Coumarin-Annulated Ferrocenyl 1,3-Oxazine Derivatives Possessing In Vitro Antimalarial and Antitrypanosomal Potency

A tailored series of coumarin-based ferrocenyl 1,3-oxazine hybrid compounds was synthesized and investigated for potential antiparasitic activity, drawing inspiration from the established biological efficacy of the constituent chemical motifs. The structural identity of the synthesized compounds was confirmed by common spectroscopic techniques: NMR, HRMS and IR. Biological evaluation studies reveal that the compounds exhibit higher in vitro antiparasitic potency against the chemosensitive malarial strain (3D7 P. falciparum) over the investigated trypanosomiasis causal agent (T. b. brucei 427) with mostly single digit micromolar IC50 values. When read in tandem with the biological performance of previously reported structurally similar non-coumarin, phenyl derivatives (i.e., ferrocenyl 1,3-benzoxazines and α-aminocresols), structure-activity relationship analyses suggest that the presence of the coumarin nucleus is tolerated for biological activity though this may lead to reduced efficacy. Preliminary mechanistic studies with the most promising compound (11b) support hemozoin inhibition and DNA interaction as likely mechanistic modalities by which this class of compounds may act to produce plasmocidal and antitrypanosomal effects.

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Microwave-Assisted Synthesis of (Piperidin-1-yl)quinolin-3-yl)methylene)hydrazinecarbothioamides as Potent Inhibitors of Cholinesterases: A Biochemical and In Silico Approach

Molecules ◽

10.3390/molecules26030656 ◽

2021 ◽

Vol 26 (3) ◽

pp. 656

Author(s):

Rubina Munir ◽

Muhammad Zia-ur-Rehman ◽

Shahzad Murtaza ◽

Sumera Zaib ◽

Noman Javid ◽

...

Keyword(s):

Neurodegenerative Disorder ◽

Critical Role ◽

Public Health Problem ◽

Microwave Assisted Synthesis ◽

Major Public Health Problem ◽

Spectroscopic Techniques ◽

Dual Inhibitor ◽

Microwave Assisted ◽

Ic50 Values

Alzheimer’s disease (AD), a progressive neurodegenerative disorder, characterized by central cognitive dysfunction, memory loss, and intellectual decline poses a major public health problem affecting millions of people around the globe. Despite several clinically approved drugs and development of anti-Alzheimer’s heterocyclic structural leads, the treatment of AD requires safer hybrid therapeutics with characteristic structural and biochemical properties. In this endeavor, we herein report a microwave-assisted synthesis of a library of quinoline thiosemicarbazones endowed with a piperidine moiety, achieved via the condensation of 6/8-methyl-2-(piperidin-1-yl)quinoline-3-carbaldehydes and (un)substituted thiosemicarbazides. The target N-heterocyclic products were isolated in excellent yields. The structures of all the synthesized compounds were fully established using readily available spectroscopic techniques (FTIR, 1H- and 13C-NMR). Anti-Alzheimer potential of the synthesized heterocyclic compounds was evaluated using acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes. The in vitro biochemical assay results revealed several compounds as potent inhibitors of both enzymes. Among them, five compounds exhibited IC50 values less than 20 μM. N-(3-chlorophenyl)-2-((8-methyl-2-(piperidin-1-yl)quinolin-3-yl)methylene)hydrazine carbothioamide emerged as the most potent dual inhibitor of AChE and BChE with IC50 values of 9.68 and 11.59 μM, respectively. Various informative structure–activity relationship (SAR) analyses were also concluded indicating the critical role of substitution pattern on the inhibitory efficacy of the tested derivatives. In vitro results were further validated through molecular docking analysis where interactive behavior of the potent inhibitors within the active pocket of enzymes was established. Quinoline thiosemicarbazones were also tested for their cytotoxicity using MTT assay against HepG2 cells. Among the 26 novel compounds, there were five cytotoxical and 18 showed proliferative properties.

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SYNTHESIS AND ANTIMALARIAL ACTIVITY OF SOME NEW 3-PHENYL-2-THIOXOTHIAZOLIDIN-4-ONE DERIVATIVES

International Journal of Current Pharmaceutical Research ◽

10.22159/ijcpr.2017.v9i3.18897 ◽

2017 ◽

Vol 9 (3) ◽

pp. 58

Author(s):

Mehul Zaveri ◽

Neha Kawathekar

Keyword(s):

Antimalarial Activity ◽

Research Work ◽

Aromatic Aldehydes ◽

Maximum Activity ◽

Spectroscopic Techniques ◽

Activity Data ◽

Antimalarial Agents ◽

Ic50 Values ◽

Current Therapies

Objective: Current therapies to treat P. falciparum malaria are heavily reliant on artemisinin-based combinations. However, resistance to artemisinin has recently been identified, and resistance to key artemisinin partner drugs is already widespread. Therefore, there is an urgent need for new antimalarial drugs with improved attributes over older therapies. The objective of this research work is to synthesize new antimalarial agents more effective against clinically relevant malarial strains.Methods: In present work, a series of ten 3-phenyl-2-thioxothiazolidin-4-one (MF1-MF10) derivatives, were synthesized by Knoevenagel condensation of N-phenyl rhodanine (I1) with substituted aromatic or hetro aromatic aldehydes using microwave irradiation. N-phenyl rhodanine (I1) was synthesized by a conventional reaction involving methyl-2-mercaptoacetate (1) and phenyl Isothiocyanates in presence of triethylamine. All the synthesized compounds were characterized by various spectroscopic techniques and evaluated for in-vitro antimalarial activity by microdilution technique against resistance strains of Plasmodium falciparum.Results: The antimalarial activity data showed that six compounds (MF1, MF3, MF4, MF5, MF7 and MF8) exhibited IC50 values ranging from 1.0-1.30 µg/ml, three compounds (MF2, MF6 and MF10) displayed IC50 values in the range of 0.9-1.0 µg/ml. Compound MF9 showed most significant result with maximum activity (IC50 = 0.85µg/ml).Conclusion: The antimalarial activity results revealed that compound MF9 possess potent activity and could be identified as a promising lead for further investigation.

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Synthetic (E)-3-Phenyl-5-(phenylamino)-2-styryl-1,3,4-thiadiazol-3-ium Chloride Derivatives as Promising Chemotherapy Agents on Cell Lines Infected with HTLV-1

Molecules ◽

10.3390/molecules25112537 ◽

2020 ◽

Vol 25 (11) ◽

pp. 2537

Author(s):

Danilo Sousa-Pereira ◽

Thais Silva de Oliveira ◽

Rojane O. Paiva ◽

Otávio Augusto Chaves ◽

José C. Netto-Ferreira ◽

...

Keyword(s):

Molecular Docking ◽

T Cell ◽

Cell Lines ◽

Pharmacokinetic Profile ◽

Biological Evaluation ◽

Spectroscopic Techniques ◽

Time Resolved ◽

Adult T Cell Leukemia ◽

Human T Cell ◽

Ic50 Values

Synthesis of four compounds belonging to mesoionic class, (E)-3-phenyl-5-(phenylamino)-2-styryl-1,3,4-thiadiazol-3-ium chloride derivatives (5a–d) and their biological evaluation against MT2 and C92 cell lines infected with human T-cell lymphotropic virus type-1 (HTLV-1), which causes adult T-cell leukemia/lymphoma (ATLL), and non-infected cell lines (Jurkat) are reported. The compounds were obtained by convergent synthesis under microwave irradiation and the cytotoxicity was evaluated using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays. Results showed IC50 values of all compounds in the range of 1.51–7.70 μM in HTLV-1-infected and non-infected cells. Furthermore, it was observed that 5b could induce necrosis after 24 h for Jurkat and MT2 cell lines. The experimental (fluorimetric method) and theoretical (molecular docking) results suggested that the mechanism of action for 5b could be related to its capacity to intercalate into DNA. Moreover, the preliminary pharmacokinetic profile of the studied compounds (5a–d) was obtained through human serum albumin (HSA) binding affinity using multiple spectroscopic techniques (circular dichroism, steady-state and time-resolved fluorescence), zeta potential and molecular docking calculations. The interaction HSA:5a–d is spontaneous and moderate (Ka ~ 104 M−1) via a ground-state association, without significantly perturbing both the secondary and surface structures of the albumin in the subdomain IIA (site I), indicating feasible biodistribution in the human bloodstream.

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Synthesis, in silico pharmacokinetics and biological evaluation of some new thiazolidinedione as PPAR-γ agonists and antibacterial agents

Letters in Drug Design & Discovery ◽

10.2174/1570180818666210427102554 ◽

2021 ◽

Vol 18 ◽

Author(s):

Zohor Mohammad Mahdi Alzhrani ◽

Mohammad Mahboob Alam ◽

Syed Nazreen

Keyword(s):

Antibacterial Agents ◽

Antimicrobial Agents ◽

Antibacterial Activities ◽

Biological Evaluation ◽

New Drugs ◽

Diabetic Patients ◽

Spectroscopic Techniques ◽

Standard Drug ◽

Ppar Γ

Background: The frequent uses of antimicrobial agents to treat infections in diabetic patients make them more drug resistance than non diabetic patients which accounts for higher mortality rate of diabetic patients. Therefore, it is a necessity today to synthesize new drugs with dual mode of action as antidiabetic and antibacterial agents. In the present work, new derivatives containing thiazolidinedione and 1,3,4-oxadiaozle have been synthesized and screened for PPAR-γ and antibacterial activities. Methods: Compound 5-12 have been synthesized from 2-methoxy benzaldehyde and thiazolidinedione and characterized using different spectroscopic techniques such as IR, NMR and mass spectrometry. These compounds were tested for in vitro PPAR-γ transactivation, PPAR-γ gene expression and antibacterial activities. Finally molecular docking was carried out to see the binding interactions of molecules with the target protein. Results: All the compounds follow Lipinski rule suggesting the synthesized derivatives have good drug likeness properties. Compound 11 and 12 exhibited promising PPAR-γ transactivation with 73.69% and 76.50%, respectively as well as showed significant antibacterial activity with comparable MIC of 3.12 μg/disc to standard drug amoxicillin. The docking result was found to be in consistent with the in vitro PPAR-γ transactivation results. Conclusion: Compounds 11 and 12 can be further investigated as lead molecules for the development of new and effective antidiabetic and antibacterial agents.

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Design, Synthesis, and Biological Evaluation of Pyridineamide Derivatives Containing a 1,2,3-Triazole Fragment as Type II c-Met Inhibitors

Molecules ◽

10.3390/molecules25010010 ◽

2019 ◽

Vol 25 (1) ◽

pp. 10 ◽

Cited By ~ 1

Author(s):

Hehua Xiong ◽

Jianxin Cheng ◽

Jianqing Zhang ◽

Qian Zhang ◽

Zhen Xiao ◽

...

Keyword(s):

Antitumor Activity ◽

Cell Lines ◽

Inhibitory Activity ◽

Docking Simulation ◽

Binding Mode ◽

Biological Evaluation ◽

Design Synthesis ◽

Ic50 Values ◽

Mcf 7

A series of 4-(pyridin-4-yloxy)benzamide derivatives containing a 1,2,3-triazole fragment were designed, synthesized, and their inhibitory activity against A549, HeLa, and MCF-7 cancer cell lines was evaluated. Most compounds exhibited moderate to potent antitumor activity against the three cell lines. Among them, the promising compound B26 showed stronger inhibitory activity than Golvatinib, with IC50 values of 3.22, 4.33, and 5.82 μM against A549, HeLa, and MCF-7 cell lines, respectively. The structure–activity relationships (SARs) demonstrated that the modification of the terminal benzene ring with a single electron-withdrawing substituent (fluorine atom) and the introduction of a pyridine amide chain with a strong hydrophilic group (morpholine) to the hinge region greatly improved the antitumor activity. Meanwhile, the optimal compound B26 showed potent biological activity in some pharmacological experiments in vitro, such as cell morphology study, dose-dependent test, kinase activity assay, and cell cycle experiment. Finally, the molecular docking simulation was performed to further explore the binding mode of compound B26 with c-Met.

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Zinc(II) Terpyridine Complexes: Substituent Effect on Photoluminescence, Antiproliferative Activity, and DNA Interaction

Molecules ◽

10.3390/molecules24244519 ◽

2019 ◽

Vol 24 (24) ◽

pp. 4519 ◽

Cited By ~ 7

Author(s):

Jiahe Li ◽

Rongping Liu ◽

Jinzhang Jiang ◽

Xing Liang ◽

Ling Huang ◽

...

Keyword(s):

Tumor Cells ◽

Antiproliferative Activity ◽

Conformational Transition ◽

Dna Interaction ◽

Docking Studies ◽

In Vitro Cytotoxicity ◽

Human Carcinoma ◽

Ic50 Values ◽

The Difference

A series of ZnCl2 complexes (compounds 1–10) with 4′-(substituted-phenyl)-2,2′:6′,2′′-terpyridine that bears hydrogen (L1), p-methyl (L2), p-methoxy (L3), p-phenyl (L4), p-tolyl (L5), p-hydroxyl (L6), m-hydroxyl (L7), o-hydroxyl (L8), p-carboxyl (L9), or p-methylsulfonyl (L10) were prepared and then characterized by 1H NMR, electrospray mass-spectra (ESI-MS), IR, elemental analysis, and single crystal X-ray diffraction. In vitro cytotoxicity assay was used to monitor the antiproliferative activities against tumor cells. Absorption spectroscopy, fluorescence titration, circular dichroism spectroscopy, and molecular modeling studied the DNA interactions. All of the compounds display interesting photoluminescent properties and different maximal emission peaks due to the difference of the substituent groups. The cell viability studies indicate that the compounds have excellent antiproliferative activity against four human carcinoma cell lines, A549, Bel-7402, MCF-7, and Eca-109, with the lowest IC50 values of 0.33 (10), 0.66 (6), 0.37 (7), and 1.05 (7) μM, respectively. The spectrophotometric results reveal that the compounds have strong affinity binding with DNA as intercalator and induce DNA conformational transition. Molecular docking studies indicate that the binding is contributed by the π…π stacking and hydrogen bonds, providing an order of nucleotide sequence binding selectivity as ATGC > ATAT > GCGC. These compounds intercalate into the base pairs of the DNA of the tumor cells to affect their replication and transcription, and the process is supposed to play an important role in the anticancer mechanism.

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α-Glucosidase Inhibition and Molecular Docking Studies of Natural Brominated Metabolites from Marine Macro Brown Alga Dictyopteris hoytii

Marine Drugs ◽

10.3390/md17120666 ◽

2019 ◽

Vol 17 (12) ◽

pp. 666 ◽

Cited By ~ 8

Author(s):

Najeeb Ur Rehman ◽

Kashif Rafiq ◽

Ajmal Khan ◽

Sobia Ahsan Halim ◽

Liaqat Ali ◽

...

Keyword(s):

Molecular Docking ◽

Brown Alga ◽

Docking Studies ◽

Spectroscopic Techniques ◽

Molecular Docking Studies ◽

Ethyl Methyl ◽

2D Noesy ◽

Ic50 Value ◽

Ic50 Values

Bioassay guided isolation of the methanolic extract of marine macro brown alga Dictyopteris hoytii afforded one new metabolite (ethyl methyl 2-bromobenzene 1,4-dioate, 1), one new natural metabolite (diethyl-2-bromobenzene 1,4-dioate, 2) along with six known metabolites (3–8) reported for the first time from this source. The structure elucidation of all these compounds was achieved by extensive spectroscopic techniques including 1D (1H and 13C) and 2D (NOESY, COSY, HMBC and HSQC) NMR and mass spectrometry and comparison of the spectral data of known compounds with those reported in literature. The in vitro α-glucosidase inhibition studies confirmed compound 7 to be the most active against α-glucosidase enzyme with IC50 value of 30.5 ± 0.41 μM. Compounds 2 and 3 demonstrated good inhibition with IC50 values of 234.2 ± 4.18 and 289.4 ± 4.91 μM, respectively, while compounds 1, 5, and 6 showed moderate to low inhibition. Furthermore, the molecular docking studies of the active compounds were performed to examine their mode of inhibition in the binding site of the α-glucosidase enzyme.

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Design, Synthesis, Molecular Docking, ADME and Biological Evaluation Studies of Some New 1,3,4-oxadiazole Linked Benzimidazoles as Anticancer Agents and Aromatase Inhibitors

10.21203/rs.3.rs-975581/v1 ◽

2021 ◽

Author(s):

ulviye acar çevik ◽

Ismail Celik ◽

Ayşen IŞIK ◽

Yusuf Özkay ◽

Zafer Asım Kaplancıklı

Keyword(s):

Molecular Docking ◽

Cell Line ◽

Cell Lines ◽

Anticancer Agents ◽

Evaluation Studies ◽

Biological Evaluation ◽

Binding Modes ◽

Anticancer Activities ◽

Mcf 7

Abstract In this study, due to the potential anticancer effects of the benzimidazole ring system, a series of benzimidazole-1,3,4-oxadiazole derivatives were synthesized and characterized by 1H NMR, 13C NMR, and MS spectra analyses. In the in vitro anticancer assay, all the compounds tested anticancer activities using MTT-based assay against five cancer cell lines (MCF-7, A549, HeLa, C6, and HepG2). Among them, compound 5a exhibited the most potent activity with IC50 values of 5,165±0,211 μM and 5,995±0,264 μM against MCF-7 and HepG2 cell lines. Compound 5a was included in the BrdU test to determine the DNA synthesis inhibition effects for both cell types. Furthermore, compound 5c was also found to be more effective than doxorubicin on the HeLa cell line. The selectivity of anticancer activity was evaluated in NIH3T3 (mouse embryo fibroblast cell line) cell line. In vitro, enzymatic inhibition assays of aromatase enzyme were performed for compound 5a acting on the MCF-7 cell line. For compound 5a, in silico molecular docking against aromatase enzyme was performed to determine possible protein-ligand interactions and binding modes.

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Synthesis, Biological Evaluation and Docking Studies of 13-Epimeric 10-fluoro- and 10-Chloroestra-1,4-dien-3-ones as Potential Aromatase Inhibitors

Molecules ◽

10.3390/molecules24091783 ◽

2019 ◽

Vol 24 (9) ◽

pp. 1783 ◽

Cited By ~ 1

Author(s):

Rebeka Jójárt ◽

Péter Traj ◽

Édua Kovács ◽

Ágnes Horváth ◽

Gyula Schneider ◽

...

Keyword(s):

Biological Activity ◽

Inhibitory Action ◽

Molecular Level ◽

Docking Studies ◽

Biological Evaluation ◽

Computational Simulations ◽

Simultaneous Application ◽

Methyl Group ◽

Ic50 Values

Fluorination of 13-epimeric estrones and their 17-deoxy counterparts was performed with Selectfluor as the reagent. In acetonitrile or trifluoroacetic acid (TFA), 10β-fluoroestra-1,4-dien-3-ones were formed exclusively. Mechanistic investigations suggest that fluorinations occurred via SET in acetonitrile, but another mechanism was operative in TFA. Simultaneous application of N-chlorosuccinimide (NCS) and Selectfluor in TFA led to a 1.3:1 mixture of 10β-fluoroestra-1,4-dien-3-one and 10β-chloroestra-1,4-dien-3-one as the main products. The potential inhibitory action of the 10-fluoro- or 10-chloroestra-1,4-dien-3-one products on human aromatase was investigated via in vitro radiosubstrate incubation. The classical estrane conformation with trans ring anellations and a 13β-methyl group seems to be crucial for the inhibition of the enzyme, while test compounds bearing the 13β-methyl group exclusively displayed potent inhibitory action with submicromolar or micromolar IC50 values. Concerning molecular level explanation of biological activity or inactivity, computational simulations were performed. Docking studies reinforced that besides the well-known Met374 H-bond connection, the stereocenter in the 13 position has an important role in the binding affinity. The configuration inversion at C-13 results in weaker binding of 13α-estrone derivatives to the aromatase enzyme.

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SYNTHESIS, BIOLOGICAL EVALUATION, AND DOCKING STUDY OF NOVEL 2-PHENYL-1- BENZOPYRAN-4-ONE DERIVATIVES - AS A POTENT CYCLOOXYGENASE-2 INHIBITOR

Asian Journal of Pharmaceutical and Clinical Research ◽

10.22159/ajpcr.2019.v12i3.30466 ◽

2019 ◽

pp. 304-310

Author(s):

NATARAJAN KIRUTHIGA ◽

THANGAVELU PRABHA ◽

CHELLAPPA SELVINTHANUJA ◽

KULANDAIVEL SRINIVASAN ◽

THANGAVEL SIVAKUMAR

Keyword(s):

Chronic Diseases ◽

Radical Scavenging ◽

Data Bank ◽

Docking Study ◽

Biological Evaluation ◽

Cyclooxygenase 2 ◽

Spectroscopic Techniques ◽

Cox 2 ◽

Anti Inflammatory

Objective: The inflammation and oxidative stress were related together in the generation of reactive oxygen species, which is responsible for the enhancement of inflammation associated with various chronic diseases. Methods: The aim of this study is to synthezise and characterizes the flavones (2-phenyl-1-benzopyran-4-one) derivatives and analyzed by their docking hypothetical data as an effective anti-inflammatory mediator against cyclooxygenase-2 (COX-2) enzyme. Further, the evaluation of various in vitro antioxidant and anti-inflammatory studies was carried out. Results: The 10 compounds were synthesized and characterized by ultraviolet, infrared, nuclear magnetic resonance, and mass spectroscopic techniques. The docking data results of these 10 flavones derivatives against COX-2 enzymes (Protein Data Bank ID: 3LN1) showed the binding energy ranging between −5.53 kcal/mol and −7.02 kcal/mol when compared with that of the standard diclofenac (−6.34 kcal/mol). The in vitro studies suggest that the lipophilic character of the side chain donor, along with the hydroxyl substituted flavones found to have significant half maximal inhibitory concentration values. Conclusion: Based on these in silico and in vitro evaluation results, these synthesized compounds could act as a promising inhibitor to target the COX- 2 enzyme. Hence, those compounds were effective in the management of chronic diseases by exhibits free radical scavenging and anti-inflammatory property.

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