Synthesis,Characterization and Biological Evaluation of New 3,5-Disubstituted-Pyrazoline Derivatives as Potential Anti-Mycobacterium tuberculosis H37Ra Compounds

A total of fourteen pyrazoline derivatives were synthesized through cyclo-condensation reactions by chalcone derivatives with different types of semicarbazide. These compounds were characterized by IR, 1D-NMR (¹H, ¹³C and Distortionless Enhancement by Polarization Transfer - DEPT-135) and 2D-NMR (COSY, HSQC and HMBC) as well as mass spectroscopy analysis (HRMS). The synthesized compounds were tested for their antituberculosis activity against Mycobacterium tuberculosis H37Ra in vitro. Based on this activity, compound 4a showed the most potent inhibitory activity, with a minimum inhibitory concentration (MIC) value of 17 μM. In addition, six other synthesized compounds, 5a and 5c–5g, exhibited moderate activity, with MIC ranges between 60 μM to 140 μM. Compound 4a showed good bactericidal activity with a minimum bactericidal concentration (MBC) value of 34 μM against Mycobacterium tuberculosis H37Ra. Molecular docking studies for compound 4a on alpha-sterol demethylase was done to understand and explore ligand–receptor interactions, and to hypothesize potential refinements for the compound.     

4-Hydroxy-2-quinolones. 56. 4-(Adamant-1-yl)thiazolyl-2-amides of 1-R-4-Hydroxy-2-oxoquinoline-3-carboxylic Acids as Potential Antitubercular Agents

The synthesis, antitubercular, anti-HIV, and antitumor activity of the 4-(adamant-1-yl)thiazolyl-2-amides of 1-R-4-hydroxy-2-oxoquinoline-3-carboxylic acids have been studied. An efficient method for purifying the 4-hydroxy-2-oxoquinoline derivatives from their metal salts is proposed.     

Identification of individual DNA molecule of Mycobacterium tuberculosis by nested PCR-RFLP and capillary electrophoresis

The improvement of sensitivity and differentiation in rapidly identifying a small amount of mycobacteria in sputum has significant implications for reducing tuberculosis transmission. We previously applied the conventional PCR and capillary electrophoresis (CE) to establish the restriction fragment length polymorphism (RFLP) pattern of mycobacterial 65-kDa heat shock protein (hsp65) gene from colony specimens. However, the previous analysis did not provide enough sensitivity for sputum specimens in which the limitation of analysis might be hindered by PCR inhibitors and primer-dimers formation during amplification. In the current study, nested PCR (nPCR) had been redesigned for PCR-RFLP analysis (PRA) of mycobacterial hsp65 gene using CE. The results show both Mycobacterium tuberculosis complex and mycobacteria other than tuberculosis could be identified in the presence of PCR inhibitors. The interference due to primer-dimers was also minimized. Based on the Poisson distribution, the repeatability of single DNA molecule detection was greatly affected by sampling probability and might be improved significantly by increasing the sample loading. The PRA using nPCR and CE is not only able to detect the individual mycobacterial DNA molecule but also potentially differentiate the species.     

Development of Novel Isatin-Tethered Quinolines as Anti-Tubercular Agents against Multi and Extensively Drug-Resistant Mycobacterium tuberculosis

We describe the design and synthesis of two isatin-tethered quinolines series (Q6a–h and Q8a–h), in connection with our research interest in developing novel isatin-bearing anti-tubercular candidates. In a previous study, a series of small molecules bearing a quinoline-3-carbohydrazone moiety was developed as anti-tubercular agents, and compound IV disclosed the highest potency with MIC value equal to 6.24 µg/mL. In the current work, we adopted the bioisosteric replacement approach to replace the 3,4,5-trimethoxy-benzylidene moiety in the lead compound IV with the isatin motif, a privileged scaffold in the TB drug discovery, to furnish the first series of target molecules Q6a–h. Thereafter, the isatin motif was N-substituted with either a methyl or benzyl group to furnish the second series Q8a–h. All of the designed quinoilne-isatin conjugates Q6a–h and Q8a–h were synthesized and then biologically assessed for anti-tubercular actions towards drug-susceptible, MDR, and XDR strains. Superiorly, the N-benzyl-bearing compound Q8b possessed the best activities against the examined M. tuberculosis strains with MICs equal 0.06, 0.24, and 1.95 µg/mL, respectively.     

Syntheses and biological evaluation of new triazole-spirochromone conjugates as inhibitors of Mycobacterium tuberculosis

A series of novel 1,2,3-triazole fused spirochromone conjugates have been synthesized bearing both spirochromone moiety as well as a 1,2,3-triazole moiety. Some of the compounds have exhibited potential activity against Mycobacterium tuberculosis (virulent strain H37Rv). In particular 5e proved to be the most potent derivative exhibiting MIC = 0.78 μg/mL.     

5-氟尿嘧啶光敏性偶联衍生物的合成、表征及抗癌活性研究

设计合成了六种新型的适用于新一代肿瘤治疗法--光动力学疗法研究的5-氟尿嘧啶(5-Fu)光敏性偶联衍生物. 目标化合物的结构经过¹H NMR, ¹³C NMR, IR和元素分析确证, 并通过HPLC法测定了它们及5-Fu的表观油水分配系数. 其中四种化合物2a, 3a, 1b和4b分别采用四氮唑盐法(MTT法)对白血病细胞株HL-60和磺酰罗丹明B蛋白染色法(SRB法)对肝癌细胞株BEL-7402进行了体外抗癌活性测试. 结果表明, 噻吩一取代产物2a的表观油水分配系数大于二取代产物3a, 与生物活性测试结果表明的2a和3a对HL-60和BEL-7402的抑制率呈正相关性|而由于N-C键过于稳定不易断裂, 导致两种硝基苄基衍生物1b和4b对HL-60和BEL-7402的抑制率都比较低.     

Synthesis and Preliminary Screening of O-β-D-Galactopyranosides as Potential Mimic of UDP-Galp against Mycobacterium tuberculosis

O-Galactopyranosides were synthesized as potential mimics of uridine 5c-diphosphate galactopyranose (UDP-Galp), which is the substrate of the mutase enzyme involved in the mycobacterial cell wall biosynthesis by converting UDP-Galp to UDP-Galf. In vitro assay against the Mycobacterium tuberculosis H₃₇Rv strain gave promising results with minimum inhibitory concentration (MIC) values in the range of 3.13 to 25 μg/mL.     

Assessment of terbium (III) as a luminescent probe for the detection of tuberculosis biomarkers

A detection method for nicotinic acid, a specific metabolite marker of Mycobacterium tuberculosis present in cultures and patients' breath, is studied in complex solutions containing other metabolites and in biological media such as urine, saliva and breath condensate. The method is based on the analysis of the luminescence increase of Tb³⁺ complexes in the presence of nicotinic acid due to the energy transfer from the excited ligand to the lanthanide ion. It is shown that other potential markers found in M. tuberculosis culture supernatant, such as methyl phenylacetate, p-methyl anisate, methyl nicotinate and 2-methoxy biphenyl, can interfere with nicotinic acid via a competitive absorption of the excitation photons. A new strategy to circumvent these interferences is proposed with an upstream trapping of volatile markers preceding the detection of nicotinic acid in the liquid phase via the luminescence of Tb³⁺ complexes. The cost of the method is evaluated and compared with the Xpert MTB/RIF test endorsed by the World Health Organization.     

Synthesis and in vitro antimalarial and antitubercular activity of gold(III) complexes containing thiosemicarbazone ligands

Gold(III) thiosemicarbazone complexes derived from [Au(damp-C¹,N)Cl₂] (2), where damp = dimeth-ylaminoethylphenyl, have been synthesized. The compounds were characterised using various spectroscopic and analytical techniques, including NMR spectroscopy, mass spectrometry, infrared spectroscopy and elemental analysis. The gold complexes were screened for in vitro antimalarial and antitubercular activity. Although incorporation of the gold(III) centre into thiosemicarbazone scaffolds enhanced their efficacy against the malaria parasite Plasmodium falciparum, this trend was not observed for the antitubercular activity of selected thiosemicarbazones against the Mycobacterium tuberculosis virulent strain H₃₇Rv.     

Synthesis of the new ring system pyrrolizino[2,3-b]indol-4(5H)-one

Derivatives of the new ring system pyrrolizino[2,3-b]indol-4(5H)-one were prepared in four steps starting from substituted benzonitriles bearing a functionalized amino group in the adjacent position. The unsubstituted- and the dimethoxy-pyrrolizinoindolones 5a and 5b exhibited modest activity against the HL-60(TB) human leukemia cell line, whereas the N-methylated dimethoxy-pyrrolizinoindolone 6b showed to be selective against MOLT-4 leukemia, A549/ATCC, HOP-92, and NCI-H460 non-small cell lung cancer, and CAKI-1 renal cancer cell lines.     

Design and Synthesis of Pyrido[1,2-e]purin-4（3H）-one Derivatives as Potential PDE 5 Inhibitors

A novel series of pyrido[ 1,2-e]purin-4（3H）-one derivatives containing polar substituents on 5＇-position were designed and prepared as potential PDE5 inhibitors. This paper reports the synthetic routes, 1H-NMR data, and the PDE5 inhibitory activities of the target compounds. The polar piperazinyl group contained （on 5＇-position） compound, 3B2, showed the highest activity among the tested derivatives but less potency than sildenafil 1.     

Solvent-Free Synthesis of 2-Amino-3-aryl-5-substituted Thiophenes as Anti-inflammatory Agents using KF-Al2O3 under Microwave Irradiation

The synthesis of 2-amino-3-aryl-5-substituted thiophenes as anti-inflammatory agents catalyzed by KF-Al₂O₃ under microwave irradiation is reported.     

Synthesis and Biological Evaluation of Harmirins,Novel Harmine–Coumarin Hybrids as Potential Anticancer Agents

As cancer remains one of the major health burdens worldwide, novel agents, due to the development of resistance, are needed. In this work, we designed and synthesized harmirins, which are hybrid compounds comprising harmine and coumarin scaffolds, evaluated their antiproliferative activity, and conducted cell localization and cell cycle analysis experiments. Harmirins were prepared from the corresponding alkynes and azides under mild reaction conditions using Cu(I) catalyzed azide–alkyne cycloaddition, leading to the formation of the 1H-1,2,3-triazole ring. Antiproliferative activity of harmirins was evaluated in vitro against four human cancer cell lines (MCF-7, HCT116, SW620, and HepG2) and one human non-cancer cell line (HEK293T). The most pronounced activities were exerted against MCF-7 and HCT116 cell lines (IC₅₀ in the single-digit micromolar range), while the most selective harmirins were 5b and 12b, substituted at C-3 and O-7 of the β-carboline core and bearing methyl substituent at position 6 of the coumarin ring (SIs > 7.2). Further experiments demonstrated that harmirin 12b is localized exclusively in the cytoplasm. In addition, it induced a strong G1 arrest and reduced the percentage of cells in the S phase, suggesting that it might exert its antiproliferative activity through inhibition of DNA synthesis, rather than DNA damage. In conclusion, harmirin 12b is a novel harmine and coumarin hybrid with significant antiproliferative activity and warrants further evaluation as a potential anticancer agent.     

Synthesis and NMR spectral assignments of novel 1,4-benzothiazepine-5-one derivatives

The one-pot reaction between 2-aminobenzo[d]isothiazol-3-one and alkyl propiolates in presence of triphenylphosphine leads to the corresponding alkyl 4-amino-5-oxobenzo[f][1,4]thiazepine-3-carboxylates. A plausible mechanism of the reaction is proposed and unambiguous evidence for the structures is obtained from a detailed magnetic resonance spectral analysis. 1D and 2D NMR spectra such as COSY, ¹H-¹³C and ¹H-¹⁵N HSQC and HMBC heteronuclear correlations and an INADEQUATE experiment are reported and discussed.     

Design,Synthesis, Biological Evaluation,and Molecular Modeling of 2-Difluoromethylbenzimidazole Derivatives as Potential PI3Kα Inhibitors

PI3Kα is one of the potential targets for novel anticancer drugs. In this study, a series of 2-difluoromethylbenzimidazole derivatives were studied based on the combination of molecular modeling techniques 3D-QSAR, molecular docking, and molecular dynamics. The results showed that the best comparative molecular field analysis (CoMFA) model had q² = 0.797 and r² = 0.996 and the best comparative molecular similarity indices analysis (CoMSIA) model had q² = 0.567 and r² = 0.960. It was indicated that these 3D-QSAR models have good verification and excellent prediction capabilities. The binding mode of the compound 29 and 4YKN was explored using molecular docking and a molecular dynamics simulation. Ultimately, five new PI3Kα inhibitors were designed and screened by these models. Then, two of them (86, 87) were selected to be synthesized and biologically evaluated, with a satisfying result (22.8 nM for 86 and 33.6 nM for 87).     

New and efficient synthesis of 5′-amino-5′-(S)-methyl-2′,5′-dideoxynucleosides

A short, efficient synthesis of 5′-amino-5′-(S)-methyl-2′,5′-dideoxynucleosides 1 has been developed through the diastereoselective addition of methylmagnesium bromide or methyllithium to an intermediate tert-butylsulfinimide.     

Design,Synthesis, and Evaluation of Novel 2H-Benzo[b][1,4]thiazin-3(4H)-one Derivatives as New Acetylcholinesterase Inhibitors

Alzheimer’s disease (AD) is a slowly progressive neurodegenerative disease that causes dementia in people aged 65 and over. In the present study, a series of thiadiazole hybrid compounds with benzothiazine derivatives as acetylcholinesterase inhibitors were developed and evaluated for their biological activity. The AChE and BChE inhibition potentials of all compounds were evaluated by using the in vitro Ellman method. The biological evaluation showed that compounds 3i and 3j displayed significant inhibitory activity against AChE. Compounds 3i and 3j showed IC₅₀ values of 0.027 µM and 0.025 µM against AChE, respectively. The reference drug donepezil (IC₅₀ = 0.021 µM) also showed significant inhibition against AChE. Further docking simulation also revealed that these compounds (3i and 3j) interacted with the active site of the enzyme similarly to donepezil. The antioxidant study revealed that compounds 3i and 3j exhibited greater antioxidant effects. An in vitro blood–brain barrier permeability study showed that compounds 3i and 3j are promising compounds against AD. The cytotoxicity study of compounds 3i and 3j showed non-cytotoxic with an IC₅₀ value of 98.29 ± 3.98 µM and 159.68 ± 5.53 µM against NIH/3T3 cells, respectively.     

Discovery of Novel Tricyclic 5H-Pyridazino[4,5-b]indoles as Potent Antitumor Agents: Design,Synthesis and Biological Evaluation

A novel series of 5H-pyridazino[4,5-b]indoles(L-01-L-32) was synthesized and characterized by means of ¹H NMR, MS and elemental analysis. The cytotoxicity of the target compounds against Bel-7402 and HT-1080 cell lines were evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide(MTT) assay. Most of them exhibited moderate to excellent cytotoxicity, and six compounds(L-04, L-06, L-18, L-20, L-21 and L-23) possessed dramatically increased cytotoxicity superior to Gefitinib. Of these initial hits, compound L-21 displayed remarkable cytotoxicity against the tested cell lines with half maximal inhibitory concentration(IC₅₀) values of 4.6 and 2.1 μmol/L, respectively, which was 13.9- to 25.6-fold more potent than positive control.     

Synthesis and antiviral properties of aza-analogues of ganciclovir derived from 5,5-bis(hydroxymethyl)pyrrolidin-2-one

Novel aza-analogues of ganciclovir were obtained from 1,5,5-tris(pivaloyloxymethyl)pyrrolidin-2-one by a one-pot base silylation/nucleoside coupling procedure. The compounds were evaluated for, but found to be devoid of, antiviral activity in vitro.     

Synthesis and Structure–Activity Relationship Studies of Benzimidazole-4,7-dione-Based P2X3 Receptor Antagonists as Novel Anti-Nociceptive Agents

P2X3 receptors (P2X3R) are ATP-gated ion channels predominantly expressed in C- and Aδ-fiber primary afferent neurons and have been introduced as a novel therapeutic target for neurological disorders, including neuropathic pain and chronic cough. Because of its localized distribution, antagonism of P2X3R has been thoroughly considered, and the avoidance of issues related to CNS side effects has been proven in clinical trials. In this article, benzimidazole-4,7-dione-based derivatives were introduced as a new chemical entity for the development of P2X3R antagonists. Starting from the discovery of a hit compound from the screening of 8364 random library compounds in the Korea Chemical Bank, which had an IC₅₀ value of 1030 nM, studies of structure–activity and structure–property relationships enabled further optimization toward improving the antagonistic activities as well as the drug’s physicochemical properties, including metabolic stability. As for the results, the final optimized compound 14h was developed with an IC₅₀ value of 375 nM at P2X3R with more than 23-fold selectivity versus P2X2/3R, along with properties of metabolic stability and improved solubility. In neuropathic pain animal models evoked by either nerve ligation or chemotherapeutics in male Sprague-Dawley rats, compound 14h showed anti-nociceptive effects through an increase in the mechanical withdrawal threshold as measured by von Frey filament following intravenous administration.