Design, synthesis and structure-activity relationships of 4-phenyl-1H-1,2,3-triazole phenylalanine derivatives as novel HIV-1 capsid inhibitors with promising antiviral activities.

Abstract:

:HIV-1 CA is involved in different stages of the viral replication cycle, performing essential roles in both early (uncoating, reverse transcription, nuclear import, integration) and late events (assembly). Recent efforts have demonstrated HIV-1 CA protein as a prospective therapeutic target for the development of new antivirals. The most extensively studied CA inhibitor, PF-3450074 (PF-74, discovered by Pfizer), that targets an inter-protomer pocket within the CA hexamer. Herein we reported the design, synthesis, and biological evaluation of a series of 4-phenyl-1H-1,2,3-triazole phenylalanine derivatives as HIV-1 CA inhibitors based on PF-74 scaffold. Most of the analogues demonstrated potent antiviral activities, among them, the anti-HIV-1 activity of 6a-9 (EC50 = 3.13 μM) is particularly prominent. The SPR binding assay of selected compounds (6a-9, 6a-10, 5b) suggested direct and effective interaction with recombinant CA proteins. The mechanism of action studies also demonstrated that 6a-9 displays the effects in both the early and late stages of HIV-1 replication. To explore the potential binding mode of the here presented analogues, 6a-9 was analyzed by MD simulation to predict its binding to the active site of HIV-1 CA monomer. In conclusion, this novel series of antivirals can serve as a starting point for the development of a new generation of HIV-1 treatment regimen and highlights the potentiality of CA as a therapeutic target.

journal_name

Eur J Med Chem

authors

Sun L,Huang T,Dick A,Meuser ME,Zalloum WA,Chen CH,Ding X,Gao P,Cocklin S,Lee KH,Zhan P,Liu X

doi

10.1016/j.ejmech.2020.112085

subject

Has Abstract

pub_date

2020-03-15 00:00:00

pages

112085

eissn

0223-5234

issn

1768-3254

pii

S0223-5234(20)30052-0

journal_volume

190

pub_type

杂志文章
  • Single-molecule chemiluminescent photosensitizer for a self-activating and tumor-selective photodynamic therapy of cancer.

    abstract::While photodynamic therapy is known for significant advantages over conventional cancer therapies, its dependence on light has limited it to treating tumors on or just under the skin or on the outer lining of organs/cavities. Herein, we have developed a single-molecule photosensitizer capable of intracellular self-act...

    journal_title:European journal of medicinal chemistry

    pub_type: 杂志文章

    doi:10.1016/j.ejmech.2019.111683

    authors: Pinto da Silva L,Núnez-Montenegro A,Magalhães CM,Ferreira PJO,Duarte D,González-Berdullas P,Rodríguez-Borges JE,Vale N,Esteves da Silva JCG

    更新日期:2019-12-01 00:00:00

  • Synthesis and in vitro antiproliferative activity of new 1,3,4-oxadiazole derivatives possessing sulfonamide moiety.

    abstract::Synthesis of a new series of 1,3,4-oxadiazole derivatives possessing sulfonamide moiety is described. Their in vitro antiproliferative activities against NCI-58 human cancer cell lines of nine different cancer types were tested. Compound 1k with p-methoxybenzenesulfonamido moiety showed the highest mean %inhibition va...

    journal_title:European journal of medicinal chemistry

    pub_type: 杂志文章

    doi:10.1016/j.ejmech.2014.11.011

    authors: Gamal El-Din MM,El-Gamal MI,Abdel-Maksoud MS,Yoo KH,Oh CH

    更新日期:2015-01-27 00:00:00

  • Comparative chemometric modeling of cytochrome 3A4 inhibitory activity of structurally diverse compounds using stepwise MLR, FA-MLR, PLS, GFA, G/PLS and ANN techniques.

    abstract::Twenty-eight structurally diverse cytochrome 3A4 (CYP3A4) inhibitors have been subjected to quantitative structure-activity relationship (QSAR) studies. The analyses were performed with electronic, spatial, topological, and thermodynamic descriptors calculated using Cerius 2 version 10 software. The statistical tools ...

    journal_title:European journal of medicinal chemistry

    pub_type: 杂志文章

    doi:10.1016/j.ejmech.2008.12.004

    authors: Roy K,Pratim Roy P

    更新日期:2009-07-01 00:00:00

  • 5-Ene-4-thiazolidinones induce apoptosis in mammalian leukemia cells.

    abstract::The article presents the synthesis of 5-ene-4-thiazolidinone derivatives with pyrazole core linked by enamine group. The structure and purity of compounds were confirmed by analytical and spectral data including X-ray analysis. Target compounds were screened for their anticancer activity and selective antileukemic act...

    journal_title:European journal of medicinal chemistry

    pub_type: 杂志文章

    doi:10.1016/j.ejmech.2016.03.089

    authors: Senkiv J,Finiuk N,Kaminskyy D,Havrylyuk D,Wojtyra M,Kril I,Gzella A,Stoika R,Lesyk R

    更新日期:2016-07-19 00:00:00

  • Synthesis and in vitro evaluation of novel spiroketopyrazoles as acetyl-CoA carboxylase inhibitors and potential antitumor agents.

    abstract::Acetyl-CoA carboxylase (ACC) is a rate-limiting enzyme in de novo fatty acid synthesis, which plays a critical role in the growth and survival of cancer cells. In this study, a series of spiroketopyrazole derivatives bearing quinoline moieties were synthesized, and in vitro anticancer activities of these compounds as ...

    journal_title:European journal of medicinal chemistry

    pub_type: 杂志文章

    doi:10.1016/j.ejmech.2020.113036

    authors: Huang T,Wu X,Yan S,Liu T,Yin X

    更新日期:2020-11-27 00:00:00

  • Design and studies of multiple mechanism of anti-Candida activity of a new potent Trp-rich peptide dendrimers.

    abstract:PURPOSE:Eight peptide dendrimers were designed as structural mimics of natural cationic amphiphilic peptides with antifungal activity and evaluated for their anti-Candida potential against the wild type strains and mutants. METHODS:Dendrimer 14 containing four Trp residues and dodecyl tail and a slightly smaller dendr...

    journal_title:European journal of medicinal chemistry

    pub_type: 杂志文章

    doi:10.1016/j.ejmech.2015.10.013

    authors: Zielińska P,Staniszewska M,Bondaryk M,Koronkiewicz M,Urbańczyk-Lipkowska Z

    更新日期:2015-11-13 00:00:00

  • Modification of the anabaseine pyridine nucleus allows achieving binding and functional selectivity for the α3β4 nicotinic acetylcholine receptor subtype.

    abstract::We report the design, synthesis and pharmacological screening of a group of analogues of anabaseine 2, a naturally occurring unselective nicotinic agonist. The novel nAChR ligands 5-15 were planned following a molecular modeling analysis which suggested the replacement of the pyridine ring of 2 with a 3-substituted be...

    journal_title:European journal of medicinal chemistry

    pub_type: 杂志文章

    doi:10.1016/j.ejmech.2015.11.045

    authors: Matera C,Quadri M,Sciaccaluga M,Pomè DY,Fasoli F,De Amici M,Fucile S,Gotti C,Dallanoce C,Grazioso G

    更新日期:2016-01-27 00:00:00

  • Targeting gliomas with triazene-based hybrids: Structure-activity relationship, mechanistic study and stability.

    abstract::Herein we report novel hybrid compounds based on valproic acid and DNA-alkylating triazene moieties, 1, with therapeutic potential for glioblastoma multiforme chemotherapy. We identified hybrid compounds 1d and 1e to be remarkably more potent against glioma and more efficient in decreasing invasive cell properties tha...

    journal_title:European journal of medicinal chemistry

    pub_type: 杂志文章

    doi:10.1016/j.ejmech.2019.03.048

    authors: Braga C,Vaz AR,Oliveira MC,Matilde Marques M,Moreira R,Brites D,Perry MJ

    更新日期:2019-06-15 00:00:00

  • 4-Aminoquinoline derived antimalarials: synthesis, antiplasmodial activity and heme polymerization inhibition studies.

    abstract::A new series of 4-aminoquinoline derivatives have been synthesized and found to be active against both susceptible and resistant strains of Plasmodium falciparum in vitro. Compound 1-[3-(7-chloro-quinolin-4-ylamino)-propyl]-3-cyclopropyl-thiourea (7) exhibited superior in vitro activity against resistant strains of P....

    journal_title:European journal of medicinal chemistry

    pub_type: 杂志文章

    doi:10.1016/j.ejmech.2010.07.068

    authors: Solomon VR,Haq W,Smilkstein M,Srivastava K,Puri SK,Katti SB

    更新日期:2010-11-01 00:00:00

  • Hitting on the move: Targeting intrinsically disordered protein states of the MDM2-p53 interaction.

    abstract::Intrinsically disordered proteins are an emerging class of proteins without a folded structure and currently disorder-based drug targeting remains a challenge. p53 is the principal regulator of cell division and growth whereas MDM2 consists its main negative regulator. The MDM2-p53 recognition is a dynamic and multist...

    journal_title:European journal of medicinal chemistry

    pub_type: 杂志文章

    doi:10.1016/j.ejmech.2019.111588

    authors: Neochoritis CG,Atmaj J,Twarda-Clapa A,Surmiak E,Skalniak L,Köhler LM,Muszak D,Kurpiewska K,Kalinowska-Tłuścik J,Beck B,Holak TA,Dömling A

    更新日期:2019-11-15 00:00:00

  • Cannabinoid agonists showing BuChE inhibition as potential therapeutic agents for Alzheimer's disease.

    abstract::Designing drugs with a specific multi-target profile is a promising approach against multifactorial illnesses as Alzheimer's disease. In this work, new indazole ethers that possess dual activity as both cannabinoid agonists CB2 and inhibitors of BuChE have been designed by computational methods. On the basis of this k...

    journal_title:European journal of medicinal chemistry

    pub_type: 杂志文章

    doi:10.1016/j.ejmech.2013.11.026

    authors: González-Naranjo P,Pérez-Macias N,Campillo NE,Pérez C,Arán VJ,Girón R,Sánchez-Robles E,Martín MI,Gómez-Cañas M,García-Arencibia M,Fernández-Ruiz J,Páez JA

    更新日期:2014-02-12 00:00:00

  • Structure-activity relationships (SAR) of triazine derivatives: Promising antimicrobial agents.

    abstract::The emergence of drug resistance has created unmet medical need for the development of new classes of antibiotics. Innovation of new antibacterial agents with new mode of action remains a high priority universally. Triazines are six-membered, nitrogen-containing heterocyclic scaffold with a wide range of pharmaceutica...

    journal_title:European journal of medicinal chemistry

    pub_type: 杂志文章,评审

    doi:10.1016/j.ejmech.2019.111804

    authors: Liu H,Long S,Rakesh KP,Zha GF

    更新日期:2020-01-01 00:00:00

  • pH and reduction dual-responsive dipeptide cationic lipids with α-tocopherol hydrophobic tail for efficient gene delivery.

    abstract::A series of tocopherol-based cationic lipid 3a-3f bearing a pH-sensitive imidazole moiety in the dipeptide headgroup and a reduction-responsive disulfide linkage were designed and synthesized. Acid-base titration of these lipids showed good buffering capacities. The liposomes formed from 3 and co-lipid 1, 2-dioleoyl-s...

    journal_title:European journal of medicinal chemistry

    pub_type: 杂志文章

    doi:10.1016/j.ejmech.2017.02.010

    authors: Liu Q,Su RC,Yi WJ,Zheng LT,Lu SS,Zhao ZG

    更新日期:2017-03-31 00:00:00

  • Antiproliferative potency of novel benzofuran-2-carboxamides on tumour cell lines: cell death mechanisms and determination of crystal structure.

    abstract::In this manuscript the synthesis and biological activity of novel heterocyclic derivatives of benzofuran-2-carboxamides 3a-j and 6a-f is presented. Biological evaluation in vitro revealed that only few compounds exerted concentration-depended antiproliferative effects on tumour cell lines at micromolar concentrations....

    journal_title:European journal of medicinal chemistry

    pub_type: 杂志文章

    doi:10.1016/j.ejmech.2012.11.009

    authors: Hranjec M,Sović I,Ratkaj I,Pavlović G,Ilić N,Valjalo L,Pavelić K,Kraljević Pavelić S,Karminski-Zamola G

    更新日期:2013-01-01 00:00:00

  • Synthesis and characterization of novel phosphonocarboxylate inhibitors of RGGT.

    abstract::Phosphonocarboxylate (PC) analogs of the anti-osteoporotic drugs, bisphosphonates, represent the first class of selective inhibitors of Rab geranylgeranyl transferase (RabGGTase, RGGT), an enzyme implicated in several diseases including ovarian, breast and skin cancer. Here we present the synthesis and biological char...

    journal_title:European journal of medicinal chemistry

    pub_type: 杂志文章

    doi:10.1016/j.ejmech.2014.06.062

    authors: Coxon FP,Joachimiak L,Najumudeen AK,Breen G,Gmach J,Oetken-Lindholm C,Way R,Dunford JE,Abankwa D,Błażewska KM

    更新日期:2014-09-12 00:00:00

  • Repurposing ibuprofen to control Staphylococcus aureus biofilms.

    abstract::Drug repurposing arises as an interesting alternative to overcome the limited efficacy of current available antibiotics by reducing time, cost and risk associated with drug innovation. In this study, the activity of ibuprofen, a non-steroidal anti-inflammatory drug (NSAID), was evaluated on the control of pre-establis...

    journal_title:European journal of medicinal chemistry

    pub_type: 杂志文章

    doi:10.1016/j.ejmech.2019.01.046

    authors: Oliveira IM,Borges A,Borges F,Simões M

    更新日期:2019-03-15 00:00:00

  • Design, synthesis and receptor affinity of novel conformationally restricted σ ligands based on the [4.3.3]propellane scaffold.

    abstract::A series of novel diastereoisomeric σ ligands 3 was designed, synthesized and pharmacologically evaluated. The highly rigid [4.3.3]propellane scaffold was used to fix the three dimensional orientation of the pharmacophoric moieties required for σ affinity. The syn,syn-configured aminocarbamate syn,syn-3a reveals the m...

    journal_title:European journal of medicinal chemistry

    pub_type: 杂志文章

    doi:10.1016/j.ejmech.2013.09.021

    authors: Torres-Gómez H,Lehmkuhl K,Schepmann D,Wünsch B

    更新日期:2013-01-01 00:00:00

  • Design, synthesis, and biological evaluation of new 2'-deoxy-2'-fluoro-4'-triazole cytidine nucleosides as potent antiviral agents.

    abstract::A series of 4'-[1,2,3]triazole-2'-deoxy-2'-fluoro-β-d-arabinofuranosylcytosines (9-17) were prepared by Cu(I)-mediated [3 + 2] cycloaddition reactions (CuAAC) of 1-(4'-azido-2'-deoxy-2'-fluoro-β-d-arabinofuranosyl)cytosine (1) with appropriate alkynes in good yields. Their structures were fully established by (1)H NMR...

    journal_title:European journal of medicinal chemistry

    pub_type: 杂志文章

    doi:10.1016/j.ejmech.2013.02.042

    authors: Wu J,Yu W,Fu L,He W,Wang Y,Chai B,Song C,Chang J

    更新日期:2013-05-01 00:00:00

  • The race to treat COVID-19: Potential therapeutic agents for the prevention and treatment of SARS-CoV-2.

    abstract::The unforeseen emergence of coronavirus disease 2019 (COVID-19), a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) at the Wuhan province of China in December 2019, subsequently its abrupt spread across the world has severely affected human life. In a short span of time, COVID-19 has sacked more than one m...

    journal_title:European journal of medicinal chemistry

    pub_type: 杂志文章,评审

    doi:10.1016/j.ejmech.2021.113157

    authors: Shagufta,Ahmad I

    更新日期:2021-01-12 00:00:00

  • Inhibitors of phosphopantetheine adenylyltransferase.

    abstract::Phosphopantetheine adenylyltransferase (PPAT) is an essential enzyme in Coenzyme A biosynthesis. Because bacterial PPAT and mammalian PPAT are dissimilar, this enzyme is an attractive antibacterial target. Based on the structure of the substrate, 4-phosphopantetheine, a dipeptide library was designed, synthesised and ...

    journal_title:European journal of medicinal chemistry

    pub_type: 杂志文章

    doi:10.1016/s0223-5234(03)00047-3

    authors: Zhao L,Allanson NM,Thomson SP,Maclean JK,Barker JJ,Primrose WU,Tyler PD,Lewendon A

    更新日期:2003-04-01 00:00:00

  • Discovery of fast-acting dual-stage antimalarial agents by profiling pyridylvinylquinoline chemical space via copper catalyzed azide-alkyne cycloadditions.

    abstract::To identity fast-acting, multistage antimalarial agents, a series of pyridylvinylquinoline-triazole analogues have been synthesized via CuAAC. Most of the compounds display significant inhibitory effect on the drug-resistant malarial Dd2 strain at low submicromolar concentrations. Among the tested analogues, compound ...

    journal_title:European journal of medicinal chemistry

    pub_type: 杂志文章

    doi:10.1016/j.ejmech.2020.112889

    authors: Huang G,Solano CM,Melendez J,Yu-Alfonzo S,Boonhok R,Min H,Miao J,Chakrabarti D,Yuan Y

    更新日期:2021-01-01 00:00:00

  • Synthesis and immunofluorescence assay of a new biotinylated paclitaxel.

    abstract::7-(5'-Biotinylamidopropanoyl)paclitaxel was synthesised by chemical methods; its immunofluorescence assay and the cell uptake experiments were performed by use of human leukemia U937 cells. The results indicate that paclitaxel is arresting cell cycle at the G(2)M phase only. ...

    journal_title:European journal of medicinal chemistry

    pub_type: 杂志文章

    doi:10.1016/s0223-5234(02)01337-5

    authors: Sambaiah T,King KY,Tsay SC,Mei NW,Hakimclahi S,Lai YK,Lieu CH,Hwu JR

    更新日期:2002-04-01 00:00:00

  • Synthesis and evaluation of novel rutaecarpine derivatives and related alkaloids derivatives as selective acetylcholinesterase inhibitors.

    abstract::A series of novel rutaecarpine derivatives and related alkaloid derivatives 3-aminoalkanamido-substituted rutaecarpine 4a-f and 7,8-dehydrorutaecarpine 5a-c, and 6-aminoalkanamido-substituted 3-[2-(3-Indolyl)ethyl]-4(3a)-quinazolinones 8a-c, were synthesized and subjected to pharmacological evaluation as acetylcholine...

    journal_title:European journal of medicinal chemistry

    pub_type: 杂志文章

    doi:10.1016/j.ejmech.2009.12.044

    authors: Wang B,Mai YC,Li Y,Hou JQ,Huang SL,Ou TM,Tan JH,An LK,Li D,Gu LQ,Huang ZS

    更新日期:2010-04-01 00:00:00

  • Covalent binding design strategy: A prospective method for discovery of potent targeted anticancer agents.

    abstract::Cancer remains the most serious disease that threatens human health. Molecularly targeted cancer therapies, specifically small-molecule protein kinase inhibitors, form an important part of cancer therapy. Targeted covalent modification represents a proven approach to drug discovery with the recent FDA approvals of afa...

    journal_title:European journal of medicinal chemistry

    pub_type: 杂志文章,评审

    doi:10.1016/j.ejmech.2017.09.024

    authors: Wang L,Zhao J,Yao Y,Wang C,Zhang J,Shu X,Sun X,Li Y,Liu K,Yuan H,Ma X

    更新日期:2017-12-15 00:00:00

  • Synthesis and biological evaluation of C1-O-substituted-3-(3-butylamino-2-hydroxy-propoxy)-xanthen-9-one as topoisomerase IIα catalytic inhibitors.

    abstract::Topoisomerase II poison blocks the transitorily generated DNA double-strand breaks (DSBs) from religation, thereby causes severe DNA damage and gene toxicity. While topoisomerase II catalytic inhibitor does not form cleavable DNA-enzyme complex because its function attributes to inhibition of the catalytic steps of th...

    journal_title:European journal of medicinal chemistry

    pub_type: 杂志文章

    doi:10.1016/j.ejmech.2016.07.046

    authors: Park S,Hong E,Kwak SY,Jun KY,Lee ES,Kwon Y,Na Y

    更新日期:2016-11-10 00:00:00

  • Synthesis and in vitro and in vivo biological evaluation of novel derivatives of flexicaulin A as antiproliferative agents.

    abstract::As our research focuses on anticancer drugs, a series of novel derivatives of flexicaulin A (FA), an ent-kaurene diterpene, condensed with an aromatic ring were synthesized, and their antiproliferative activities against four human cancer cell lines (TE-1, EC109, MCF-7, and MGC-803) were evaluated. The activities of m...

    journal_title:European journal of medicinal chemistry

    pub_type: 杂志文章

    doi:10.1016/j.ejmech.2020.112789

    authors: Huo JF,Hu TX,Dong YL,Zhao JZ,Liu XJ,Li LL,Zhang XY,Li YF,Liu HM,Ke Y,Wang C

    更新日期:2020-12-15 00:00:00

  • 4-Fluoro-3',4',5'-trimethoxychalcone as a new anti-invasive agent. From discovery to initial validation in an in vivo metastasis model.

    abstract::Invasion and metastasis are responsible for 90% of cancer-related mortality. Herein, we report on our quest for novel, clinically relevant inhibitors of local invasion, based on a broad screen of natural products in a phenotypic assay. Starting from micromolar chalcone hits, a predictive QSAR model for diaryl propenon...

    journal_title:European journal of medicinal chemistry

    pub_type: 杂志文章

    doi:10.1016/j.ejmech.2015.06.029

    authors: Roman BI,De Ryck T,Patronov A,Slavov SH,Vanhoecke BW,Katritzky AR,Bracke ME,Stevens CV

    更新日期:2015-08-28 00:00:00

  • Anticonvulsant activity, crystal structures, and preliminary safety evaluation of N-trans-cinnamoyl derivatives of selected (un)modified aminoalkanols.

    abstract::Adequate control of seizures remains an unmet need in epilepsy. In order to identify new anticonvulsant agents, a series of N-trans-cinnamoyl derivatives of selected aminoalkanols was synthetized. The compounds were obtained in the reaction of N-acylation carried out in a two-phase system. The substances were tested i...

    journal_title:European journal of medicinal chemistry

    pub_type: 杂志文章

    doi:10.1016/j.ejmech.2015.10.051

    authors: Gunia-Krzyżak A,Żesławska E,Słoczyńska K,Koczurkiewicz P,Nitek W,Żelaszczyk D,Szkaradek N,Waszkielewicz AM,Pękala E,Marona H

    更新日期:2016-01-01 00:00:00

  • Correlation of calculated molecular orbital energies of some phenothiazine compounds with MDR reversal properties.

    abstract::Molecular orbital energies of energetically minimized series of extended aromatic and aminoalkyl side chain substituted phenothiazine compounds have been considered with respect to charge transfer (CT) binding properties to P-glycoprotein (P-gp) amino acids of the first P-gp loop. A dependency of decreasing energies o...

    journal_title:European journal of medicinal chemistry

    pub_type: 杂志文章

    doi:10.1016/j.ejmech.2005.11.011

    authors: Hilgeroth A,Molnár A,Molnár J,Voigt B

    更新日期:2006-04-01 00:00:00

  • Novel 1,3-thiazolidin-4-one derivatives as promising anti-Candida agents endowed with anti-oxidant and chelating properties.

    abstract::Pursuing our recent outcomes regarding the antifungal activity of N-substituted 1,3-thiazolidin-4-ones, we synthesized thirty-six new derivatives introducing aliphatic, cycloaliphatic and heteroaromatic moieties at N1-hydrazine connected with C2 position of the thiazolidinone nucleus and functionalizing the lactam nit...

    journal_title:European journal of medicinal chemistry

    pub_type: 杂志文章

    doi:10.1016/j.ejmech.2016.04.012

    authors: Secci D,Carradori S,Bizzarri B,Chimenti P,De Monte C,Mollica A,Rivanera D,Zicari A,Mari E,Zengin G,Aktumsek A

    更新日期:2016-07-19 00:00:00