Synthesis and Antiviral Activity of Novel 1,3,4-Thiadiazole Inhibitors of DDX3X

The human ATPase/RNA helicase X-linked DEAD-box polypeptide 3 (DDX3X) emerged as a novel therapeutic target in the fight against both infectious diseases and cancer. Herein, a new family of DDX3X inhibitors was designed, synthesized, and tested for its inhibitory action on the ATPase activity of the enzyme. The potential use of the most promising derivatives it has been investigated by evaluating their anti-HIV-1 effects, revealing inhibitory activities in the low micromolar range. A preliminary ADME analysis demonstrated high metabolic stability and good aqueous solubility. The promising biological profile, together with the suitable in vitro pharmacokinetic properties, make these novel compounds a very good starting point for further development.

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A Novel In Vitro Approach for Simultaneous Evaluation of CYP3A4 Inhibition and Kinetic Aqueous Solubility

CrossRef Listing of Deleted DOIs ◽

10.1177/1087057114552796 ◽

2014 ◽

Vol 20 (2) ◽

pp. 254-264 ◽

Cited By ~ 3

Author(s):

José Pérez ◽

Caridad Díaz ◽

Francisco Asensio ◽

Alexandra Palafox ◽

Olga Genilloud ◽

...

Keyword(s):

Drug Discovery ◽

Physicochemical Properties ◽

Safety Concern ◽

Aqueous Solubility ◽

Cyp3a4 Inhibition ◽

Use Of Resources ◽

Simultaneous Evaluation ◽

New Chemical Entities ◽

Further Development

In the early stages of the drug discovery process, evaluation of the drug metabolism and physicochemical properties of new chemical entities is crucial to prioritize those candidates displaying a better profile for further development. In terms of metabolism, drug–drug interactions mediated through CYP450 inhibition are a significant safety concern, and therefore the effect of new candidate drugs on CYP450 activity should be screened early. In the initial stages of drug discovery, when physicochemical properties such as aqueous solubility have not been optimized yet, there might be a large number of candidate compounds showing artificially low CYP450 inhibition, and consequently potential drug–drug interaction toxicity might be overlooked. In this work, we present a novel in vitro approach for simultaneous evaluation of CYP3A4 inhibition potential and kinetic aqueous solubility (NIVA-CYPI-KS). This new methodology is based on fluorogenic CYP450 activities and turbidimetric measurements for compound solubility, and it provides a significant improvement in the use of resources and a better understanding of CYP450 inhibition data.

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Preparation of Innovative Skin Compatible Films to Release Polysaccharides for Biobased Beauty Masks

Cosmetics ◽

10.3390/cosmetics5040070 ◽

2018 ◽

Vol 5 (4) ◽

pp. 70 ◽

Cited By ~ 9

Author(s):

Maria-Beatrice Coltelli ◽

Serena Danti ◽

Luisa Trombi ◽

Pierfrancesco Morganti ◽

Giovanna Donnarumma ◽

...

Keyword(s):

Immune Modulation ◽

Human Keratinocytes ◽

In Vitro Tests ◽

Biobased Materials ◽

Starting Point ◽

Good Starting Point ◽

Skin Compatibility ◽

The Impact ◽

Fast Release

The preparation and selection of biobased materials compatible with skin is essential for producing innovative and highly eco-friendly beauty masks. The use of a commercial elastomeric poly(hydroxyalkanoate) and starch was fundamental to select materials for bioplastic films with the necessary resistance in wet conditions, skin compatibility and capacity for a fast release of polysaccharides and similar active and functional molecules. Micrometric calcium carbonate was also used to control the stickiness of film during moulding. Starch release in water was investigated by gravimetric and infrared analyses. The compatibility with skin was investigated via two different in vitro tests based on human keratinocytes and human mesenchymal stromal cells. The materials were highly cytocompatible with skin, enabled immune modulation by keratinocytes and starch release in water up to 49% by weight in 30 min. These outcomes are a good starting point for boosting the production of biobased and biodegradable beauty masks, thus decreasing the impact onto environment of cosmetic products that are currently still mainly produced using petrol-based substrates.

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An Object-Oriented Framework for Interface Stress Element Method

Applied Mechanics and Materials ◽

10.4028/www.scientific.net/amm.444-445.27 ◽

2013 ◽

Vol 444-445 ◽

pp. 27-31

Author(s):

Biao Feng ◽

Bo Jin ◽

Ri Qing Lan ◽

Hao Chen

Keyword(s):

Object Oriented ◽

Interface Stress ◽

Software Framework ◽

Model Data ◽

Data Converter ◽

Object Oriented Technology ◽

Starting Point ◽

Good Starting Point ◽

Further Development ◽

Element Method

This work describes our efforts towards building an object-oriented software framework for Interface Stress Element Method (ISEM), a newly developed numerical method for discontinuous and fracture problems. Based on the improved Interface Stress Element Method and object-oriented technology, we recognized major objects in ISEM and their interrelations. Then the class hierarchy, modules organization and data interfaces scheme were presented. We also addressed implementation issues and main features of this framework, which integrated a solver, a post-processor, a preprocessor and a model data converter. Numerical examples demonstrated that this system works well, which is a good starting point for further development.

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Plant-Derived Purification, Chemical Synthesis, and In Vitro/In Vivo Evaluation of a Resveratrol Dimer, Viniferin, as an HCV Replication Inhibitor

Viruses ◽

10.3390/v11100890 ◽

2019 ◽

Vol 11 (10) ◽

pp. 890 ◽

Cited By ~ 5

Author(s):

Sungjin Lee ◽

Karabasappa Mailar ◽

Mi Il Kim ◽

Minkyung Park ◽

Jiseon Kim ◽

...

Keyword(s):

Water Solubility ◽

Synthesis Method ◽

Drug Candidate ◽

In Vivo Evaluation ◽

New Class ◽

Pharmacokinetic Properties ◽

Viral Helicase ◽

Further Development

Oligostilbenoid compounds, a group of resveratrol multimers, display several anti-microbial activities through the neutralization of cytotoxic oxidants, and by inhibiting essential host and viral enzymes. In our previous study, we identified a series of oligostilbenoid compounds as potent hepatitis C virus (HCV) replication inhibitors. In particular, vitisin B, a resveratrol tetramer, exhibited the most dramatic anti-HCV activity (EC50 = 6 nM and CC50 > 10 μM) via the disruption of the viral helicase NS3 (IC50 = 3 nM). However, its further development as an HCV drug candidate was halted due to its intrinsic drawbacks, such as poor stability, low water solubility, and restricted in vivo absorption. In order to overcome these limitations, we focused on (+)-ε-viniferin, a resveratrol dimer, as an alternative. We prepared three different versions of (+)-ε-viniferin, including one which was extracted from the grapevine root (EVF) and two which were chemically synthesized with either penta-acetylation (SVF-5Ac) or no acetylation (SVF) using a newly established synthesis method. We confirmed their anti-HCV replication activities and minimal cytotoxicity by using genotype 1b and 2a HCV replicon cells. Their anti-HCV replication action also translated into a significant reduction of viral protein expression. Anti-HCV NS3 helicase activity by EVF was also verified in vitro. Finally, we demonstrated that SVF has improved pharmacokinetic properties over vitisin B. Overall, the favorable antiviral and pharmacokinetic properties of these three versions of viniferin warrant their further study as members of a promising new class of anti-HCV therapeutics.

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l-Arginine Improves Solubility and ANTI SARS-CoV-2 Mpro Activity of Rutin but Not the Antiviral Activity in Cells

Molecules ◽

10.3390/molecules26196062 ◽

2021 ◽

Vol 26 (19) ◽

pp. 6062

Author(s):

Luca Sancineto ◽

Carmine Ostacolo ◽

David Ortega-Alarcon ◽

Ana Jimenez-Alesanco ◽

Laura Ceballos-Laita ◽

...

Keyword(s):

Water Solubility ◽

Pharmaceutical Preparations ◽

Experimental Investigations ◽

Active Principle ◽

Pharmacological Activities ◽

Solubility In Water ◽

Solubility Improvement ◽

Starting Point ◽

Pharmacokinetic Properties ◽

Good Starting Point

The COVID-19 pandemic outbreak prompts an urgent need for efficient therapeutics, and repurposing of known drugs has been extensively used in an attempt to get to anti-SARS-CoV-2 agents in the shortest possible time. The glycoside rutin shows manifold pharmacological activities and, despite its use being limited by its poor solubility in water, it is the active principle of many pharmaceutical preparations. We herein report our in silico and experimental investigations of rutin as a SARS-CoV-2 Mpro inhibitor and of its water solubility improvement obtained by mixing it with L-arginine. Tests of the rutin/L-arginine mixture in a cellular model of SARS-CoV-2 infection highlighted that the mixture still suffers from unfavorable pharmacokinetic properties, but nonetheless, the results of this study suggest that rutin might be a good starting point for hit optimization.

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Novel azoles with potent antileishmanial activity

Future Microbiology ◽

10.2217/fmb-2020-0320 ◽

2021 ◽

Author(s):

Tarun Mathur ◽

Manoj Kumar ◽

Tarani K Barman ◽

V Samuel Raj ◽

Dilip J Upadhyay ◽

...

Keyword(s):

Tissue Culture ◽

Visceral Leishmaniasis ◽

Leishmania Donovani ◽

Antileishmanial Activity ◽

In Vitro Activity ◽

Macrophage Cell Line ◽

Macrophage Cell ◽

Starting Point ◽

Good Starting Point

Aim: To investigate the antileishmanial activity of novel azole compounds against Leishmania donovani, which causes deadly visceral leishmaniasis disease. Materials & methods: A focused azole-based library was screened against both promastigotes and amastigotes forms of L. donovani strains in flat-bottomed 96-well tissue-culture plates and J774A.1 macrophage cell-line infected with L. donovani. The comprehensive screening of azole-based library against L. donovani strains provided novel hits, which can serve as a good starting point to initiate hit to lead optimization campaign. Results: Hits identified from azole-based library exhibited potent in vitro activity against promastigotes and amastigotes of L. donovani. Conclusion: These potent novel azole hits could be a good starting point to carry out for further medicinal chemistry exploration for antileishmania program.

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High Throughput Virtual Screening to Discover Inhibitors of the Main Protease of the Coronavirus SARS-CoV-2

10.20944/preprints202004.0161.v1 ◽

2020 ◽

Cited By ~ 3

Author(s):

Birgit Strodel ◽

Olujide Olubiyi ◽

Maryam Olagunju ◽

Monika Keutmann ◽

Jennifer Loschwitz

Keyword(s):

Enzyme Dynamics ◽

Drug Candidates ◽

X Ray Crystallography ◽

Protease Enzyme ◽

Main Protease ◽

Starting Point ◽

Good Starting Point ◽

Approved Drugs ◽

Fda Approved Drugs

We use state-of-the-art computer-aided drug design (CADD) techniques to identify prospective inhibitors of the main protease enzyme, Mpro of the COVID-19 virus. With the high-resolution X-ray crystallography structure of this viral enzyme recently being solved, CADD provides a veritable tool for rapidly screening diverse sets of compounds with the aim of identifying ligands capable of forming energetically favorable complexes with Mpro . From our screening of 1,082,653 compounds derived from the ZINC, the DrugBank, and our in-house African natural product libraries, and a rescreening protocol incorporating enzyme dynamics via ensemble docking, we have been able to identify a range of prospective Mpro inhibitors, which include FDA-approved drugs, drug candidates in clinical trials, as well as natural products. The top-ranking compounds are characterized by the presence of an extended ring system combined with functional groups that allow the ligands to adapt flexibly to the Mpro active site as, for example, present in the biflavonoid amentoflavone, one of the most promising compounds identified here. This particular chemical architecture leads to considerable stronger binding than found for reference compounds with in vitro demonstrated M pro inhibition and anticoronavirus activity. The compounds determined in this work thus represent a good starting point for the design of inhibitors of SARS-CoV-2 replication.

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A Novel Class of Azoles with potent Anti-Leishmanial activity

10.1101/2020.10.16.342329 ◽

2020 ◽

Author(s):

Tarun Mathur ◽

Manoj Kumar ◽

Tarani Kanta Barman ◽

V. Samuel Raj ◽

Dilip J. Upadhyay ◽

...

Keyword(s):

Tissue Culture ◽

Visceral Leishmaniasis ◽

Leishmania Donovani ◽

Medicinal Chemistry ◽

Lead Optimization ◽

Starting Point ◽

Good Starting Point

AbstractObjectivesTo investigate the anti-leishmanial activity of novel azole compounds against Leishmania donovani, which causes deadly visceral leishmaniasis disease.MethodsA focused azole-based library was screened both against promastigotes and amastigotes forms of L. donovani strains in flat-bottomed 96-well tissue-culture plates and J774A.1 macrophages infected with L. donovani. The comprehensive screening azole-based library against L. donovani strains provided novel hits, which can serve as a good starting point to initiate hit to lead optimization campaign.ResultsHits identified from azole-based library exhibited potent in vitro activity against promastigotes and amastigotes of L. donovani.ConclusionsThese potent novel azole hits could be a good starting point to carry out for further medicinal chemistry exploration for anti-leishmania program.

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In silico approaches using pharmacophore model combined with molecular docking for discovery of novel ULK1 inhibitors

Future Medicinal Chemistry ◽

10.4155/fmc-2020-0253 ◽

2021 ◽

Author(s):

Siyu He ◽

Yang Liu ◽

Qihang Li ◽

Weiping Lyu ◽

Feng Feng ◽

...

Keyword(s):

Pharmacophore Model ◽

Docking Studies ◽

Dynamics Simulation ◽

Autophagic Flux ◽

The Novel ◽

Starting Point ◽

Docking Approach ◽

Good Starting Point

Background: Discovery of effective autophagy-initiating kinase ULK1 inhibitors has attracted more and more attention in cancer treatment. Methodology & results: The present study describes the application of a pharmacophore-based virtual screening and structure-based docking approach guided drug design. Compound U-2 exhibited a nanomolar range of IC50 against the ULK1 target. Molecular dynamics simulation was used to assess the quality of docking studies. The determinants of binding affinity were investigated, and a different binding pattern was observed. Subsequently, prediction properties of ADMET (absorption, distribution, metabolism, excretion and toxicity) and hepatotoxicity in vitro studies indicated that U-2 possessed good drug-like properties. Moreover, western blot analysis indicated that the compound inhibited autophagic flux in cells. Conclusion: The present study provides an appropriate guideline for discovering novel ULK1 inhibitors. The novel compound may serve as a good starting point for further development and optimizations.

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Identification of Novel Functionalized Carbohydrazonamides Designed as Chagas Disease Drug Candidates

Medicinal Chemistry ◽

10.2174/1573406415666190627103013 ◽

2020 ◽

Vol 16 (6) ◽

pp. 774-783

Author(s):

Mayara S.S. do Nascimento ◽

Vitória R.F. Câmara ◽

Juliana S. da Costa ◽

Juliana M.C. Barbosa ◽

Alessandra S.M. Lins ◽

...

Keyword(s):

Chagas Disease ◽

Mammalian Cells ◽

Selectivity Index ◽

Amine Group ◽

Standard Drug ◽

Drug Candidates ◽

Starting Point ◽

Good Starting Point ◽

Novel Drug

Background:: Although several research efforts have been made worldwide to discover novel drug candidates for the treatment of Chagas disease, the nitroimidazole drug benznidazol remains the only therapeutic alternative in the control of this disease. However, this drug presents reduced efficacy in the chronic form of the disease and limited safety after long periods of administration, making it necessary to search for new, more potent and safe prototypes. Objective:: We described herein the synthesis and the trypanocidalaction of new functionalized carbohydrazonamides (2-10) against trypomastigote forms of Trypanosoma cruzi. Methods: These compounds were designed through the application of molecular hybridization concept between two potent anti-T. cruzi prototypes, the nitroimidazole derivative megazol (1) and the cinnamyl N-acylhydrazone derivative (14) which have been shown to be twice as potent in vitro as benznidazole. Results:: The most active compounds were the (Z)-N'-((E)-3-(4-nitrophenyl)-acryloyl)-1-methyl-5- nitro-1H-imidazol-2-carbohydrazonamide (6) (IC50=9.50 μM) and the (Z)-N'-((E)-3-(4- hydroxyphe-nyl)-acryloyl)-1-methyl-5-nitro-1H-imidazol-2-carbohydrazonamide (8) (IC50=12.85 μM), which were almost equipotent to benznidazole (IC50=10.26 μM) used as standard drug. The removal of the amine group attached to the imine subunit in the corresponding N-acylhydrazone derivatives (11-13) resulted in less potent or inactive compounds. The para-hydroxyphenyl derivative (8) presented also a good selectivity index (SI = 32.94) when tested against mammalian cells from Swiss mice. Conclusion:: The promising trypanocidal profile of new carbohydrazonamide derivatives (6) and (8) was characterized. These compounds have proved to be a good starting point for the design of more effective trypanocidal drug candidates.

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