HIV-1 integrase (IN) is an attractive and validated target for the development of novel therapeutics against AIDS. Significant efforts have been devoted to the identification of IN inhibitors using various methods. In this context, through virtual screening of the NCI database and structure-based drug design strategies, we identified several pharmacophoric fragments and incorporated them on various aromatic or heteroaromatic rings. In addition, we designed and synthesized a series of 5-aryl(heteroaryl)-isoxazole-3-carboxylic acids as biological isosteric analogues of β-diketo acid containing inhibitors of HIV-1 IN and their derivatives. Further computational docking studies were performed to investigate the mode of interactions of the most active ligands with the IN active site. Results suggested that some of the tested compounds could be considered as lead compounds and suitable for further optimization.
AbildgaardJBolvigS & HansenPE (1998) Unraveling the electronic and vibrational contributions to deuterium isotope effects on 13C chemical shifts using ab initio model calculations. Analysis of the observed isotope effects on sterically perturbed intramolecular hydrogen-bonded o-hydroxy acyl aromatics. Journal of the American Chemical Society120: 9063–9069.
2.
AdamWFellR & ShulzMH (1993) Synthesis and fluoride ion- triggered chemiluminescence (CIEEL mechanism) of siloxy-substituted benzofuran dioxeatanes. Tetrahedron49: 2227–2238.
3.
AnthonyNJ (2004) HIV-1 integrase: A target for new AIDS chemotherapeutics. Current Topics in Medicinal Chemistry4: 979–990.
4.
Asante-AppiahE & SkalkaAM (1997) Molecular mechanism in retrovirus DNA integration. Antiviral Research36: 139–156.
5.
Asante-AppiahE & SkalkaAM (1999) HIV-1 integrase: Structural organization, conformational changes, and catalysis. Advances in Virus Research52: 351–369.
6.
Asante-AppiahEMerkelG & SkalkaAM (1998) Purification of untagged retroviral integrases by immobilized metal ion affinity chromatography. Protein Expression & Purification12: 105–110.
7.
AutreyRL & TahkFC (1967) The synthesis and stereochemistry of some isatylideneacetic acid derivatives. Tetrahedron23: 901–917.
8.
BarrecaMLLeeKWChimirriA & BriggsJM (2003) Molecular dynamics studies of the wild-type and double mutant HIV-1 integrase complexed with the 5CITEP inhibitor: Mechanism for inhibition and drug resistance. Biophysical Journal8: 1450–1463.
9.
BattagliaADondoniA & TaddeiF (1970) Isoxazoles from nitrile oxides and acetylenes. Substituent effect on the pmr spectra of disubstituted isoxazoles. Journal of Heterocyclic Chemistry7: 721–724.
10.
BaumstarkALChrisopeDRKeelRA & BoykinDW (1980) A carbon-13 nmr assignment study of 3,5-diarylisoxazoles. Journal of Heterocyclic Chemistry17: 1719–1721.
11.
BillichA (2003) S-1360 Shionogi-GlaxoSmithKline. Current Opinion in Investigational Drugs4: 206–209.
12.
BrownPO (1998) In Retroviruses. Edited by CoffinJMHughesSH and VarmusHE. Cold Spring Harbor: Cold Spring Harbor Press, pp. 161–203.
13.
BuolamwiniJK & AssefaH (2002) CoMFA and CoMSIA 3D docking studies on conformationally-restrained cinnamoyl HIV-1 integrase inhibitors: Exploration of a binding mode at the active site. Journal of Medicinal Chemistry45: 841–852.
14.
BushmanFD & CraigieR (1991) Activities of human immunodeficiency virus (HIV) integration protein in vitro: Specific cleavage and integration of HIV DNA. Proceedings of the National Academy of Sciences, USA88: 1339–1343.
15.
ChangGGuidaWC & StillWC (1989) An internal coordinate Monte Carlo method for searching conformational space. Journal of the American Chemical Society111: 4379–4386.
16.
ChenI-JNeamatiN & MacKerrelA (2002) Structure-based inhibitor design targeting HIV-1 integrase. Current Drug Targets — Infectious Disorders2: 217–234.
17.
ChenI-JNeamatiNNicklausMCOrrAAndersonLBarchiJJJrKelleyJAPommierY & MacKerrelADJr (2000) Identification of HIV-1 integrase inhibitors via three-dimensional database searching using ASV and HIV-1 integrases as targets. Bioorganic & Medicinal Chemistry8: 2385–2398.
18.
ChiuTK & DaviesDR (2004) Structure and function of HIV-1 integrase. Current Topics in Medicinal Chemistry4: 965–977.
19.
ChuppJP & OlinJF (1967) Chemical and physical properties of some rotational isomers of α-haloacetanilides. A novel unreactive halogen system. Journal of the Chemical Society — Perkin Transactions1: 2297–2303.
20.
D'AngeloJMouscadetJFDesmaeleDZouhiriF & LehH (2001) HIV-1 integrase: The next target for AIDS therapy?Pathologie Biologie49: 237–246.
21.
DayamR & NeamatiN (2003) Small-molecule HIV-1 integrase inhibitors: The 2001–2002 update. Current in Pharmaceutical Design9: 1789–1802.
22.
De ClercqE (2000) Current lead natural products for the chemotherapy of human immunodeficiency virus (HIV) infection. Medicinal Research Reviews20: 323–349.
23.
EllisonV & BrownPO (1994) A stable complex between integrase and viral DNA ends mediates human immunodeficiency virus integration in vitro. Proceedings of the National Academy of Sciences, USA91: 7316–7320.
24.
EmersonDWTitusRL & GonzãlesRM (1991) Evidence for ketene intermediates in the decarbonylation of 2,4-dioxo acids and esters and 2-oxobutanedioc acid esters. Journal of Organic Chemistry56: 5301–5307.
25.
GarridoDOABuldainG & FrydmanB (1984) 1,4-Diaminoalkanes from pyrroles. A new synthetic approach to subtituted putrescines. Journal of Organic Chemistry49: 2619–2622.
26.
GasteigerJ & MarsiliM (1980) Iterative partial equalization of orbital electronegativity — A rapid access to atomic charges. Tetrahedron36: 3219–3228.
27.
GoldgurYCraigieRCohenGHFujiwaraTYoshinagaTFujishitaTSugimotoHEndoTMuraiH & DaviesDR (1999) Structure of the HIV-1 integrase catalytic domain complexed with an inhibitor: A platform for antiviral drug design. Proceedings of the National Academy of Sciences, USA96: 13040–13043.
28.
GroblerJAStillmockKHuBWitmerMFelockPEspesethASWolfeAEgbertsonMBourgeoisMMelamedJWaiJSYoungSVaccaJ & HazudaDJ (2002) Diketo acid inhibitor mechanism and HIV-1 integrase: Implication for metal binding in the active site of phosphotranferase enzymes. Proceedings of the National Academy of Sciences, USA99: 6661–6666.
29.
HazudaDJAnthonyNJGomezRPJollySMWaiJSZhuangLFisherTEEmbreyMGuareJPJrEgbertsonMSVaccaJPHuffJRFelockPJWitmerMVStillmockKADanovichRGroblerJMillerMDEspesethASJinLChenIWLinJHKassahunKEllisJDWongBKXuWPearsonPGSchleifWACorteseREminiESummaVHollowayMK & YoungSD (2004) A naphthyridine carboxamide provides evidence for discordant resistance between mechanistically identical inhibitors of HIV-1 integrase. Proceedings of the National Academy of Sciences, USA101: 11233–11238.
30.
HazudaDJFelockPJHastingsJCPramanickB & WolfeAL (1997) Differential divalent cation requirements uncouple the assembly and catalityc reactions of human immunodeficiency virus type 1 integrase. Journal of Virology71: 7005–7011.
31.
HazudaDJFelockPJWitmerMWolfeAStillmockKGroblerJAEspesethAGabryelskiLSchleifWBlauC & MillerMD (2000) Inhibitors of strand transfer that prevent integration and inhibit HIV-1 replication in cells. Science287: 646–650.
32.
HennessyEJ & BuchwaldSL (2003) Synthesis of substituted oxindoles from α-chloroacetanilides via palladium-catalyzed C-H functionalization. Journal of the American Chemical Society125: 12084–12085.
33.
HongHNeamatiNWangSNicklausMCMazumderAZhaoHBurkeTRJrPommierY & MilneGWA (1997) Discovery of HIV-1 integrase inhibitors by pharmacophore searching. Journal of Medicinal Chemistry40: 930–936.
34.
HongHNeamatiNWinslowHEChristensenJLOrrAPommierY & MilneGW (1998) Identification of HIV-1 integrase inhibitors based on a four-point pharmacophore. Antiviral Chemistry & Chemotherapy6: 461–472.
35.
HouseHOLarsonJK & MuellerHC (1968) Perhydroindan derivatives. X. The Diels-Alder reaction with 6-methoxyindene derivatives. Journal of Organic Chemistry33: 961–968.
36.
JahangirBrookMAMacLeanDB & HollandHL (1987) A new route to the indolopyridonaphthyridine ring system: Synthesis of N-benzyl-13b,14-dihydronauclefine and N-benzyl-13b,14-dihydroangustine. Tetrahedron43: 5761–5768.
37.
JohnsonAAMarchandC & PommierY (2004) HIV-1 integrase inhibitors: A decade of research and two drugs in clinical trial. Current Topics in Medicinal Chemistry4: 1059–1077.
38.
KatritzkyAR & AkutagawaK (1985) Carbon dioxide: A reagent for the protection of nucleophilic centres and the simultaneous activation of alternative locations to electrophilic attack. Part I. A new synthetic method for the 2-substitution of 1-unsubstituted indoles. Tetrahedron Letters26: 5935–5938.
39.
KeesKLCaggianoTJSteinerKEFitzgeraldJJKatesMJChristosTEKulishoffJMMooreRD & McCalebML (1995) Studies on new acidic azoles as glucose-lowering agents in obese, diabetic db/db mice. Journal of Medicinal Chemistry38: 617–628.
40.
KingGSMagnusPD & RzepaHS (1972) Reductive and oxidative cleavage. Journal of the Chemical Society- Perkin Transactions1: 437–443.
41.
KrausGAFultonBS & WooHyung S (1984) Aliphatic acyl transfer in the Baker-Venkataraman reaction. Journal of Organic Chemistry49: 3212–3214.
42.
KulkoskyJJonesKSKatzRAMackJP & SkalkaAM (1992) Residues critical for retroviral integrative recombination in a region that is highly conserved among retroviral/retrotransposon integrases and bacterial insertion sequence transposases. Molecular & Cellular Biology12: 2331–2338.
43.
LipinskiCA (1986) Bioisosterism in drug design. In Annual Reports in Medicinal Chemistry, vol. 2. Edited by AllenC. London: Academic Press, pp. 283–291.
44.
LongDRRichardsCD & RossMSF (1978) The stereochemistry of 2-oxoindolin-3-ylidene derivatives. Journal of Heterocyclic Chemistry15: 633–636.
45.
LongYQJiangXHDayamRSanchezTShoemakerRSeiS & NeamatiN (2004) Rational design and synthesis of novel dimeric diketoacid-containing inhibitors of HIV-1 integrase: Implication for binding to two metal ions on the active site of integrase. Journal of Medicinal Chemistry47: 2561–2573.
46.
MakhijaMTKasliwalRTKulkarniVM & NeamatiN (2004) De novo design and synthesis of HIV-1 integrase inhibitors. Bioorganic & Medicinal Chemistry12: 2317–2333.
47.
MarchandCJohnsonAAKarkiRGPaisGCZhangXCowansageKPatelTANicklausMCBurkeTRJr & PommierY (2003) Metal-dependent inhibition of HIV-1 integrase by beta-diketo acids and resistance of the soluble double-mutant (F185K/C280S). Molecular Pharmacology64: 600–609.
48.
MaurinCBaillyF & CotelleP (2003) Structure-activity relationships of HIV-1 integrase inhibitors- enzyme-ligand interactions. Current Medicinal Chemistry10: 1795–1810.
49.
MelekMJonesJMO'DeaMHPaisGBurkeTRJrPommierYNeamatiN & GellertM (2002) Effect of HIV integrase inhibitors on the RAG1/2 recombinase. Proceedings of the National Academy of Sciences, USA99: 134–137.
50.
MilneGWANicklausMCDriscollJS & WangS (1994) National Cancer Institute drug information system 3D database. Journal of Chemical Information & Computer Sciences34: 1219–1224.
51.
MorrisGMGoodsellDSHallidayRSHueyRHartWEBelewRK & OlsonAJ (1998) Automated docking using a Lamarckian genetic algorithm an empirical binding free energy function. Journal of Computational Chemistry19: 163–166.
52.
MorrisGMGoodsellDSHueyR & OlsonA (1996) Distributed automated docking of flexible ligands to proteins: Parallel application of AutoDock 2.4*. Journal of Computational-Aided Molecular Design10: 293–304.
53.
NeamatiN (2001) Structure-based HIV-1 integrase inhibitor design: A future perspective. Expert Opinion on Investigational Drugs10: 281–296.
54.
NeamatiN (2002) Patented small molecule inhibitors of HIV-1 integrase: A ten-year saga. Expert Opinion on Therapeutic Patents12: 709–724.
55.
NeamatiN & BarchiJJJr (2002) New paradigms in drug design and discovery. Current Topics in Medicinal Chemistry2: 211–227.
56.
NeamatiNHongHMazumderAWangSSunderSNicklausMCMilneGWAProskaB & PommierY (1997) Depsides and Depsidones as inhibitors of HIV-1 Integrase: Discovery of novel inhibitors through 3D database searching. Journal of Medicinal Chemistry40: 942–951.
57.
NeamatiNHongHOwenJMSunderSWinslowHEChristensenJLZhaoHBurkeTRJrMilneGW & PommierY (1998) Salicylhydrazine-containing inhibitors of HIV-1 integrase: Implication for a selective chelation in the integrase active site. Journal of Medicinal Chemistry41: 3202–3209.
58.
NeamatiNHongHSunderSMilneGW & PommierY (1997) Potent inhibitors of human immunodeficiency virus type-1 integrase: Identification of a novel four-point pharmacophore and tetracyclines as novel inhibitors. Molecular Pharmacology52: 1041–1055.
59.
NeamatiNLinZKarkiRGOrrACowansageKStrumbergDPaisGCVoigtJHNicklausMCWinslowHEZhaoHTurpinJAYiJSkalkaAMBurkeTRJr & PommierY (2002) Metal-dependent inhibition of HIV-1 integrase. Journal of Medicinal Chemistry45: 5661–5670.
60.
NeamatiNMarchandC & PommierY (2000) HIV-1 integrase inhibitors: Past, present, and future. In Advances in Pharmacology, vol. 49. San Diego: Academic Press, pp. 147–165.
61.
NeamatiNMarchandCWinslowHE & PommierY (2001) Human immunodeficiency virus type 1 integrase-targeted inhibitor design. Antiretroviral Therapy5: 87–104.
62.
NiHSotrifferCA & McCammonJA (2001) Ordered water and ligand mobility in the HIV-1 integrase-5CITEP complex: A molecular dinamics study. Journal of Medicinal Chemistry44: 3043–3047.
63.
NicklausMCNeamatiNHongHMazumderASunderSChenJMilneGWA & PommierY (1997) HIV-1 integrase pharmacophore: Discovery of inhibitors through three-dimensional database searching. Journal of Medicinal Chemistry40: 920–929.
64.
OualiMLaboulaisCLehHGillDXhuvaniEZouhiriFDesmaeleDd'AngeloJAuclairC & MouscadetJF (2000) Tautomers of styrylquinoline derivatives containing a methoxy substituent: Computation of their population in aqueous solution and their interaction with RSV integrase catalytic core. Acta Biochimica Polonica47: 11–22.
65.
PaisGCG & BurkeTRJr (2002) Novel aryl diketo-containig inhibitors of HIV-1 integrase. Drugs of the Future27: 1101–1111.
66.
PaisGCZhangXMarchandCNeamatiNCowansageKSvarovskaiaESPathakVKTangYNicklausMPommierY & BurkeTRJr (2002) Structure activity of 3-aryl-1,3-diketo-containing compounds as HIV-1 integrase inhibitors. Journal of Medicinal Chemistry45: 3184–3194.
67.
ParrilAL (2003) HIV-1 integrase inhibition: Binding sites, structure activity relationships and future perspectives. Current Medicinal Chemistry10: 1875–1888.
68.
PataniGA & LaVoieE (1996) Bioisosterism: A rational approach in drug design. Chemical Reviews96: 3147–3176.
69.
PenningTDTalleyJJBertenshawSRCarterJSCollinsPWDocterSGranetoMJLeeLFMalechaJWMiyashiroJMRogersRSRogierDJYuSSAndersonGDBurtonEGCogburnJNGregorySAKoboldtCMPerkinsWESeibertKVeenhuizenAWZhangYY & IsaksonPC (1997) Synthesis and biological evaluation of the 1,5-diarylpyrazole class of cyclooxygenase-2 inhibitors: Identification of 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide (SC-58635, celecoxib). Journal of Medicinal Chemistry40: 1347–1365.
70.
PommierYMarchandC & NeamatiN (2000) Retroviral integrase inhibitors year 2000: Update and perspectives. Antiviral Research47: 139–148.
71.
PommierYPilonABajajKMazumderA & NeamatiN (1997) HIV-1 integrase as a target for antiviral drugs. Antiviral Chemistry & Chemotherapy8: 483–503.
72.
RooneyCSRandallWCStreeterKBZieglerCCragoeEJJrSchwamHMichelsonSRWilliamsHWEichlerEDugganDEUlmEH & NollRM (1983) Inhibitors of glycolic acid oxidase. 4-Substituted 3-hydroxy-1H-pyrrole-2,5-dione derivatives. Journal of Medicinal Chemistry26: 700–714.
73.
SargesRHowardHRKoeBK & WeissmanA (1989) A novel class of ‘GABAergic’ agents: 1-aryl-3-(aminoalkylidene)oxindoles. Journal of Medicinal Chemistry32: 437–444.
74.
SchamesJRHenchmanRHSiegelJSSotrifferCANiH & McCammonJA (2004) Discovery of a novel binding trench in HIV integrase. Journal of Medicinal Chemistry47: 1879–1981.
75.
SechiMAngotziGDallocchioRDessìACartaFSanniaLMarianiAFioriSSanchezTMovsessianLPlasenciaC & NeamatiN (2004) Design and synthesis of novel dihydroxyindole-2-carboxylic acids as HIV-1 integrase inhibitors. Antiviral Chemistry & Chemotherapy15: 67–81.
76.
SechiMDerudasMDallocchioRDessìABacchiASanniaLCartaFPalombaMRagabOChanCShoemakerRSeiSDayamR & NeamatiN (2004) Design and synthesis of novel indole β-diketo acid derivatives as HIV-1 integrase inhibitors. Journal of Medicinal Chemistry47: 5298–5310.
77.
SechiMSanniaLOrecchioniMCartaFPagliettiG & NeamatiN (2003) Structural investigation of 3,5-disubstituted isoxazoles by 1H-nuclear magnetic resonance. Journal of Heterocyclic Chemistry40: 1097–1102.
78.
SotrifferCANiH & McCammonAJ (2000) HIV-1 Integrase inhibitor interactions at the active site: Prediction of binding modes unaffected by crystal packing. Journal of the American Chemical Society122: 6136–6137.
79.
SotrifferCANiH & McCammonAJ (2000) Active site binding modes of HIV-1 Integrase inhibitors. Journal of Medicinal Chemistry43: 4109–4117.
TanakaATerasawaTHagiharaHSakumaYIshibeNSawadaMTakasugiH & TanakaH (1998) Inhibitors of acyl-CoA:cholesterol O-acyltransferase. 2. Identification and structure-activity relationships of a novel series of N-alkyl-N-(heteroaryl-substituted benzyl)-N'-arylureas. Journal of Medicinal Chemistry41: 2390–2410.
82.
WaiJSEgbertsonMSPayneLSFisherTEEmbreyMWTranLOMelamedJYLangfordHMGuareJPJrZhuangLGreyVEVaccaJPHollowayMKNaylor-OlsenAMHazudaDJFelockPJWolfeALStillmockKASchleifWAGabryelskiLJ & YoungSD (2000) 4-Aryl-2,4-dioxobutanoic acid inhibitors of HIV-1 integrase and viral replication in cells. Journal of Medicinal Chemistry43: 4923–4926.
83.
ZhaoHNeamatiNMazumderASunderSPommierY & BurkeTRJr (1997) Hydrazide-containing inhibitors of HIV-1 integrase. Journal of Medicinal Chemistry40: 1186–1194.
