Inhibitors of HIV-1 attachment. Part 4: A study of the effect of piperazine substitution patterns on antiviral potency in the context of indole-based derivatives

Wang, Tao; Kadow, John F.; Zhang, Zhongxing; Yin, Zhiwei; Gao, Qi; Wu, Dedong; Parker, Dawn D.; Yang, Zheng; Zadjura, Lisa; Robinson, Brett S.; Gong, Yi; Blair, Wade; Shi, Pei Yong; Yamanaka, Gregory; Lin, Pin Fang; Meanwell, Nicholas A.

doi:10.1016/j.bmcl.2009.07.076

Cited by 49 publications

(40 citation statements)

References 31 publications

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“…31 The lack of binding by 22b is consistent with the results of the structure-activity relationship study of related compounds that the bulky substituent at 4-position of the azaindole 1 diminished the biological activity. 9–11 Loss of binding activity at this concentration is consistent with the reported low binding activity of the DNP conjugate study and indicates that the Northern site of the linker attachment is likely responsible for the loss in binding, not the fact that DNP conjugates with antibodies are reversibly formed.…”

supporting

confidence: 83%

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Chemically Programmed Antibodies As HIV-1 Attachment Inhibitors

Sato

Inokuma

Otsubo

et al. 2013

ACS Med. Chem. Lett.

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Herein we describe the design and application of two small-molecule anti-HIV compounds for the creation of chemically programmed antibodies. N-acyl-β-lactam derivatives of two previously described molecules BMS-378806 and BMS-488043 that inhibit the interaction between HIV-1 gp120 and T-cells were synthesized and used to program the binding activity of aldolase antibody 38C2. Discovery of a successful linkage site to BMS-488043 allowed for the synthesis of chemically programmed antibodies with affinity for HIV-1 gp120 and potent HIV-1 neutralization activity. Derivation of a successful conjugation strategy for this family of HIV-1 entry inhibitors enables its application in chemically programmed antibodies and vaccines and may facilitate the development of novel bispecific antibodies and topical microbicides.

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supporting

confidence: 83%

“…Structure-activity relationship studies of 2 , 9–11 found that bulky substituents at the 4-position of the azaindole unit decreased the inhibition activity of the compound. Thus a Northern sector connection would be ill-advised.…”

mentioning

confidence: 99%

Chemically Programmed Antibodies As HIV-1 Attachment Inhibitors

Sato

Inokuma

Otsubo

et al. 2013

ACS Med. Chem. Lett.

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“…The indole ring is considered the central core of these compounds because of its sensitivity to potency, offering the opportunity for structural modification. On the other hand, the piperazine ring turned out to be of critical importance for the antiviral activity (4,6), biologically and electronically. Because of its anti-HIV properties, its usual interaction at the entrance of the Phe43 cavity, and vast presence in a significant amount of anti-HIV compounds with reported activities.…”

Section: Was Used As the Reference For Docking Calculationsmentioning

confidence: 99%

Piperazine-based HIV-1 entry inhibitors: Massive in silico library design and screening for gp120 attachment inhibitors

Castillo-Pazos

Romo-Mancillas

Barroso-Flores

2018

Preprint

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HIV-1 attachment, despite being an ideal target stage to stop infection from the beginning, remains as one of the HIV lifecycle phases with less amount of designed and commercially . CC-BY 4.0 International license It is made available under a (which was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint . http://dx.doi.org/10.1101/330142 doi: bioRxiv preprint first posted online May. 24, 2018; 2 available inhibitors. To contribute to the urgently needed discovery of new active compounds that could become part of the current highly active antiretroviral therapy, and as an attempt to explore a massive chemical space, high-throughput virtual screening of 16.3 million combinatorially generated and piperazine-cored compounds, was accomplished. Docking calculations, molecular dynamics simulations, and QSAR analyses were carried out to assess the suitability of each ligand to bind gp120 envelope glycoprotein, thus preventing it from binding to CD4 co-receptor. Ligand 255 stands out as a promising candidate to be tested beyond computational methodologies, and the 4,5,6,7-tetrahydroindole fragment is reported as a better group to bind inside the Phe43 cavity than the substituted indoles reported in the literature.

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“…The rapid worldwide spread of AIDS, therefore, has prompted an intense research effort to discover new, selective and safe drugs for the treatment of HIV/AIDS. Especially Wang and co-workers described that indolyl glyoxamide piperazines showed the anti-HIV-1 activity [12]. In this paper, nine new indolyl glyoxamide derivatives (3a-i) were synthesized and preliminarily evaluated as HIV-1 inhibitors in vitro.…”

Section: Introductionmentioning

confidence: 99%

Anti HIV-1 Agents 6. Synthesis and Anti-HIV-1 Activity of Indolyl Glyoxamides

Wang

Huang²,

Yu³

et al. 2012

med chem

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In order to discover compounds with superior anti-human immunodeficiency virus type 1 (HIV-1) activity, 9 new indolyl glyoxamide derivatives (3a-i) were synthesized and preliminarily evaluated as HIV-1 inhibitors in vitro. Among all the derivatives, especially compounds 3e and 3h showed the potent anti-HIV-1 activity with EC(50) values of 6.83 and 4.35 µg/mL, and TI values of >27.15 and 49.45, respectively. It demonstrated that introduction of the substituent R(3) as the halogen atom and the position of R(3) were generally important to their activity.

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Inhibitors of HIV-1 attachment. Part 4: A study of the effect of piperazine substitution patterns on antiviral potency in the context of indole-based derivatives

Cited by 49 publications

References 31 publications

Chemically Programmed Antibodies As HIV-1 Attachment Inhibitors

Chemically Programmed Antibodies As HIV-1 Attachment Inhibitors

Piperazine-based HIV-1 entry inhibitors: Massive in silico library design and screening for gp120 attachment inhibitors

Anti HIV-1 Agents 6. Synthesis and Anti-HIV-1 Activity of Indolyl Glyoxamides

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