Letters in Drug Design & Discovery最新文献

{"title":"Drug Repurposing for Thioredoxin Interacting Protein Through Molecular Networking, Pharmacophore Modelling, and Molecular Docking Approaches","authors":"J. S, Ayushi Kar, B. P, Darshini J, A. Swaroop","doi":"10.2174/1570180820666230612150634","DOIUrl":"https://doi.org/10.2174/1570180820666230612150634","url":null,"abstract":"\u0000\u0000Diabetes Mellitus (DM) has emerged as one of the major causes behind global all-cause mortality between the age group of 20-79 years. Thioredoxin Interacting Protein (TXNIP) is a naturally occurring protein that primarily acts by binding to TRX protein, thereby inhibiting its ability to maintain the cellular reduced environment and subsequent oxidative stress, which leads to dysfunctional insulin production and pancreatic islet beta cell apoptosis.\u0000\u0000\u0000\u0000By inhibiting the levels of TXNIP, a search for new molecules was carried out by employing an in-silico approach.\u0000\u0000\u0000\u0000Molecular networking study was carried out using Cytoscape, wherein previously FDA-approved drugs were screened to check their ability to interact with TXNIP. This provided 14 drug molecules, which along with 11 previously obtained drug molecules that inhibit TXNIP, were subjected to pharmacophore generation. A pharmacophore was generated using the PharmaGist web server, which when visualised showed two hydrogen bond acceptors and one aromatic ring. Based on the generated pharmacophore model, we carried out virtual screening using ZINCPharmer. A total of 116 HITs were generated based on this pharmacophore model. We then subjected the 116 molecules to Molecular Docking against TXNIP (PDB: 4GEI) by using PyRx and the standard molecules, metformin and rosiglitazone.\u0000\u0000\u0000\u0000Compared to the standard, we found 10 molecules that had a better binding affinity towards TXNIP. These 10 molecules were further taken for ADMET studies. From this, all 10 compounds showed good significant ADMET properties.\u0000\u0000\u0000\u0000From the preliminary studies, these 10 molecules showed good activity in the reversal of diabetes mellitus by reducing the levels of TXNIP.\u0000","PeriodicalId":18063,"journal":{"name":"Letters in Drug Design & Discovery","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"73520914","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"“Thiophene”: A Sulphur Containing Heterocycle As A Privileged Scaffold","authors":"Ajay Mahaputra Kumar, Yuthika Narayan, Amana Parveen","doi":"10.2174/1570180820666230609113629","DOIUrl":"https://doi.org/10.2174/1570180820666230609113629","url":null,"abstract":"\u0000\u0000In the rapidly expanding chemical realm of heterocyclic compounds with interesting therapeutic properties, the thiophene nucleus has established itself as a prospective entity. The biological activity of comparable substances produced via different pathways is of varying magnitudes. Medicinal chemists use their understanding of multiple synthetic pathways and the various physicochemical properties of such compounds to create a combinatorial library and conduct thorough searches for lead molecules. Due to their vast spectrum of biological actions, heterocyclic compounds play a crucial role in Medicinal chemistry and are extensively researched in the field of drug design and development. Thiophene, a sulfur-containing heterocyclic scaffold, has emerged as a rather well-explored scaffold for the synthesis of a library of molecules with biological functions, including antibacterial, antipsychotic, anticancer, analgesic, anti-inflammatory, anti-arrhythmic, and so on. Depending on the kind and position of substitution, thiophene analogues have been shown to bind to a wide spectrum of cancer-specific protein targets. As a result, thiophene analogues have been found to exert their biological effects by inhibiting various cancer-related signalling pathways. The study of thiophene in Medicinal chemistry resulted in molecules that combine the thiophene moiety with traditional drug components in a single molecule. This review covers the biological and medical activity of compounds containing a thiophene nucleus, as well as information on thiophene behaviour, synthesis, and agents, with a focus on synthetic techniques, biological profiles, and structure-activity relationship (SAR) research.\u0000","PeriodicalId":18063,"journal":{"name":"Letters in Drug Design & Discovery","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"80545471","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Gardenin B, a natural inhibitor for USP7: in vitro evaluation and in silico identification","authors":"Ximing Xu, Siyu Zhang, Yujie Sun, Zhongyue Bai, Yifan Wang, Guang-rui Zhao, Fengli Yao, Yacong Yang, Yu Hu, Xionghao Li, Fang Liu, Peng Wang","doi":"10.2174/1570180820666230607102138","DOIUrl":"https://doi.org/10.2174/1570180820666230607102138","url":null,"abstract":"\u0000\u0000Ubiquitin-specific protease 7 (USP7) is one of the most widely studied Deubiquitinating enzymes (DUBs). The protein level of USP7 is highly expressed in a variety of malignant cancers, which suggests that it is a prognostic marker of cancers and a potential drug target for oncotherapy.\u0000\u0000\u0000\u0000The aim of this study was to identify natural and effective USP7 inhibitors in order to understand the activation of the USP7/p53 pathway by natural inhibitors.\u0000\u0000\u0000\u0000In this study, the USP7 enzyme activity screening system and p53 luciferase reporter system were applied for the discovery of natural USP7 inhibitors targeting the catalytic active site. Molecular docking and molecular dynamics (MD) simulation revealed the combined mechanism between USP7 with gardenin B.\u0000\u0000\u0000\u0000The gardenin B was screened from our home-lab natural products (160 flavonoids) and had cytotoxicity in HCT116 cells (IC50 = 46.28 ± 2.16μM). Preliminary in vitro studies disclosed its antiproliferative activity and activated p53 signaling pathway in HCT116 cells. We found that the complex formed by gardenin B and 5vsk (ledock score = -6.8645, MM/GBSA score = -53.349) had the optimal binding conformation. Moreover, the MD simulation showed that the π-π interactions between gardenin B with His461 and Phe409 and the hydrogen bonds interaction between gardenin B with Leu406 and Phe409 played an important role in maintaining the close binding of the complexes.\u0000\u0000\u0000\u0000In conclusion, gardenin B could be used as a natural product inhibitor of USP7 for further optimized design and development potential.\u0000","PeriodicalId":18063,"journal":{"name":"Letters in Drug Design & Discovery","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-06-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"91098866","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Design and Synthesis of Novel Phthalazine Scaffolds Linked to 1,3,4–oxadiazolyl–1,2,3–triazoles as Potent Anticancer Agents: A Computational Docking Analysis","authors":"T. Allaka, P. V. Kishore, A. K. Dunga, Yugandhar Kethavarapu, S. K. Nechipadappu, P. Pothana, R. Ganta","doi":"10.2174/1570180820666230606110125","DOIUrl":"https://doi.org/10.2174/1570180820666230606110125","url":null,"abstract":"\u0000\u0000A study on the chemical and biological properties of molecules simultaneously comprising various heterocycles, such as fused 1,3,4–oxadiazole and 1,2,3–triazoles, has been conducted as part of our ongoing research in the field of medicinal and organic chemistry. In the present study, novel 1,3,4-oxadiazoles and 1,2,3-triazoles incorporating a phthalazine ring have been synthesized and evaluated for their anticancer activity and docking analysis.\u0000\u0000\u0000\u0000In this study, we performed ligand–based pharmacophore modeling as a promising design strategy of substituted phthalazin–1(2H)–one–1,3,4–oxadiazole acetamides (4); 1,2,3–triazole–1,3,4–oxadiazolyl)phthalazin-1(2H)-one (5) were synthesized from key intermediate 2-((5-mercapto-1,3,4-oxadiazol-2-yl)methyl)-4-methylphthalazin-1(2H)-one 2. The prepared compounds were characterized by proton and carbon nuclear magnetic resonance spectroscopy, infrared, elemental analysis, and mass spectroscopy. Synthesized scaffolds were screened for their anticancer activity against three cell lines, MCF-7, T-47D, and MDA-MB-231, by MTT assay. The prepared ligands were docked by using the input protocols, like RCSB, AutoDock 4.2, ACD ChemSketch, Open Babel, and SwissADME.\u0000\u0000\u0000\u0000The final compound 5f exhibited excellent activity (IC50 = 10.21 ± 2.2, 7.53 ± 0.1 µM) against T-47D and MCF-7 cancer cell lines, respectively, and compounds 4b and 5b showed the highest % growth of inhibition (61.25 ± 0.52, 62.48 ± 0.20 µg/mL) against T-47D and MCF-7 cell lines, which has been found to be equivalent to that reported by the standard cisplatin. The prepared ligand 5f exhibited greatest bonding with amino acids AlaX:191, MetX:193, ValX:196, ThrX:140, PheX:192, TyrX:155, AsnX:90, LysX:159, LeuX:95, and IleX:14, with a docking score of –11.53 Kcal/mol, respectively. These compounds were further evaluated for their ADMET and physicochemical properties by using SwissADME.\u0000\u0000\u0000\u0000Phthalazine with 1,3,4–oxadiazole substituents and 1,2,3–triazoles containing 1,3,4–oxadiazole ring displayed excellent anticancer activity; some interesting relationship has also been evidenced between the synthesised structures and their antimicrobial activity and docking studies. In light of all the above findings, it can be concluded that these molecules may serve as lead molecules for further synthetic and biological evaluation.\u0000","PeriodicalId":18063,"journal":{"name":"Letters in Drug Design & Discovery","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"90150489","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Design of Podophyllotoxin-based Hybrid Compounds as Potential Anticancer Agents","authors":"Lei Zhang, Hezhen Wang, Xun Sun, Chunyong Wei, Jing Wang","doi":"10.2174/1570180820666230606161639","DOIUrl":"https://doi.org/10.2174/1570180820666230606161639","url":null,"abstract":"\u0000\u0000Cancer has been regarded as the leading cause of death worldwide. Identifying new anti-neoplastics with high potency and low toxicity is urgent.\u0000\u0000\u0000\u0000Podophyllotoxin-based hybrid compounds were synthesized by esterification and characterized using NMR and HR-MS. In vitro cytotoxicity and molecular mechanism studies were performed.\u0000\u0000\u0000\u0000Podophyllotoxin was hybridized with three selected known natural compounds via esterification to develop candidates with increased biological activity or decreased toxicity. The CCK-8 assay, cell cycle analysis, AO/EB staining, immunofluorescent analysis, and molecular modeling were used for investigation.\u0000\u0000\u0000\u0000Compound B4 displayed potent anticancer effect on HepG2 and HSC-2 cell lines, with IC50 values of 0.809 ± 0.183 and 0.267 ± 0.038 μM, respectively. Furthermore, B4 exhibited less antiproliferative activity in 293T cells with an IC50 value of 2.303 ± 0.216 μM. In addition, B4 demonstrated strong induction of S phase arrest and apoptosis, as well as demolished the microtubules in HSC-2 cells. Molecular docking study revealed that B4 could bind into the colchicine site of β-tubulin, as well as the interface of the α/β-tubulin dimer.\u0000\u0000\u0000\u0000Hybrid B4 exhibited potential anticancer activity, and further investigations can help in identifying novel lead molecules.\u0000","PeriodicalId":18063,"journal":{"name":"Letters in Drug Design & Discovery","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"91410348","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Novel 1,3,4-trisubstituted pyrazolopyrimidine derivatives show potent antiproliferative activity in mantle cell lymphoma","authors":"G. Zhao, Fansheng Ran, Lun Dong, Yang Liu","doi":"10.2174/1570180820666230602093051","DOIUrl":"https://doi.org/10.2174/1570180820666230602093051","url":null,"abstract":"\u0000\u0000Pyrazolopyrimidine scaffold is an important pharmacophore in drug discovery. This pharmacophore has been reported to produce numerous biological activities, of which anticancer is an important one. The development of novel pyrazolopyrimidine derivatives is of great importance for antitumor drug research.\u0000\u0000\u0000\u0000Compound 6, a pyrazolopyrimidine derivative reported by our group, showed weak antiproliferative activity with IC50 values of over 30 μM against mantle cell lymphoma (MCL) cell lines. In this study, we will further perform the structural optimization of compound 6 to screen highly active pyrazolopyrimidine derivatives.\u0000\u0000\u0000\u0000A novel series of 1,3,4-trisubstituted pyrazolopyrimidine derivatives were synthesized and their structures were elucidated by 1H-NMR, 13C-NMR, and HRMS. The antiproliferative activities of target compounds against MCL cell lines (Mino, Jeko-1, and Z138) were evaluated by the CellTiter-Glo luminescent cell viability assay. The effect of representative compounds to induce apoptosis was evaluated by Annexin V/Propidium Iodide (PI)-binding assay. Mitochondrial membrane potential and reactive oxygen species (ROS) levels in 15c-treated Z138 cells were tested by JC-1 and DCFH-DA probes, respectively.\u0000\u0000\u0000\u0000Most compounds demonstrated improved antiproliferative activity against MCL cell lines compared to the lead compound 6, especially 15c, 15f, 15g, 15j, and 15o, with IC50 values at low micromolar levels. In addition, compound 15c could induce apoptosis in a dose-dependent manner in Z138 cells through reduction of mitochondrial membrane potential and enhancing reactive oxygen species production.\u0000\u0000\u0000\u0000The results showed that 1,3,4-trisubstituted pyrazolopyrimidine derivatives could be valuable lead compounds for the further development of anti-lymphoma agents.\u0000","PeriodicalId":18063,"journal":{"name":"Letters in Drug Design & Discovery","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"86465691","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Structure-guided Development of Novel Benzothiophene Derivatives as PLK1-PBD Inhibitors","authors":"Jixia Yang, Yue Zhang, D. Huang, Jing Zhang, Xiaocong Yang, Xiang‐Duan Tan, Tingting Chai, Lindeng Ma, Bingyang Zhao, Ying Chen","doi":"10.2174/1570180820666230602153458","DOIUrl":"https://doi.org/10.2174/1570180820666230602153458","url":null,"abstract":"\u0000\u0000Polo-like kinase 1 (PLK1), a validated target for tumor therapy, plays a key role in mitosis and is over-expressed in many tumors. In addition to its N-terminal kinase domain, PLk1 also harbors a C-terminal polo-box domain (PBD).\u0000\u0000\u0000\u0000A candidate based on PLK1-PBD was developed as a promising compound for future development.\u0000\u0000\u0000\u0000Seventeen small molecule PLK1-PBD inhibitors were designed, synthesized and evaluated for PLK1-PBD inhibitory activities by fluorescence polarization (FP) assay. The compounds with better inhibitory activities were further assessed for their anti-proliferative activities using a CCK-8 method.\u0000\u0000\u0000\u0000The inhibitory rates of compounds 7a, 7d, 14a, 14d, 14e and 14f exceeded 98%. The IC50 values of compounds 7d, 14d, 14e, and 14f were 0.73 μM, 0.67 μM, 0.89 μM and 0.26 μM, proving better than MCC1019. Compound 14f showed the best inhibitory activity (IC50: 0.26 μM) and antiproliferative activities against three cancer cell lines (HeLa, HepG2 and MG63). Especially, compound 14f also exhibited acceptable safety profiles in the human ether-a-go-go related gene (hERG) and normal cell tests. The results of docking and prediction studies indicated that compound 14f had a high binding affinity to the target, with good drug-like absorption, distribution, metabolism, elimination, and toxicity (ADMET) properties.\u0000\u0000\u0000\u0000Compound 14f can be a promising compound for future development.\u0000","PeriodicalId":18063,"journal":{"name":"Letters in Drug Design & Discovery","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"86433341","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Analysis of the safety and effectiveness of Lenvatinib + TACE-HAIC + PD-1 inhibitor for intermediate and advanced hepatocellular carcinoma","authors":"Yun-Qiang Tang, Yuguang Yang, Hui Tang, Cong Mai, Xin Zhang, Jiawen Kuang","doi":"10.2174/1570180820666230601113529","DOIUrl":"https://doi.org/10.2174/1570180820666230601113529","url":null,"abstract":"\u0000\u0000Hepatocellular carcinoma (HCC) is the sixth most prevalent cancer and the fourth leading cause of cancer death in the world.\u0000\u0000\u0000\u0000This study aimed to investigate the efficacy and safety of Lenvatinib + PD-1 inhibitor + TACE-HAIC (LePTaHAIC) versus Sorafenib + TACE (SorTACE) for patients with intermediate and advanced HCC.\u0000\u0000\u0000\u0000In this retrospective study, patients diagnosed with BCLC stage B/C HCC were included. All patients were treated with LePTaHAIC (LePTaHAIC group) or SorTACE (SorTACE group) between September 2019 and September 2020. Outcomes, including progression-free survival (PFS), conversion surgical resection rate, objective remission rate (ORR), overall survival (OS), and treatment-related adverse events (AEs) were analyzed and compared between the two treatment modalities.\u0000\u0000\u0000\u0000In total, 65 eligible patients were recruited, with 35 assigned to receive LePTaHAIC and 30 assigned to undergo SorTACE. Median PFS (11.4 vs. 5.13 months) and OS (26 vs. 10.08 months) in the LePTaHAIC group were significantly higher compared to the SorTACE group (both P<0.0001). The ORR (mRECIST standard) of the LePTaHAIC group was markedly higher compared to the SorTACE group (71.4% vs. 40%, P=0.01). In the LePTaHAIC group, 11 patients underwent surgical resection (BCLC stage B: n=4, BCLC stage C: n=7) and 3 patients achieved complete pathological remission (pCR), while one patient in the SorTACE group underwent surgical resection. The conversion surgical resection rate of the LePTaHAIC group was significantly higher compared to the SorTACE group [31.4% (11/35) vs. 3.3% (1/30), P=0.004]. Patients with LePTaHAIC had more frequent grade 3-4 treatment-related AEs, especially thrombocytopenia, compared to the SorTACE group (22.9% vs. 3.3%, P=0.02).\u0000\u0000\u0000\u0000LePTaHAIC exhibited acceptable toxic effects and improved survival compared to SorTACE in intermediate and advanced HCC.\u0000","PeriodicalId":18063,"journal":{"name":"Letters in Drug Design &amp; Discovery","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"72791565","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A comparative study of using Poly (D, L, lactide-co-Glycolic Acid) and Chitosan nanoparticle as vaccine delivery system for a recombinant fusion protein of Newcastle disease virus","authors":"S. Arul, K. Vijayarani, K. Kumanan","doi":"10.2174/1570180820666230524154107","DOIUrl":"https://doi.org/10.2174/1570180820666230524154107","url":null,"abstract":"\u0000\u0000The more effective method of preventing many infectious diseases is vaccination. Numerous infectious diseases that affect both humans and animals have significantly decreased as a result of routine immunization\u0000\u0000\u0000\u0000The present study aimed to compare the efficacy of in-house built chitosan and Polylactide co-glycolic acid (PLGA) nanoparticles coupled with Pichia pastoris expressed immunogenic fusion (F) protein of Newcastle disease (ND).\u0000\u0000\u0000\u0000Synthesis of biodegradable nanoparticles such as PLGA and chitosan offers a promising opportunity as a vaccine delivery system.\u0000\u0000\u0000\u0000Chitosan nanoparticles and PLGA nanoparticles were synthesized by ionic gelation, and double emulsion solvent evaporation, respectively, and the size was 38.6± 0.84 nm and 320 ±1.5nm, respectively. They demonstrated good epitope integrity of recombinant fusion protein and in-vitro release kinetics studies have proved consistent release profile of protein\u0000\u0000\u0000\u0000In vivo pathogenicity assay of separately injected nanoparticles has proved no abnormal signs and mortality in chickens. Specific pathogen-free (SPF) chicks were vaccinated with chitosan and PLGA nanoparticles and a recombinant fusion protein of the ND virus. It was demonstrated that PLGA nanoparticles coupled with a fusion protein of Newcastle disease virus conferred a marginally better immune response than chitosan nanoparticles. Comparative study-based results showed that PLGA-based nanoparticles proved a better vaccine delivery vehicle and generated an effective immune response without needing further adjuvants.\u0000\u0000\u0000\u0000The present study is a scientific platform for developing the PLGA-based vaccine delivery vehicle to improve immune responses against many infectious diseases.\u0000","PeriodicalId":18063,"journal":{"name":"Letters in Drug Design &amp; Discovery","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-05-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"87989768","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Design, docking, synthesis, and in vitro evaluation of potent anti-tubercular agents targeting DNA Gyrase","authors":"Asha B. Thomas, Manjiri D. Bhosale, K. Lokhande, Kakumani VenkateswaraSwamy, Soumya Basu, S. Chitlange","doi":"10.2174/1570180820666230523155640","DOIUrl":"https://doi.org/10.2174/1570180820666230523155640","url":null,"abstract":"\u0000\u0000Tuberculosis caused by Mycobacterium tuberculosis has been reported to infect about two-third of the global population and to continuously develop multidrug resistance. DNA gyrase, a type II topoisomerase, is a promising target of the quinolone class of drugs in the treatment of tuberculosis.\u0000\u0000\u0000\u0000The present study is focused on the design and synthesis of newer nitrogen heterocyclics containing indole, n-methyl piperazine, piperidine, and pyrrolidine ring structures\u0000\u0000\u0000\u0000Initially designed compounds were evaluated for their affinity to the DNA gyrase target. The molecular docking performed using FlexX indicated compounds IIb5 (1-(R)-(4-hydroxyphenyl)(4-methylpiperazin-1-yl)methyl)-3-((S)-(4-hydroxyphenyl)(4-methylpiperazin-1-yl)methyl)urea and IIc5 ((1-(R)-(4-hydroxyphenyl)(4-methylpiperazin-1-yl)methyl)-3-((S)-(4-hydroxyphenyl)(4-methylpiperazin-1-yl)methyl) thiourea to exhibit promising binding affinity (dock score of -15.01 and -13.77) when compared to the reference MFX moxifloxacin (dock score -4.40) with the target 5BS8 (DNA gyrase). Further, the best 10 compounds were synthesized by one-pot synthesis employing the reaction of indole/N-methyl piperazine/piperidine/pyrrolidine with N-substituted benzaldehydes in the presence of acetamide/urea/thiourea to afford the compounds in 54.60% to 85.47% yield. The synthesized compounds were suitably characterized using chromatographic and spectroscopic tools.\u0000\u0000\u0000\u0000In the microplate Alamar Blue assay (MABA), compounds IIb1, IIIc2, IIIb1, and IIb5 exhibited good minimum inhibitory concentrations of 1.6µg/mL, 3.12µg/mL, and 12.5µg/mL, respectively, when compared to the standard rifampicin with 0.8µg/mL inhibitory concentration. The MTB gyrase supercoiling assay performed using Mycobacterium tuberculosis gyrase supercoiling assay kit demonstrated compound IIb5 at a concentration of 300µg/mL to show gyrase inhibition in comparison to MFX at 60 µg/mL. In the MTT assay performed using the human breast cancer cell line MCF-7, compounds IIc2, IIb5, and IIb1 showed IC50 values of 2.57µM, 12.54µM, and 12.75µM, respectively, compared to doxorubicin (1.10µM) at 7-48hrs and 72hrs of the study.\u0000\u0000\u0000\u0000Based on these observations, N-methyl piperazine class of compounds can serve as a lead/pharmacophore for the rational design of potent molecules against MTB gyrase to combat the growing issue of MDR-TB.\u0000","PeriodicalId":18063,"journal":{"name":"Letters in Drug Design &amp; Discovery","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"76493494","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}