scholarly journals Novel Selective IDO1 Inhibitors with Isoxazolo[5,4-d]pyrimidin-4(5H)-one Scaffold

2021 ◽  
Vol 14 (3) ◽  
pp. 265
Author(s):  
Ana Dolšak ◽  
Tomaž Bratkovič ◽  
Larisa Mlinarič ◽  
Eva Ogorevc ◽  
Urban Švajger ◽  
...  

Indoleamine 2,3-dioxygenase 1 (IDO1) is a promising target in immunomodulation of several pathological conditions, especially cancers. Here we present the synthesis of a series of IDO1 inhibitors with the novel isoxazolo[5,4-d]pyrimidin-4(5H)-one scaffold. A focused library was prepared using a 6- or 7-step synthetic procedure to allow a systematic investigation of the structure-activity relationships of the described scaffold. Chemistry-driven modifications lead us to the discovery of our best-in-class inhibitors possessing p-trifluoromethyl (23), p-cyclohexyl (32), or p-methoxycarbonyl (20, 39) substituted aniline moieties with IC50 values in the low micromolar range. In addition to hIDO1, compounds were tested for their inhibition of indoleamine 2,3-dioxygenase 2 and tryptophan dioxygenase, and found to be selective for hIDO1. Our results thus demonstrate a successful study on IDO1-selective isoxazolo[5,4-d]pyrimidin-4(5H)-one inhibitors, defining promising chemical probes with a novel scaffold for further development of potent small-molecule immunomodulators.

2012 ◽  
Vol 18 (2) ◽  
pp. 226-231 ◽  
Author(s):  
Hwangseo Park ◽  
So Ya Park ◽  
Jung Jin Oh ◽  
Seong Eon Ryu

VH1-like phosphatase Z (VHZ) has proved to be a promising target for the development of therapeutics for the treatment of human cancers. Here, we report the first example for a successful application of structure-based virtual screening to identify the novel small-molecule inhibitors of VHZ. These inhibitors revealed high potencies with the associated IC50 values ranging from 3 to 20 µM and were also screened for having desirable physicochemical properties as a drug candidate. Therefore, they deserve consideration for further development by structure-activity relationship studies to optimize inhibitory and anticancer activities. Structural features relevant to the stabilization of the newly identified inhibitors in the active site of VHZ are discussed in detail.


Molecules ◽  
2021 ◽  
Vol 26 (11) ◽  
pp. 3128
Author(s):  
Aldar A. Munkuev ◽  
Evgenii S. Mozhaitsev ◽  
Arina A. Chepanova ◽  
Evgeniy V. Suslov ◽  
Dina V. Korchagina ◽  
...  

Tyrosyl-DNA phosphodiesterase 1 (Tdp1) is a promising target for anticancer therapy due to its ability to counter the effects topoisomerase 1 (Top1) poison, such as topotecan, thus, decreasing their efficacy. Compounds containing adamantane and monoterpenoid residues connected via 1,2,4-triazole or 1,3,4-thiadiazole linkers were synthesized and tested against Tdp1. All the derivatives exhibited inhibition at low micromolar or nanomolar concentrations with the most potent inhibitors having IC50 values in the 0.35–0.57 µM range. The cytotoxicity was determined in the HeLa, HCT-116 and SW837 cancer cell lines; moderate CC50 (µM) values were seen from the mid-teens to no effect at 100 µM. Furthermore, citral derivative 20c, α-pinene-derived compounds 20f, 20g and 25c, and the citronellic acid derivative 25b were found to have a sensitizing effect in conjunction with topotecan in the HeLa cervical cancer and colon adenocarcinoma HCT-116 cell lines. The ligands are predicted to bind in the catalytic pocket of Tdp1 and have favorable physicochemical properties for further development as a potential adjunct therapy with Top1 poisons.


Viruses ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 873
Author(s):  
Raphael J. Eberle ◽  
Danilo S. Olivier ◽  
Marcos S. Amaral ◽  
Ian Gering ◽  
Dieter Willbold ◽  
...  

Since the first report of a new pneumonia disease in December 2019 (Wuhan, China) the WHO reported more than 148 million confirmed cases and 3.1 million losses globally up to now. The causative agent of COVID-19 (SARS-CoV-2) has spread worldwide, resulting in a pandemic of unprecedented magnitude. To date, several clinically safe and efficient vaccines (e.g., Pfizer-BioNTech, Moderna, Johnson & Johnson, and AstraZeneca COVID-19 vaccines) as well as drugs for emergency use have been approved. However, increasing numbers of SARS-Cov-2 variants make it imminent to identify an alternative way to treat SARS-CoV-2 infections. A well-known strategy to identify molecules with inhibitory potential against SARS-CoV-2 proteins is repurposing clinically developed drugs, e.g., antiparasitic drugs. The results described in this study demonstrated the inhibitory potential of quinacrine and suramin against SARS-CoV-2 main protease (3CLpro). Quinacrine and suramin molecules presented a competitive and noncompetitive inhibition mode, respectively, with IC50 values in the low micromolar range. Surface plasmon resonance (SPR) experiments demonstrated that quinacrine and suramin alone possessed a moderate or weak affinity with SARS-CoV-2 3CLpro but suramin binding increased quinacrine interaction by around a factor of eight. Using docking and molecular dynamics simulations, we identified a possible binding mode and the amino acids involved in these interactions. Our results suggested that suramin, in combination with quinacrine, showed promising synergistic efficacy to inhibit SARS-CoV-2 3CLpro. We suppose that the identification of effective, synergistic drug combinations could lead to the design of better treatments for the COVID-19 disease and repurposable drug candidates offer fast therapeutic breakthroughs, mainly in a pandemic moment.


2021 ◽  
Vol 14 (3) ◽  
pp. 268
Author(s):  
Ignacio Fernández-Pastor ◽  
Victor González-Menéndez ◽  
Frederick Annang ◽  
Clara Toro ◽  
Thomas A. Mackenzie ◽  
...  

A novel cyclic antimalarial and antitrypanosome hexapeptide, pipecolisporin (1), was isolated from cultures of Nigrospora oryzae CF-298113, a fungal endophyte isolated from roots of Triticum sp. collected in a traditional agricultural land of Montefrío, Granada, Spain. The structure of this compound, including its absolute configuration, was elucidated by HRMS, 1-D and 2-D NMR spectroscopy, and Marfey’s analysis. This metabolite displayed interesting activity against Plasmodium falciparum and Trypanosoma cruzi, with IC50 values in the micromolar range, and no significant cytotoxicity against the human cancer cell lines A549, A2058, MCF7, MIA PaCa-2, and HepG2.


Author(s):  
Islam Md Alrazi ◽  
Kei Sadakane ◽  
Shinsaku Maruta

Abstract The mitotic kinesin Eg5 is a plus-end directed homotetrameric molecular motor essential for the formation of bipolar spindles during cell division. Kinesin Eg5 is overexpressed in cancer cells and hence considered as a target for cancer therapy; the inhibitors specific for Eg5 have been developed as anticancer drugs. In this study, we synthesized a novel functional photoresponsive inhibitor composed of spiropyran and azobenzene derivatives to control Eg5 function with multistage inhibitory activity accompanied by the formation of different isomerization states. The photochromic inhibitor spiropyran-sulfo-azobenzene (SPSAB) exhibited three isomerization states: spiro (SP)-trans, merocyanine (MC)-cis and MC-trans, upon exposure to visible light, ultraviolet and in the dark, respectively. SPSAB-induced reversible changes in the inhibitory activity of ATPase and motor activities correlating with photoisomerization among the three states. Among the three isomerization states of SPSAB, the SP-trans isomer showed potent inhibitory activity at an IC50 value of 30 µM in the basal ATPase assay. MC-trans and MC-cis exhibited less inhibitory activity at IC50 values of 38 and 86 µM, respectively. The results demonstrated that the novel photochromic inhibitor enabled precise control of Eg5 function at three different levels using light irradiation.


Molecules ◽  
2018 ◽  
Vol 23 (10) ◽  
pp. 2540 ◽  
Author(s):  
Wenhao Wu ◽  
Xintong Liang ◽  
Guoquan Xie ◽  
Langdi Chen ◽  
Weixiong Liu ◽  
...  

A series of novel ligustrazine derivatives 8a–r were designed, synthesized, and evaluated as multi-targeted inhibitors for anti-Alzheimer’s disease (AD) drug discovery. The results showed that most of them exhibited a potent ability to inhibit both ChEs, with a high selectivity towards AChE. In particular, compounds 8q and 8r had the greatest inhibitory abilities for AChE, with IC50 values of 1.39 and 0.25 nM, respectively, and the highest selectivity towards AChE (for 8q, IC50 BuChE/IC50 AChE = 2.91 × 106; for 8r, IC50 BuChE/IC50 AChE = 1.32 × 107). Of note, 8q and 8r also presented potent inhibitory activities against Aβ aggregation, with IC50 values of 17.36 µM and 49.14 µM, respectively. Further cellular experiments demonstrated that the potent compounds 8q and 8r had no obvious cytotoxicity in either HepG2 cells or SH-SY5Y cells, even at a high concentration of 500 μM. Besides, a combined Lineweaver-Burk plot and molecular docking study revealed that these compounds might act as mixed-type inhibitors to exhibit such effects via selectively targeting both the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChEs. Taken together, these results suggested that further development of these compounds should be of great interest.


2020 ◽  
Vol 21 (19) ◽  
pp. 7162
Author(s):  
Elizaveta D. Gladkova ◽  
Ivan V. Nechepurenko ◽  
Roman A. Bredikhin ◽  
Arina A. Chepanova ◽  
Alexandra L. Zakharenko ◽  
...  

A series of berberine and tetrahydroberberine sulfonate derivatives were prepared and tested against the tyrosyl-DNA phosphodiesterase 1 (Tdp1) DNA-repair enzyme. The berberine derivatives inhibit the Tdp1 enzyme in the low micromolar range; this is the first reported berberine based Tdp1 inhibitor. A structure–activity relationship analysis revealed the importance of bromine substitution in the 12-position on the tetrahydroberberine scaffold. Furthermore, it was shown that the addition of a sulfonate group containing a polyfluoroaromatic moiety at position 9 leads to increased potency, while most of the derivatives containing an alkyl fragment at the same position were not active. According to the molecular modeling, the bromine atom in position 12 forms a hydrogen bond to histidine 493, a key catalytic residue. The cytotoxic effect of topotecan, a clinically important topoisomerase 1 inhibitor, was doubled in the cervical cancer HeLa cell line by derivatives 11g and 12g; both displayed low toxicity without topotecan. Derivatives 11g and 12g can therefore be used for further development to sensitize the action of clinically relevant Topo1 inhibitors.


Author(s):  
Nóra Török ◽  
Rita Maszlag-Török ◽  
Kinga Molnár ◽  
Zoltán Szolnoki ◽  
Ferenc Somogyvári ◽  
...  

Earlier studies reported alterations of the kynurenine (KYN) pathway of tryptophan (TRP) metabolism in Parkinson’s disease (PD). The first rate-limiting enzymes indoleamine 2,3-dioxygenase (IDO) and tryptophan dioxygenase were observed upregulated, resulting elevated KYN/TRP ratios in the serum and cerebrospinal fluid samples of patients with PD. An increasing number of single nucleotide polymorphisms (SNPs) have been identified in a population of PD. However, little is known if genetic variations of the IDO contribute to disturbance of the KYN metabolism in and the pathogenesis of PD. SNP analysis of IDO1 was performed by allelic discrimination assay with fluorescently labelled TaqMan probes and a subgroup analysis was conducted according to the age of PD onset. The frame shifts variant rs34155785, intronic variant rs7820268, and promotor region variant rs9657182 SNPs of 105 PD patients without comorbidity were analyzed and compared to 129 healthy controls. No significant correlation was found in three SNPs between PD patients and healthy controls. However, the subgroup analysis revealed that A alleles of rs7820268 SNP or rs9657182 SNP carriers contribute to later onset of PD than non-carriers. The study suggested that SNPs of IDO1 influenced the age onset of PD and genotyping of SNPs in certain alleles potentially serves as a risk biomarker of PD.


Author(s):  
Анастасия Николаевна Кошечко ◽  
Алина Сергеевна Шилова

Введение. Предпринята попытка исследования рецепции антропологического идеала в романе Ф. М. Достоевского «Братья Карамазовы» русскими религиозными философами порубежной эпохи XIX–XX вв. Аутентичное понимание и интерпретация ключевых идей писателя о человеческом идеале, его ценностях и смысле жизни возможны только в контексте православной антропологии. Важность этого материала не ограничивается осмыслением проблемы антропологического идеала и его влияния на дальнейшее развитие русской религиозно-философской мысли, позволяет исследовать особенности художественного мира романа, в том числе специфику репрезентации в идейном поле произведения авторского начала, мировоззрения писателя. Материал и методы. Материалом исследования послужили работы В. С. Соловьева «Три речи в память Достоевского», В. В. Розанова «Легенда о Великом инквизиторе», Н. А. Бердяева «Миросозерцание Достоевского», Н. О. Лосского «Достоевский и его христианское миропонимание», канонический текст романа Ф. М. Достоевского «Братья Карамазовы». Используются культурно-исторический, сравнительно-сопоставительный, структурно-типологический методы. Результаты и обсуждение. Наука о Достоевском начинается именно с трудов русских религиозных философов и мыслителей конца XIX – начала XX в., которые идеи о сущности человека, его предназначении, идеале делают содержательным ядром своих размышлений. Итоговый роман Великого Пятикнижия «Братья Карамазовы» как квинтэссенция жизненного и творческого пути Достоевского, неразрывно связанный с духовными и аксиологическими императивами православной антропологии, наиболее часто привлекается религиозными философами для рефлексии ключевых доминант собственных философских концепций, анализа и аргументации идей. Этот материал позволяет исследовать особенности художественного мира романа, специфику репрезентации в идейном поле произведения мировоззрения писателя и авторского начала, антропологического идеала, неразрывно связанного для Достоевского с такими духовными и ценностными доминантами, как Христос, Православие, святость, народность, добро и зло, и выявить его влияние на дальнейшее развитие русской религиозно-философской мысли. Заключение. Антропологический идеал Достоевского, по мысли религиозных философов, опирается на православное учение о человеке, раскрывающее как антиномичность человеческой природы (pro et contra в терминологии писателя), так и бытийную ее устремленность к Богу, Истине, потребность в добре, вне которых личность осознает свое не-бытие. Доминантами антропологического идеала писателя, которые находят отражение в трудах религиозных философов, становятся святость, красота как этическая доминанта личности, укорененность в ценностях и смыслах христоцентричной в своих основаниях русской культуры. Introduction. This article attempts to study the reception of the anthropological ideal in the novel by F. M. Dostoevsky “The Brothers Karamazov” by Russian religious philosophers of the late 19th–20th centuries. Authentic understanding and interpretation of the writer’s key ideas about the human ideal, its values and the meaning of life is possible only in the context of Orthodox anthropology. The importance of this material is not limited to comprehending the problem of the anthropological ideal and its influence on the further development of Russian religious and philosophical thought; moreover, it allows one to explore the peculiarities of the artistic world of the novel, including the specifics of the representation of the author’s principle in the ideological field of the work, the peculiarities of the writer’s worldview. Material and methods. The research material was the work of V. S. Solovyov “Three Speeches in memory of Dostoevsky”, V. V. Rozanov “The Legend of the Grand Inquisitor”, N. А. Berdyaeva “Dostoevsky’s worldview”, N. O. Lossky “Dostoevsky and his Christian worldview”, the canonical text of the novel by F. M. Dostoevsky “The Brothers Karamazov”. The work uses cultural and historical, comparative, structural and typological methods. Results and discussion. The science of Dostoevsky begins precisely with the works of Russian religious philosophers and thinkers of the late XIX – early XX centuries, which ideas about the essence of man, his purpose, ideally make him a meaningful core of his thoughts. The final novel of the Great Pentateuch “The Brothers Karamazov” as a quintessence of Dostoevsky’s life and creative path, inextricably connected with the spiritual and axiological imperatives of Orthodox anthropology, is most often attracted by religious philosophers to reflect key dominants of their own philosophical concepts, analyze and argue ideas. This material allows us to explore the features of the artistic world of the novel, the specifics of representation in the ideological field of the work of the writer’s worldview and author’s beginning, the features of the anthropological ideal, inextricably linked for Dostoevsky with such spiritual and value dominants as Christ, Orthodoxy, holiness, nationality, good and evil, and to identify its influence on the further development of Russian religious and philosophical thought. Conclusion. Dostoevsky’s anthropological ideal, according to religious philosophers, is based on the Orthodox doctrine of man, revealing both the antinomy of human nature («pro et contra» in the writer’s terminology) and its previous striving for God, Truth, the need for good, outside of which the person is aware of his non-existence. The dominants of the anthropological ideal of the writer, which are reflected in the works of religious philosophers, are holiness, beauty as the ethical dominant of the person, and reproach in the values and meanings of Christ-centered Russian culture in their foundations.


2020 ◽  
Vol 75 (12) ◽  
pp. 3544-3551
Author(s):  
Chun-Hsing Liao ◽  
Wei-Chien Chen ◽  
Li-Hua Li ◽  
Yi-Tsung Lin ◽  
Sz-Yun Pan ◽  
...  

Abstract Background Iron is an essential nutrient for almost all aerobic organisms, including Stenotrophomonas maltophilia. Fur is the only known transcriptional regulator presumptively involved in iron homeostasis in S. maltophilia. AmpR, a LysR-type transcriptional regulator, is known to regulate β-lactamase expression and β-lactam resistance in S. maltophilia. Objectives To identify the novel regulator involved in controlling the viability of S. maltophilia in an iron-depleted condition and to elucidate the underlying regulatory mechanisms. Methods The potential regulator involved in iron homeostasis was identified by studying the cell viabilities of different regulator mutants in 2,2′-dipyridyl (DIP)-containing medium. Iron-chelating activity was investigated using the chrome azurol S (CAS) activity assay. An iron source utilization bioassay was carried out to examine utilization of different iron sources. Gene expression was determined by quantitative real-time PCR, and the Etest method was used to evaluate antibiotic susceptibility. Results Of the 14 tested mutants, the ampR mutant, KJΔAmpR, showed a growth compromise in DIP-containing medium. AmpR regulated stenobactin synthesis in an iron-depleted condition, but showed little involvement in the uptake and utilization of ferri-stenobactin and ferric citrate. AmpR was up-regulated by iron limitation and β-lactam challenge. S. maltophilia clinical isolates grown under conditions of iron depletion were generally more resistant to β-lactams compared with conditions of iron repletion. Conclusions AmpR is a dual transcriptional regulator in S. maltophilia, which regulates the β-lactam-induced β-lactamase expression and iron depletion-mediated stenobactin synthesis. AmpR is, therefore, a promising target for the development of inhibitors.


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