Synthesis, Enantiomeric Resolution and Biological Evaluation of HIV Capsid Inhibition Activity for Racemic, (S)- and (R)-PF74

PF74 is a capsid-targeting inhibitor of HIV replication that effectively perturbs the highly sensitive viral uncoating process. A lack of information regarding the optical purity (enantiomeric excess) of the single stereogenic centre of PF74 has resulted in ambiguity as to the potency of different samples of this compound. Herein is described the synthesis of enantiomerically enriched (S)- and (R)-PF74 and further enrichment of the samples (≥98%) using chiral HPLC resolution. The biological activities of each enantiomer were then evaluated, which determined (S)-PF74 (IC50 1.5 µM) to be significantly more active than (R)-PF74 (IC50 19 µM). Computational docking studies were then conducted to rationalise this large discrepancy in activity, which indicated different binding conformations for each enantiomer. The binding energy of the conformation adopted by the more active (S)-PF74 (ΔG = −73.8 kcal/mol) was calculated to be more favourable than the conformation adopted by the less active (R)-enantiomer (ΔG = −55.8 kcal/mol) in agreement with experimental observations.

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Enantioselective Synthesis, Tautomerism, Molecular Docking And Biological Evaluation of 4-Hydroxy-3-(3-Oxo-1-Phenylbutyl)-2H-Chromen-2-One Analogues

10.21203/rs.3.rs-982583/v1 ◽

2021 ◽

Author(s):

Zakia Afzal ◽

Naghmana Rashid ◽

Humaira Nadeem ◽

Arif-ullah Khan

Keyword(s):

Molecular Docking ◽

Anticoagulant Activity ◽

Enantiomeric Excess ◽

Docking Studies ◽

Biological Evaluation ◽

Chiral Hplc ◽

Aryl Group ◽

Standard Drug ◽

Antibacterial And Antifungal Activities

Abstract Keeping in view the aim of better alternatives of 4-Hydroxy-3-(3-oxo-1-phenylbutyl)-2H-chromen-2-one (warfarin), eleven analogs of warfarin have been synthesized with the goal to increase enantioselectivity of (S) enantiomer by using appropriate catalyst and minimize tautomerism by replacing methyl group of the side chain with aryl group. There are many reports of the serious complications with warfarin use, which are associated with the tautomeric forms of warfarin. The key step was highly enantioselective Michael addition of variously substituted chalcone and 4-hydroxycoumarin by using cinchona based 9-amino-9-deoxyepiquinine as chiral catalyst. Synthesized compounds were characterized by IR, 1HNMR,13CNMR, EIMS and CD studies. Enantiomeric excess (%ee) was determined by chiral HPLC which was upto 98%. Synthesized analogues were screened for anticoagulant, antibacterial and antifungal activities. In-vitro anticoagulant activity was evaluated by plasma recalcification time (PRT) method and out of eleven, ten synthesized compounds showed improved IC50 values as compaired to IC50 values of standard drug warfarin. Compound 4 showed 68.25% inhibation against staphylococcus aureus and compound 7 showed 68% inhibation against bacillus subtillis, gram positive strains of bacteria, compound 6 shows 70% inhibation against fungal strain candida albicans. Furthermore, molecular docking studies were carried out with Vitamin K1 epoxide reductase VKOR1 receptor 3kp9, a potential target of warfarin for anticoagulant activity.

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Synthesis and Biological Evaluation of 1-(Diarylmethyl)-1H-1,2,4-triazoles and 1-(Diarylmethyl)-1H-imidazoles as a Novel Class of Anti-Mitotic Agent for Activity in Breast Cancer

Pharmaceuticals ◽

10.3390/ph14020169 ◽

2021 ◽

Vol 14 (2) ◽

pp. 169

Author(s):

Gloria Ana ◽

Patrick M. Kelly ◽

Azizah M. Malebari ◽

Sara Noorani ◽

Seema M. Nathwani ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Cells ◽

Breast Cancer Cells ◽

Docking Studies ◽

Biological Evaluation ◽

Mitotic Catastrophe ◽

Phase Cell ◽

Computational Docking ◽

Er Positive ◽

Mcf 7

We report the synthesis and biochemical evaluation of compounds that are designed as hybrids of the microtubule targeting benzophenone phenstatin and the aromatase inhibitor letrozole. A preliminary screening in estrogen receptor (ER)-positive MCF-7 breast cancer cells identified 5-((2H-1,2,3-triazol-1-yl)(3,4,5-trimethoxyphenyl)methyl)-2-methoxyphenol 24 as a potent antiproliferative compound with an IC50 value of 52 nM in MCF-7 breast cancer cells (ER+/PR+) and 74 nM in triple-negative MDA-MB-231 breast cancer cells. The compounds demonstrated significant G2/M phase cell cycle arrest and induction of apoptosis in the MCF-7 cell line, inhibited tubulin polymerisation, and were selective for cancer cells when evaluated in non-tumorigenic MCF-10A breast cells. The immunofluorescence staining of MCF-7 cells confirmed that the compounds targeted tubulin and induced multinucleation, which is a recognised sign of mitotic catastrophe. Computational docking studies of compounds 19e, 21l, and 24 in the colchicine binding site of tubulin indicated potential binding conformations for the compounds. Compounds 19e and 21l were also shown to selectively inhibit aromatase. These compounds are promising candidates for development as antiproliferative, aromatase inhibitory, and microtubule-disrupting agents for breast cancer.

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Synthesis and Biological Evaluation of Alanine Derived Bioactive p-Toluenesulphonamide Analogs

International Journal of Research in Pharmaceutical Sciences ◽

10.26452/ijrps.v11i4.3440 ◽

2020 ◽

Vol 11 (4) ◽

pp. 6449-6458

Author(s):

Melford C Egbujor ◽

Uchechukwu C Okoro ◽

Samuel A Egu ◽

Pius I Egwuatu ◽

Florence U Eze ◽

...

Keyword(s):

Molecular Docking ◽

Antimalarial Activity ◽

Biological Activities ◽

Analytical Data ◽

Antioxidant Properties ◽

Antimicrobial Properties ◽

Docking Studies ◽

Biological Evaluation ◽

Agar Dilution

Sulphonamides and carboxamides have great pharmacological importance. The purpose of the study was to synthesize alanine-derived bioactive sulphonamides bearing carboxamides and evaluate their biological activities. The reaction of p-toluenesulphonyl chloride with L-alanine afforded compound 1, which was acetylated to obtain compound 2. The chlorination and ammonolysis of compound 2 gave the carboxamide backbone (3) which was coupled with aryl/heteroaryl halides to afford the hybrid compounds 4, 5 and 6. Structures were confirmed by FTIR, 1H-NMR, 13C-NMR spectra and elemental analytical data. The in vitro antimicrobial properties were determined by agar dilution, and the antioxidant properties were also investigated. Molecular docking interactions of the analogues were determined using PyRx. Compounds 4, 5 and 6 exhibited excellent in vitro antimicrobial properties in the range of 0.5-1.0mg/ml while compounds 1and 2 had half-maximal inhibitory concentration (IC50) of 1.11±0.15µg/ml and 1.12±0.13µg/ml respectively. For the molecular docking studies, compounds 5 and 6 displayed the best antitrypanosomal activity with binding affinities of -13.95 and -13.51kcal/mol respectively while compound 4 showed the highest in silico antimalarial activity having binding affinity of -11.95kcal/mol. All the alanine derived sulphonamides were observed to be potential antimicrobial, antioxidant, antitrypanosomal and antimalarial agents following the biological activities studies.

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Synthesis, Biological Evaluation and Molecular Modeling Studies of Novel C (7) Modified Analogues of Chrysin

Letters in Drug Design & Discovery ◽

10.2174/1570180816666190913183623 ◽

2020 ◽

Vol 17 (7) ◽

pp. 873-883

Author(s):

Pulabala Ramesh ◽

Vankadari Srinivasa Rao ◽

Puchakayala Muralidhar Reddy ◽

Katragadda Suresh Babu ◽

Mutheneni Srinivasa Rao

Keyword(s):

Natural Products ◽

Biological Activity ◽

Molecular Docking ◽

Biological Activities ◽

Antimicrobial Activities ◽

Docking Studies ◽

Biological Evaluation ◽

Molecular Docking Studies ◽

Fungal Strains

Background:: Most of the currently available pharmaceutical drugs are either natural products or analogues of natural products. Flavonoids are plant based natural polyphenolic compounds which exhibit a wide range of biological activities. Chrysin, a natural flavone, exhibits several biological activities like antiallergic, anti-inflammatory and anticancer. Many efforts were made to enhance the biological activity of chrysin. In continuation of our work on synthetic modifications of chrysin, amino-alcohol containing heterocyclic moiety is linked to chrysin at C (7) position to enhance its biological activity. Methods:: A series of new C (7) modified analogues of chrysin (3a-k) have been designed and synthesized in two steps. Chrysin, on reacting with epichlorohydrin in the presence of K2CO3 in DMF gave epoxide (2) which was made to react with cyclic secondary amines in the presence of LiBr to form the designed products (3a-k). All the synthesized compounds (3a-k) were well characterized by 1H NMR, 13C NMR and mass spectral data. The synthesized analogues (3a-k) were screened for their in vitro biological activities against a panel of bacterial and fungal strains. Molecular docking studies were also performed on these compounds with E. coli FabH (1HNJ) and S. cerevisiae (5EQB) enzymes, to support the observed biological activities. Results:: A series of new 2-hydroxy 3-amino chrysin derivatives (3a-k) were synthesized in two steps, starting with chrysin and their structures were characterized by spectral analysis. In vitro biological activities of these analogues against a panel of bacterial and fungal strains indicated that some of the derivatives manifested significant activities compared to standard drugs. Molecular docking and binding energy values were also correlated with experimental antimicrobial screening results. Lipinski’s “rule of five” is also obeyed by these analogues (3a-k) and exhibit drug-likeness. Conclusion:: In the present study, a series of new C (7) modified chrysin analogues (3a-k) were synthesized and tested for their in vitro antimicrobial activities. These biological studies indicated that some of the derivatives exhibited moderate to good antimicrobial activities compared to standard drugs. Molecular docking studies performed on these compounds correlated with the experimental antimicrobial activities. The results obtained in the study will be useful in establishing new drug entities to control the pathogenic epidemics.

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New Benzothiazole-based Thiazolidinones as Potent Antimicrobial Agents. Design, synthesis and Biological Evaluation

Current Topics in Medicinal Chemistry ◽

10.2174/1568026618666180206101814 ◽

2018 ◽

Vol 18 (1) ◽

pp. 75-87 ◽

Cited By ~ 19

Author(s):

Michelyne Haroun ◽

Christophe Tratrat ◽

Katerina Kositzi ◽

Evangelia Tsolaki ◽

Anthi Petrou ◽

...

Keyword(s):

Antimicrobial Activity ◽

Antimicrobial Agents ◽

Biological Activities ◽

Wide Spectrum ◽

Antimicrobial Properties ◽

Docking Studies ◽

Biological Evaluation ◽

Synthesis Methods ◽

Design Synthesis ◽

Benzothiazole Derivatives

Background: Thiazole and benzothiazole derivatives, as well as thiazolidinones are very important scaffolds in medicinal chemistry. Literature has revealed that they possess a wide spectrum of biological activities including antimicrobial activity. Objective: The goal of this paper is the designing of new benzothiazole based thiazolidinones and the evaluation of their biological activities. Methods: The designed compounds were synthesized using classical organic synthesis methods. The antimicrobial activity was evaluated using the method of microdilution. Results: The twelve newly synthesized compounds showed antimicrobial properties. All compounds appeared to be more active than ampicillin in most studied strains and in some cases, more active than streptomycin. Antifungal activity, in most cases was also better than the reference drugs ketoconazole and bifonazole. The prediction of cytotoxicity revealed that the synthesized compounds were not toxic (LD50 350-1000 mg/kg of body weight). Docking studies on the antibacterial activity confirmed the biological results. Conclusion: The twelve new compounds were synthesized and studied for their antimicrobial activity. The compounds appeared to be promising antimicrobial agents and could be the lead compounds for new, more potent drugs. According to the docking prediction, the compounds could be MurB inhibitors.

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Synthesis, Characterization, Biological Evaluation and Molecular Docking Studies of Some Oxazinyl-Thiazolidinone Derivatives

Asian Journal of Chemistry ◽

10.14233/ajchem.2020.22710 ◽

2020 ◽

Vol 32 (9) ◽

pp. 2125-2129

Author(s):

RAMARAJAN RAJALAKSHMI ◽

RAJAVEL SANTHI ◽

THANGARAJ ELAKKIYA

Keyword(s):

Antioxidant Activity ◽

Molecular Docking ◽

Biological Activities ◽

Radical Scavenging ◽

Docking Studies ◽

Biological Evaluation ◽

Molecular Docking Studies ◽

Ir Studies ◽

Wide Range

A series of new 4-thiazolidinone derivatives of 2-(4-chlorophenyl)-3-(6-(thiophen-2-yl)-4-p-tolyl-4H-1,3-oxazin-2-yl)- thiazolidin-4-one (7h-m) are synthesized because of its wide range of biological activities.1H & 13C NMR, IR studies were applied for the elucidation of all the synthesized compounds. All the synthesized compounds have been tested for antidiabetic and antioxidant activity in vitro method against standard. The analogs 7h-m was evaluated for α-amylase and α-glucosidase inhibitory potential. The structures of all the compounds have been screened for antioxidant activity using DPPH radical scavenging assay, NO scavenging method. Molecular docking studies were accomplished in addition to understand the binding affinity of those compounds with PDBID 2HR7 which showed that the synthesized derivatives bind in the lively binding site of the target protein

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Synthesis, structural characterization, biological evaluation and molecular docking studies of new platinum(ii) complexes containing isocyanides

New Journal of Chemistry ◽

10.1039/c7nj04819j ◽

2018 ◽

Vol 42 (11) ◽

pp. 8681-8692 ◽

Cited By ~ 5

Author(s):

Masood Fereidoonnezhad ◽

Hamid R. Shahsavari ◽

Sedigheh Abedanzadeh ◽

Ali Nezafati ◽

Ali Khazali ◽

...

Keyword(s):

Molecular Docking ◽

Structural Characterization ◽

Biological Activities ◽

Docking Studies ◽

Biological Evaluation ◽

Molecular Docking Studies

Platinum(ii) complexes with various isocyanides are prepared and their biological activities are studied.

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Synthesis and analysis of 4-(3-fluoropropyl)-glutamic acid stereoisomers to determine the stereochemical purity of (4S)-4-(3-[18F]fluoropropyl)-L-glutamic acid ([18F]FSPG) for clinical use

PLoS ONE ◽

10.1371/journal.pone.0243831 ◽

2020 ◽

Vol 15 (12) ◽

pp. e0243831

Author(s):

Kai-Ting Shih ◽

Ya-Yao Huang ◽

Chia-Ying Yang ◽

Mei-Fang Cheng ◽

Yu-Wen Tien ◽

...

Keyword(s):

Clinical Trials ◽

Glutamic Acid ◽

Scale Up ◽

Enantiomeric Excess ◽

Optical Purity ◽

Daily Basis ◽

Brain Diseases ◽

Ductal Adenocarcinoma ◽

Chiral Hplc ◽

Clinical Use

(4S)-4-(3-[18F]Fluoropropyl)-L-glutamic acid ([18F]FSPG) is a positron emission tomography (PET) imaging agent for measuring the system xC− transporter activity. It has been used for the detection of various cancers and metastasis in clinical trials. [18F]FSPG is also a promising diagnostic tool for evaluation of multiple sclerosis, drug resistance in chemotherapy, inflammatory brain diseases, and infectious lesions. Due to the very short half-life (110 min) of 18F nuclide, [18F]FSPG needs to be produced on a daily basis; therefore, fast and efficient synthesis and analytical methods for quality control must be established to assure the quality and safety of [18F]FSPG for clinical use. To manufacture cGMP-compliant [18F]FSPG, all four nonradioactive stereoisomers of FSPG were prepared as reference standards for analysis. (2S,4S)-1 and (2R,4R)-1 were synthesized starting from protected L- and D-glutamate derivatives in three steps, whereas (2S,4R)-1 and (2R,4S)-1 were prepared in three steps from protected (S)- and (R)-pyroglutamates. A chiral HPLC method for simultaneous determination of four FSPG stereoisomers was developed by using a 3-cm Chirex 3126 column and a MeCN/CuSO4(aq) mobile phase. In this method, (2R,4S)-1, (2S,4S)-1, (2R,4R)-1, and (2S,4R)-1 were eluted in sequence with sufficient resolution in less than 25 min without derivatization. Scale-up synthesis of intermediates for the production of [18F]FSPG in high optical purity was achieved via stereo-selective synthesis or resolution by recrystallization. The enantiomeric excess of intermediates was determined by HPLC using a Chiralcel OD column and monitored at 220 nm. The nonradioactive precursor with >98% ee can be readily distributed to other facilities for the production of [18F]FSPG. Based on the above accomplishments, cGMP-compliant [18F]FSPG met the acceptance criteria in specifications and was successfully manufactured for human use. It has been routinely prepared and used in several pancreatic ductal adenocarcinoma metastasis-related clinical trials.

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Room Temperature Flow Electrochemistry as a Means of Retaining the “Memory of Chirality” via Hofer Moest Type Reaction

10.26434/chemrxiv.11516967.v2 ◽

2020 ◽

Author(s):

Tomas Hardwick ◽

Rossana Cicala ◽

Nisar Ahmed

Keyword(s):

Continuous Flow ◽

Room Temperature ◽

Biological Activities ◽

Supporting Electrolyte ◽

Enantiomeric Excess ◽

Flow Chemistry ◽

Batch Processes ◽

Enabling Technology ◽

Chiral Compounds ◽

Memory Of Chirality

<p>Many chiral compounds have become of great interest to the pharmaceutical industry as they possess various biological activities. Concurrently, the concept of “memory of chirality” has been proven as a powerful tool in asymmetric synthesis, while flow chemistry has begun its rise as a new enabling technology to add to the ever increasing arsenal of techniques available to the modern day chemist. Here, we have employed a new simple electrochemical microreactor design to oxidise an L-proline derivative at room temperature in continuous flow. Flow performed in microreactors offers up a number of benefits allowing reactions to be performed in a more convenient and safer manner, and even allow electrochemical reactions to take place without a supporting electrolyte due to a very short interelectrode distance. By the comparison of electrochemical oxidations in batch and flow we have found that continuous flow is able to outperform its batch counterpart, producing a good yield (71%) and a better enantiomeric excess (64%) than batch with a 98% conversion. We have, therefore, provided evidence that continuous flow chemistry has the potential to act as a new enabling technology to replace some aspects of conventional batch processes. </p>

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Novel Iodinated Hydrazide-hydrazones and their Analogues as Acetyl- and Butyrylcholinesterase Inhibitors

Current Topics in Medicinal Chemistry ◽

10.2174/1568026620666200819155503 ◽

2020 ◽

Vol 20 (23) ◽

pp. 2106-2117

Author(s):

Martin Krátký ◽

Šárka Štěpánková ◽

Michaela Brablíková ◽

Katarína Svrčková ◽

Markéta Švarcová ◽

...

Keyword(s):

Biological Activities ◽

Structural Parameters ◽

Covalent Binding ◽

Docking Studies ◽

Potent Inhibition ◽

Brain Barrier Permeability ◽

Electric Eel ◽

Ic50 Values ◽

Ellman’S Method

Background: Hydrazide-hydrazones have been known as scaffold with various biological activities including inhibition of acetyl- (AChE) and butyrylcholinesterase (BuChE). Cholinesterase inhibitors are mainstays of dementias’ treatment. Objective: Twenty-five iodinated hydrazide-hydrazones and their analogues were designed as potential central AChE and BuChE inhibitors. Methods: Hydrazide-hydrazones were synthesized from 4-substituted benzohydrazides and 2-/4- hydroxy-3,5-diiodobenzaldehydes. The compounds were investigated in vitro for their potency to inhibit AChE from electric eel and BuChE from equine serum using Ellman’s method. We calculated also physicochemical and structural parameters for CNS delivery. Results: The derivatives exhibited a moderate dual inhibition with IC50 values ranging from 15.1-140.5 and 35.5 to 170.5 μmol.L-1 for AChE and BuChE, respectively. Generally, the compounds produced a balanced or more potent inhibition of AChE. N'-[(E)-(4-Hydroxy-3,5-diiodophenyl)methylidene]-4- nitrobenzohydrazide 2k and 4-fluoro-N'-(2-hydroxy-3,5-diiodobenzyl)benzohydrazide 3a were the most potent inhibitors of AChE and BuChE, respectively. Structure-activity relationships were established, and molecular docking studies confirmed interaction with enzymes. Conclusion: Many novel hydrazide-hydrazones showed lower IC50 values than rivastigmine against AChE and some of them were comparable for BuChE to this drug used for the treatment of dementia. They interact with cholinesterases via non-covalent binding into the active site. Based on the BOILEDEgg approach, the majority of the derivatives met the criteria for blood-brain-barrier permeability.

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