig. 2A) has four features, namely a hydrophobic aromatic feature (HRA) and three H-bond acceptors (HBA). Three excluded volumes were used to define the entrance of the active site. Compound 6 (GSK-364735) was mapped onto Hypo1 with high pharmacophore fit values (3.99) between the key chemical features of the compound and the pharmacophore features of Hypo1 (Fig. 2B). The Hypo1 model was applied to an in-house database as a query to find the compounds that fitted all the above features. Our in-house database is a chemical database with searchable 3D structure multiconformers, most of which are based on an available compound library. Virtual screening was carried out in CATALYST after the library compounds were minimized to the closest local minimum. A total of 89 2-pyrrolinone compounds as primary hits were obtained by use of a ‘best fit’. Among them, compounds 20–27 show pharmacophore fit values ranging from 2.23 to 2.98 when one feature of the Hypo1 is allowed to be missing in the mapping process. In order to find more active compounds based on the corrected pharmacophore model, several representative hits selected on the basis of the pharmacophore fit value were synthesized and tested for their HIV-1 IN inhibitory activities. Synthetic approaches for preparation of the hit compounds are depicted in Scheme 1. This strategy is concise with just a two-step process. Firstly, condensation of acetophenone (16) or 1-(pyridin- 2-yl) ethanone (17) with diethyl oxalate in the presence of sodium N O OH O S N S O Cl O2N O H Cl N OH O N N N HN N N OH N O S O H N O F F O OH N HN N O N N O OH NH O F NH O NN O N O OH O HO O F Cl N N OH O N H OH O F 1 2 12 4 9 6 13 N O OH O F S N O O 14 N N OH N H N O F N O O 3 N N O OH H N O F S O O 5 N H O OH F O Cl N O OH F O Cl HO O N OH O N H O F N S 7 N OH O N H O F N S O2N 8 O N O OH O 10 11 15 Figure 1. Chemical structures of the 15 training set compounds. Table 1 The IN inhibitory activities and the pharmacophore fit values of the 2-pyrrolinone derivatives N O OH R1 O R3 R2 Compound R1 R2 R3 Inhibition of HIV-1 integrase (IC50) a Pharmacophore fit valueb 30 -Processing (lM) Strand transfer (lM) 20 Ph 4-NO2-Ph– Ph 89 44 2.47 21 Ph Ph –(CH2)2-Ph-4-OMe 80 45 2.98 22 2-Py 3-Cl-Ph –(CH2)2-Ph-4-OMe 77 40 2.97 23 2-Py 3-Cl-Ph –Me >100 >100 2.59 24 Ph 4-OH-Ph –(CH2)2-Ph-4-OMe >100 100 2.97 25 Ph 3-Cl-Ph –Me >100 >100 2.23 26 Ph 4-NO2-Ph– –Me >100 >100 2.76 27 Ph Ph –CH2CH(CH2)2 >100 >100 2.26 a HIV-1 IN inhibitory activity was measured according to the procedure described in Experimental. Values are means of three determinations and deviation from the mean is <10% of the mean value. b The overall fit value is 4. K. Ma et al. / Bioorg. Med. Chem. Lett. 21 (2011) 6724–6727 6725

Author's personal copy 6726 K Ma et al/ Bioorg. Med. Chem. Lett. 21(2011)6724-6727 5.823 Figure 2. Pharmacophore models. (A)The best-ranked HipHop pharmacophore model(Hypol). The pharmacophore with four features are color coded as NS: H-bond cceptors(HBa)as green and hydrophobic aromatic(hra)features as blue Interfeature distances are given in Angstroms. (b)The mapping plot of Hiv-1 integrase inhil from the training set onto best HipHop pharmacophore model(Hypo1) superior to that of compounds substituted with methyl or isobut (23, 27). The R2 group seems also an impact factor for the activity (21 vS 24), an observation that warrants further study. For inhibi- tion of the 3'-processing reaction, the compound with pyridinyl as RI R=4-NOPh,Ph substitution(20). In order to rationalize the obtained results, we mapped the com- mon feature hypothesis 1 (Hypo1)onto compound 21. The mapping Scheme 1. General route for the synthesis of hits of 2-pyrrolinones Reagent plot showed a good agreement between chemical features of conditions:(a)NaH, toluene, rt, 90%;(b)R-NH2, R2-CHO, THF, rt, 90% compound and pharmacophoric features of Hypol(Fig. 3A). The benzene ring linked to the nitrogen atom and two carbonyl groups were well mapped onto the HRA, HBAl, and HBA3, respectively hydride furnish 2, 4-diketo esters(18, 19). At the second step, the Furthermore, we docked compound 21 into the IN active site ab- objects of 2-pyrrolinones(20-27)are successfully prepared via stracted from the IN crystal structures with the PDB entry code Mannich reaction following intramolecular ring closure in one 3L2V (Fig 3B)4 to build the binding model. Docking was performed pot just by treatment of such resulting esters with various amines with GOLD 4.1.2(The Cambridge Crystallographic Data Centre Cambridge, UK). The carbonyl groups of the ligand formed hydro- We examined the ability of the eight hits to inhibit IN catalytic gen bonds with the SER184 and HIS213 The binding mode of com- activities using in vitro assays. the chemical structures, IN inhibi- pound 21 in the active site was very close to that observed in the tory activities, and the pharmacophore fit values of these hits are crystal structure of Raltegravir with IN. Consequently, these Three compounds( 20, 21, and 22)show partial selectivity to- inhibitory activity of compounds 20-22 lanation for the in vitro hown in table 1 observations provided an excellent ex ard the In strand transfer This result agreed with the general be- Although the in inhibitory activity was not as potent as we ex- lief that the character of acyl-diketo can function as a selective pected, compound 22 exert potent inhibition on the stimulated strand transfer inhibitor. The presence of a bulky hydrophobic luciferase enzymatic activity of Hiv in TZM-bl cells with an ECso group at the nitrogen atom seems to be important due to the lack value of 0.317 HM(Table 2). More importantly, this compound pos of activity of derivatives with short and linear substituents in this sessed low cytotoxicities with a SI value of 83 position(20 vs 26, 21 vS 27, and 22 VS 23). The activity of the a pharmacophore-based virtual screening of the in-house li- ompound substituted with phenyl at the nitrogen atom(20)is brary was performed to identify HIV-1 IN inhibitors with novel ore model and the plot of the docking model. (A) Mapping of common feature hypothesis 1(Hypol) onto compounds 21 explained HIv-1IN inhibitory activity of 21.(B)Predicted binding orientation of compound 21 inside the HIv-1 IN active site

Author's personal copy hydride furnish 2,4-diketo esters (18, 19). At the second step, the objects of 2-pyrrolinones (20–27) are successfully prepared via Mannich reaction following intramolecular ring closure in one pot just by treatment of such resulting esters with various amines and aldehydes. We examined the ability of the eight hits to inhibit IN catalytic activities using in vitro assays. The chemical structures, IN inhibitory activities, and the pharmacophore fit values of these hits are shown in Table 1. Three compounds (20, 21, and 22) show partial selectivity toward the IN strand transfer. This result agreed with the general belief that the character of acyl-diketo can function as a selective strand transfer inhibitor. The presence of a bulky hydrophobic group at the nitrogen atom seems to be important due to the lack of activity of derivatives with short and linear substituents in this position (20 vs 26, 21 vs 27, and 22 vs 23). The activity of the compound substituted with phenyl at the nitrogen atom (20) is superior to that of compounds substituted with methyl or isobutyl (23, 27). The R2 group seems also an impact factor for the activity (21 vs 24), an observation that warrants further study. For inhibition of the 30 -processing reaction, the compound with pyridinyl as R1 group (22) is more potent than the compound with a phenyl substitution (20). In order to rationalize the obtained results, we mapped the common feature hypothesis 1 (Hypo1) onto compound 21. The mapping plot showed a good agreement between chemical features of the compound and pharmacophoric features of Hypo1 (Fig. 3A). The benzene ring linked to the nitrogen atom and two carbonyl groups were well mapped onto the HRA, HBA1, and HBA3, respectively. Furthermore, we docked compound 21 into the IN active site abstracted from the IN crystal structures with the PDB entry code 3L2V (Fig. 3B)24 to build the binding model. Docking was performed with GOLD 4.1.2 (The Cambridge Crystallographic Data Centre: Cambridge, UK). The carbonyl groups of the ligand formed hydrogen bonds with the SER184 and HIS213. The binding mode of compound 21 in the active site was very close to that observed in the crystal structure of Raltegravir with IN.24 Consequently, these observations provided an excellent explanation for the in vitro inhibitory activity of compounds 20–22. Although the IN inhibitory activity was not as potent as we expected, compound 22 exert potent inhibition on the stimulated luciferase enzymatic activity of HIV in TZM-bl cells with an EC50 value of 0.317 lM (Table 2). More importantly, this compound possessed low cytotoxicities with a SI value of 83. A pharmacophore-based virtual screening of the in-house library was performed to identify HIV-1 IN inhibitors with novel Figure 3. The mapping plot of the pharmacophore model and the plot of the docking model. (A) Mapping of common feature hypothesis 1 (Hypo1) onto compounds 21, which explained HIV-1IN inhibitory activity of 21. (B) Predicted binding orientation of compound 21 inside the HIV-1 IN active site. Figure 2. Pharmacophore models. (A) The best-ranked HipHop pharmacophore model (Hypo1). The pharmacophore with four features are color coded as follows: H-bond acceptors (HBA) as green and hydrophobic aromatic (HRA) features as blue. Interfeature distances are given in Angstroms. (B) The mapping plot of HIV-1 integrase inhibitor 6 from the training set onto best HipHop pharmacophore model (Hypo1). R1 O + O O O O R1 O OH O O N O OH R1 R R 2 3 a b O 16 R1 = Ph 17 R1 = 2-Py 18 R1= Ph 19 R1 = 2-Py 20 - 27 R1 = Ph-, 2-Py R2 = 4-NO2-Ph-, Ph-, 3-Cl-Ph-, 4-OH-PhR3 = Ph-, -Me, -CH2(CH3)2 -(CH2) 2-Ph-4-OMe Scheme 1. General route for the synthesis of hits of 2-pyrrolinones. Reagent and conditions: (a) NaH, toluene, rt, 90%; (b) R3 -NH2, R2 -CHO, THF, rt, 90%. 6726 K. Ma et al. / Bioorg. Med. Chem. Lett. 21 (2011) 6724–6727

Author's personal copy K Ma et aL/Bioorg. Med. Chem. Lett. 21(2011)6724-6722 6727 Table 2 implementary data The antiviral effect of the 2-pyrrolinone derivatives plementary data associated with this arti CCso(HM the online version, at doi: 10. 1016/j bmcl2011.09.054 References and notes N/A 2. Billich, A Curr. Opin. Investig. Drugs 20 Effective concentration required to protect TZM-bl cells against the stimulated 3. Pommier, Y. Johnson, AA; Marchand, C. Nat Rev. Drug Disc. 2005, 4, 23 yda, F Hickman, A Jenkins. T: Engelman, A: Craigie, R: Davies, D Sc b Cytostatic concentration required to kill TZM-bl cells by 50% 1994,266198 Selectivity index(Sn)is a ratio of CCso value/ECso va N/A: no activity 6.Nicki V: Tang. Y:Nicklaus, M:Pommier,YJMed.Chem.2002.45,3184 g, H: Mazumder, A: Sunder, S. Chen. ): Milne, G: Pommiers, Y.. Med. Chem 1997, 40, 920. 7. Nair, V: Chi, G: Ptak, R: Neamati, N.J. Med. Chem. 2006. 49, 445. Iji, M. Fujiwara, T: Garvey, E: Golden, scaffolds. Firstly, the common feature of six clinical candidates Hazen, R: Jeffrey, L; ras visualized by generating a pharmacophore model. Secondly. based on the application of resulting pharmacophore model, eight Espeseth, A Gabryelski, L: Schleif, w: Blau, C: Miller, M. D Science 2000, 28 compounds with a common 2-pyrrolinones core were selected 10. Blair, W: Perros, M. Expet Opin. Investig Drugs 2004, 13, 1065 from 89 primary hits to be synthesized in a concise strategy. Their Dayam, R: Al-Mawsawi, L Q: Zawahir, Z: witvrouw, M: Debyser, Z; Neamati, catalytic IN inhibitory activities were tested as well. The com- N.. Med. Chem.2008.51.1136 pounds 20, 21, and 22 exhibit strand transfer inhibitory activity with ICso values of 44, 45, and 40 HM, respectively. Furthermore 12.Garvey.EP:Johns/ schall Boros, EE: Thompson, JB: We A. Gartland, M.-; Foster, S.A.; Miller, the best antiviral effect was exhibited by compound 22 with al L: Wakasa-Morimoto. C: Miki. S. Nakahara K: Noshi. T. Sat Iwata, T. ECso value of 0.317 HM. The mapping analysis and the docking tudy showed that the p-methoxylphenyl moiety was well docked umma, V Abstracts of Papers, 232nd ACS National Meeting, San Francisco, CA, in the vicinity of the aromatic pocket, forming hydrophobic inter- 14. Banes, M R: Harland, L; Foord, S.M.: Hall,MD :Dix, I:Thomas,S. Williams- tent antiviral agents. Further structural optimization based on this 16. Dayam, R: Sanchez. T: Neamati,NJMed. Chem. 2005,48,8009 pharmacophore model and the potent inhibitor structure is R: Sanchez, T: Clement, O: Shoemaker, R: Sei, S: Neamati, N J Med. Chem.2005,48,111 18. De Luca. L: Barreca. M. L: Ferro. S. Christ. F: Iraci, N. Gitto. R: Monforte. A 19. Dayam, R: Al-Mawsawi, L Q: Neamati, N. Bioorg. Med. Chem Lett. 2007, 17, 20. Sato, M: Motomura. T: Aramaki, H: Matsuda, T. Yamashita, M: Ito We thank Nouri Neamati, associate professor of University of ami, H: Matsuzaki, Y, Watanabe, w: Yamataka, K/. Med. Chem. 2006. Southern California, for performing the biological assays, and Huifang Liu for the help with the work of pharmacophore modeling 21. Boros, E: Johns, B: Garvey, E; Koble, C: Miller, w. Bioorg. Med. Chem Lett 2006,16,5668 and docking. We gratefully acknowledge Xiaoyan Zhang, professor 22. Di Francesco, M: Pace, P. Fiore, F: Naimo, F: Bonelli, F: Rowley. M: Summa of Fudan University for the antiviral test We also acknowledge the 23. Smellie, A : Teig. S. L; Towbin, P.j.CompuT. Chem 1995. 16. 17 financial support from National Drug Innovative Program(Grant 24. 232." pta, S.S. Valkov, E: Engelman, A. Cherepanov, P Nature 2010,464 No.2009ZX09301-011)

Author's personal copy scaffolds. Firstly, the common feature of six clinical candidates was visualized by generating a pharmacophore model. Secondly, based on the application of resulting pharmacophore model, eight compounds with a common 2-pyrrolinones core were selected from 89 primary hits to be synthesized in a concise strategy. Their catalytic IN inhibitory activities were tested as well. The compounds 20, 21, and 22 exhibit strand transfer inhibitory activity with IC50 values of 44, 45, and 40 lM, respectively. Furthermore, the best antiviral effect was exhibited by compound 22 with an EC50 value of 0.317 lM. The mapping analysis and the docking study showed that the p-methoxylphenyl moiety was well docked in the vicinity of the aromatic pocket, forming hydrophobic interactions. The analysis is well supported by the biological activities. These results provide useful information for the design of new potent antiviral agents. Further structural optimization based on this pharmacophore model and the potent inhibitor structure is in progress. Acknowledgments We thank Nouri Neamati, associate professor of University of Southern California, for performing the biological assays, and Huifang Liu for the help with the work of pharmacophore modeling and docking. We gratefully acknowledge Xiaoyan Zhang, professor of Fudan University, for the antiviral test. We also acknowledge the financial support from National Drug Innovative Program (Grant No. 2009ZX09301-011). Supplementary data Supplementary data associated with this article can be found, in the online version, at doi:10.1016/j.bmcl.2011.09.054. References and notes 1. Neamati, N. Expert Opin. Ther. Patents 2002, 12, 709. 2. Billich, A. Curr. Opin. Investig. Drugs 2003, 4, 206. 3. Pommier, Y.; Johnson, A. A.; Marchand, C. Nat. Rev. Drug Disc. 2005, 4, 236. 4. Dyda, F.; Hickman, A.; Jenkins, T.; Engelman, A.; Craigie, R.; Davies, D. Science 1994, 266, 1981. 5. 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Table 2 The antiviral effect of the 2-pyrrolinone derivatives Compound Anti-HIV-1 activity SIc EC50a (lM) CC50b (lM) 20 N/A 790 21 N/A 830 22 0.317 26.6 83.7 24 N/Ad 459 a Effective concentration required to protect TZM-bl cells against the stimulated luciferase enzymatic activity of HIV by 50%. b Cytostatic concentration required to kill TZM-bl cells by 50%. c Selectivity index (SI) is a ratio of CC50 value/EC50 value. d N/A: no activity. K. Ma et al. / Bioorg. Med. Chem. Lett. 21 (2011) 6724–6727 6727

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复旦大学：《药物设计学》课程教学资源（教学研究）基于配体结构的药物设计_Rational design of 2-pyrrolinones as inhibitors of HIV-1 integrase