In Vitro and In Vivo Studies of the Trypanocidal Effect of Novel Quinolines

ABSTRACT Therapies for human African trypanosomiasis and Chagas disease, caused by Trypanosoma brucei and Trypanosoma cruzi, respectively, are limited, providing minimal therapeutic options for the millions of individuals living in very poor communities. Here the effects of 10 novel quinolines are evaluated in silico and by phenotypic studies using in vitro and in vivo models. Absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties revealed that most molecules did not infringe on Lipinski's rules, which is a prediction of good oral absorption. These quinolines showed high probabilities of Caco2 permeability and human intestinal absorption and low probabilities of mutagenicity and of hERG1 inhibition. In vitro screens against bloodstream forms of T. cruzi demonstrated that all quinolines were more active than the reference drug (benznidazole [Bz]), except for DB2171 and DB2192, with five (DB2187, DB2131, DB2186, DB2191, and DB2217) displaying 50% effective concentrations (EC50s) of <3 μM (4-fold lower than that of Bz). Nine quinolines were more effective than Bz (2.7 μM) against amastigotes, showing EC50s ranging from 0.6 to 0.1 μM. All quinolines were also highly active in vitro against African trypanosomes, showing EC50s of ≤0.25 μM. The most potent and highly selective candidates for each parasite species were tested in in vivo models. Results for DB2186 were promising in mice with T. cruzi and T. brucei infections, reaching a 70% reduction of the parasitemia load for T. cruzi, and it cured 2 out of 4 mice infected with T. brucei. DB2217 was also active in vivo and cured all 4 mice (100% cure rate) with T. brucei infection.

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Coumarins and Quinolones as Effective Multiple Targeted Agents Versus Covid-19: An in Silico Study

Medicinal Chemistry ◽

10.2174/1573406417666210208223924 ◽

2021 ◽

Vol 17 ◽

Author(s):

Mojgan Nejabat ◽

Razieh Ghodsi ◽

Farzin Hadizadeh

Keyword(s):

Binding Affinity ◽

In Silico ◽

Oral Absorption ◽

Antiviral Agent ◽

In Vivo Studies ◽

Reference Drug ◽

Viral Proteases ◽

In Silico Study

Background: The Covid-19 virus emerged a few months ago in China and infections rapidly escalated into a pandemic. Objective: To date, there is no selective antiviral agent for the management of pathologies associated with covid-19 and the need for an effective agent against it is essential. Method: In this work two home-made databases from synthetic quinolines and coumarins were virtually docked against viral proteases (3CL and PL), human cell surface proteases (TMPRSS2 and furin) and spike proteins (S1 and S2). Chloroquine, a reference drug without a clear mechanism against coronavirus was also docked on mentioned targets and the binding affinities compared with title compounds. Result: The best compounds of synthetic coumarins and quinolines for each target were determined. All compounds against all targets showed binding affinity between -5.80 to -8.99 kcal/mol in comparison with the FDA-approved drug, Chloroquine, with binding affinity of -5.7 to -7.98 kcal/mol. Two compounds, quinoline-1 and coumarin-24, were found to be effective on three targets – S2, TMPRSS2 and furin – simultaneously, with good predicted affinity between -7.54 to -8.85 kcal/mol. In silico ADME studies also confirmed good oral absorption for them. Furthermore, PASS prediction was calculated and coumarin-24 had higher probable activity (Pa) than probable inactivity (Pi) with acceptable protease inhibitory as well as good antiviral activity against Hepatitis C virus (HCV), Human immunodeficiency virus (HIV) and influenza. Conclusion: Quinoline-1 and Coumarin-24 have the potential to be used against Covid-19. Hence these agents could be useful in combating covid-19 infection after further in vitro and in vivo studies.

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Predicting Absorption-Distribution Properties of Neuroprotective Phosphine-Borane Compounds Using In Silico Modeling and Machine Learning

Molecules ◽

10.3390/molecules26092505 ◽

2021 ◽

Vol 26 (9) ◽

pp. 2505

Author(s):

Raheem Remtulla ◽

Sanjoy Kumar Das ◽

Leonard A. Levin

Keyword(s):

Machine Learning ◽

Neural Networks ◽

In Silico ◽

Disulfide Bonds ◽

Oral Absorption ◽

In Vivo Studies ◽

Drug Candidates ◽

In Silico Methods

Phosphine-borane complexes are novel chemical entities with preclinical efficacy in neuronal and ophthalmic disease models. In vitro and in vivo studies showed that the metabolites of these compounds are capable of cleaving disulfide bonds implicated in the downstream effects of axonal injury. A difficulty in using standard in silico methods for studying these drugs is that most computational tools are not designed for borane-containing compounds. Using in silico and machine learning methodologies, the absorption-distribution properties of these unique compounds were assessed. Features examined with in silico methods included cellular permeability, octanol-water partition coefficient, blood-brain barrier permeability, oral absorption and serum protein binding. The resultant neural networks demonstrated an appropriate level of accuracy and were comparable to existing in silico methodologies. Specifically, they were able to reliably predict pharmacokinetic features of known boron-containing compounds. These methods predicted that phosphine-borane compounds and their metabolites meet the necessary pharmacokinetic features for orally active drug candidates. This study showed that the combination of standard in silico predictive and machine learning models with neural networks is effective in predicting pharmacokinetic features of novel boron-containing compounds as neuroprotective drugs.

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Activity profile of two 5-nitroindazole derivatives over the moderately drug-resistant Trypanosoma cruzi Y strain (DTU TcII): in vitro and in vivo studies

Parasitology ◽

10.1017/s0031182020000955 ◽

2020 ◽

Vol 147 (11) ◽

pp. 1216-1228

Author(s):

Cristina Fonseca-Berzal ◽

Cristiane França da Silva ◽

Denise da Gama Jaen Batista ◽

Gabriel Melo de Oliveira ◽

José Cumella ◽

...

Keyword(s):

Trypanosoma Cruzi ◽

Positive Impact ◽

Cardiac Cells ◽

In Vivo Studies ◽

Drug Resistant ◽

Activity Profile ◽

Reference Drug ◽

Novel Drugs

AbstractIn previous studies, we have identified several families of 5-nitroindazole derivatives as promising antichagasic prototypes. Among them, 1-(2-aminoethyl)-2-benzyl-5-nitro-1,2-dihydro-3H-indazol-3-one, (hydrochloride) and 1-(2-acetoxyethyl)-2-benzyl-5-nitro-1,2-dihydro-3H-indazol-3-one (compounds 16 and 24, respectively) have recently shown outstanding activity in vitro over the drug-sensitive Trypanosoma cruzi CL strain (DTU TcVI). Here, we explored the activity of these derivatives against the moderately drug-resistant Y strain (DTU TcII), in vitro and in vivo. The outcomes confirmed their activity over replicative forms, showing IC50 values of 0.49 (16) and 5.75 μm (24) towards epimastigotes, 0.41 (16) and 1.17 μm (24) against intracellular amastigotes. These results, supported by the lack of toxicity on cardiac cells, led to better selectivities than benznidazole (BZ). Otherwise, they were not as active as BZ in vitro against the non-replicative form of the parasite, i.e. bloodstream trypomastigotes. In vivo, acute toxicity assays revealed the absence of toxic events when administered to mice. Moreover, different therapeutic schemes pointed to their capability for decreasing the parasitaemia of T. cruzi Y acute infected mice, reaching up to 60% of reduction at the peak day as monotherapy (16), 79.24 and 91.11% when 16 and 24 were co-administered with BZ. These combined therapies had also a positive impact over the mortality, yielding survivals of 83.33 and 66.67%, respectively, while untreated animals reached a cumulative mortality of 100%. These findings confirm the 5-nitroindazole scaffold as a putative prototype for developing novel drugs potentially applicable to the treatment of Chagas disease and introduce their suitability to act in combination with the reference drug.

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Library of Seleno-Compounds as Novel Agents against Leishmania Species

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02546-16 ◽

2017 ◽

Vol 61 (6) ◽

Cited By ~ 13

Author(s):

Álvaro Martín-Montes ◽

Daniel Plano ◽

Rubén Martín-Escolano ◽

Verónica Alcolea ◽

Marta Díaz ◽

...

Keyword(s):

Parasite Species ◽

Low Cost ◽

Leishmania Species ◽

Leishmania Braziliensis ◽

Reference Drug ◽

Content Type ◽

Product Profile ◽

Low Toxicity ◽

Intracellular Amastigote

ABSTRACT The in vitro leishmanicidal activities of a series of 48 recently synthesized selenium derivatives against Leishmania infantum and Leishmania braziliensis parasites were tested using promastigotes and intracellular amastigote forms. The cytotoxicity of the tested compounds for J774.2 macrophage cells was also measured in order to establish their selectivity. Six of the tested compounds (compounds 8, 10, 11, 15, 45, and 48) showed selectivity indexes higher than those of the reference drug, meglumine antimonate (Glucantime), for both Leishmania species; in the case of L. braziliensis, compound 20 was also remarkably selective. Moreover, data on infection rates and amastigote numbers per macrophage showed that compounds 8, 10, 11, 15, 45, and 48 were the most active against both Leishmania species studied. The observed changes in the excretion product profile of parasites treated with these six compounds were also consistent with substantial cytoplasmic alterations. On the other hand, the most active compounds were potent inhibitors of Fe superoxide dismutase (Fe-SOD) in the two parasite species considered, whereas their impact on human CuZn-SOD was low. The high activity, low toxicity, stability, low cost of the starting materials, and straightforward synthesis make these compounds appropriate molecules for the development of affordable antileishmanicidal agents.

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JPC-2997, a New Aminomethylphenol with HighIn VitroandIn VivoAntimalarial Activities against Blood Stages of Plasmodium

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.03762-14 ◽

2014 ◽

Vol 59 (1) ◽

pp. 170-177 ◽

Cited By ~ 10

Author(s):

Geoffrey W. Birrell ◽

Marina Chavchich ◽

Arba L. Ager ◽

Hong-Ming Shieh ◽

Gavin D. Heffernan ◽

...

Keyword(s):

Half Life ◽

Multidrug Resistant ◽

Volume Of Distribution ◽

Parasite Line ◽

Content Type ◽

Elimination Half Life ◽

Highly Active ◽

Elimination Half

ABSTRACT4-(tert-Butyl)-2-((tert-butylamino)methyl)-6-(6-(trifluoromethyl)pyridin-3-yl)-phenol (JPC-2997) is a new aminomethylphenol compound that is highly activein vitroagainst the chloroquine-sensitive D6, the chloroquine-resistant W2, and the multidrug-resistant TM90-C2BPlasmodium falciparumlines, with 50% inhibitory concentrations (IC50s) ranging from 7 nM to 34 nM. JPC-2997 is >2,500 times less cytotoxic (IC50s > 35 μM) to human (HepG2 and HEK293) and rodent (BHK) cell lines than the D6 parasite line. In comparison to the chemically related WR-194,965, a drug that had advanced to clinical studies, JPC-2997 was 2-fold more activein vitroagainstP. falciparumlines and 3-fold less cytotoxic. The compound possesses potentin vivosuppression activity againstPlasmodium berghei, with a 50% effective dose (ED50) of 0.5 mg/kg of body weight/day following oral dosing in the Peters 4-day test. The radical curative dose of JPC-2997 was remarkably low, at a total dose of 24 mg/kg, using the modified Thompson test. JPC-2997 was effective in curing threeAotusmonkeys infected with a chloroquine- and pyrimethamine-resistant strain ofPlasmodium vivaxat a dose of 20 mg/kg daily for 3 days. At the doses administered, JPC-2997 appeared to be well tolerated in mice and monkeys. Preliminary studies of JPC-2997 in mice show linear pharmacokinetics over the range 2.5 to 40 mg/kg, a low clearance of 0.22 liters/h/kg, a volume of distribution of 15.6 liters/kg, and an elimination half-life of 49.8 h. The highin vivopotency data and lengthy elimination half-life of JPC-2997 suggest that it is worthy of further preclinical assessment as a partner drug.

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Nitrotriazole-Based Compounds as Antichagasic Agents in a Long-Treatment In Vivo Assay

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02717-16 ◽

2017 ◽

Vol 61 (5) ◽

Cited By ~ 1

Author(s):

Maria V. Papadopoulou ◽

William D. Bloomer ◽

Howard S. Rosenzweig ◽

Ana Lia Mazzeti ◽

Karolina Ribeiro Gonçalves ◽

...

Keyword(s):

Body Weight ◽

Weight Gain ◽

Adverse Effects ◽

Myocardial Inflammation ◽

Reference Drug ◽

Content Type ◽

Number Of Treatment ◽

Better Than

ABSTRACT 3-Nitrotriazole-based compounds belonging to various chemical subclasses were found to be very effective against Chagas disease both in vitro and in vivo after a short administration schedule. In this study, five compounds with specific characteristics were selected to be administered for longer periods of time to mice infected with the virulent Trypanosoma cruzi Y strain to further evaluate their effectiveness as antichagasic agents and whether or not potential adverse effects occur. Benznidazole was included for comparison purposes. Complete parasitemia depletion, weight gain, 100% survival, and a lack of myocardial inflammation were observed with four of the compounds and benznidazole administered intraperitoneally at 15 or 20 mg/kg of body weight/day for 40 days. There was a significant reduction in the number of treatment days (number of doses) necessary to induce parasitemia suppression with all four compounds compared to that required with benznidazole. Partial cures were obtained with only one compound tested at 15 mg/kg/day and on the schedule mentioned above but not with benznidazole. Taken together, our data suggest that these compounds demonstrate potent trypanocidal activity comparable to or better than that of the reference drug, benznidazole, when they are administered at the same dose and on the same schedule.

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In Vitro and In Vivo Studies of Spironolactone as an Antischistosomal Drug Capable of Clinical Repurposing

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01722-18 ◽

2018 ◽

Vol 63 (3) ◽

Cited By ~ 7

Author(s):

Rafael A. Guerra ◽

Marcos P. Silva ◽

Tais C. Silva ◽

Maria C. Salvadori ◽

Fernanda S. Teixeira ◽

...

Keyword(s):

Egg Production ◽

Oral Treatment ◽

Drug Repurposing ◽

In Vivo Studies ◽

Content Type ◽

Low Concentrations ◽

Parasitic Flatworm ◽

And Control

ABSTRACT Schistosomiasis is a parasitic flatworm disease that infects over 200 million people worldwide, especially in poor communities. Treatment and control of the disease rely on just one drug, praziquantel. Since funding for drug development for poverty-associated diseases is very limited, drug repurposing is a promising strategy. In this study, from a screening of 13 marketed diuretics, we identified that spironolactone, a potassium-sparing diuretic, had potent antischistosomal effects on Schistosoma mansoni in vitro and in vivo in a murine model of schistosomiasis. In vitro, spironolactone at low concentrations (<10 µM) is able to alter worm motor activity and the morphology of adult schistosomes, leading to parasitic death. In vivo, oral treatment with spironolactone at a single dose (400 mg/kg) or daily for five consecutive days (100 mg/kg/day) in mice harboring either patent or prepatent infections significantly reduced worm burden, egg production, and hepato- and splenomegaly (P < 0.05 to P < 0.001). Taken together, with the safety profile of spironolactone, supported by its potential to affect schistosomes, these results indicate that spironolactone could be a potential treatment for schistosomiasis and make it promising for repurposing.

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Ultrashort Peptide Bioconjugates Are Exclusively Antifungal Agents and Synergize with Cyclodextrin and Amphotericin B

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00468-11 ◽

2011 ◽

Vol 56 (1) ◽

pp. 1-9 ◽

Cited By ~ 29

Author(s):

Christopher J. Arnusch ◽

Hannah Ulm ◽

Michaele Josten ◽

Yana Shadkchan ◽

Nir Osherov ◽

...

Keyword(s):

Vitamin E ◽

Amphotericin B ◽

Selective Toxicity ◽

Content Type ◽

Biologically Relevant ◽

Highly Active ◽

Transmission Electron ◽

Permeability Studies

ABSTRACTMany natural broad-spectrum cationic antimicrobial peptides (AMPs) possess a general mode of action that is dependent on lipophilicity and charge. Modulating the lipophilicity of AMPs by the addition of a fatty acid has been an effective strategy to increase the lytic activity and can further broaden the spectrum of AMPs. However, lipophilic modifications that narrow the spectrum of activity and exclusively direct peptides to fungi are less common. Here, we show that short peptide sequences can be targeted to fungi with structured lipophilic biomolecules, such as vitamin E and cholesterol. The conjugates were active againstAspergillus fumigatus,Cryptococcus neoformans, andCandida albicansbut not against bacteria and were observed to cause membrane perturbation by transmission electron microscopy and in membrane permeability studies. However, forC. albicans, selected compounds were effective without the perturbation of the cell membrane, and synergism was seen with a vitamin E conjugate and amphotericin B. Moreover, in combination with β-cyclodextrin, antibacterial activity emerged in selected compounds. Biocompatibility for selected active compounds was testedin vitroandin vivousing toxicity assays on erythrocytes, macrophages, and mice.In vitrocytotoxicity experiments led to selective toxicity ratios (50% lethal concentration/MIC) of up to 64 for highly active antifungal compounds, and noin vivomurine toxicity was seen. Taken together, these results highlight the importance of the conjugated lipophilic structure and suggest that the modulation of other biologically relevant peptides with hydrophobic moieties, such as cholesterol and vitamin E, generate compounds with unique bioactivity.

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The Orotomide Olorofim Is Efficacious in an Experimental Model of Central Nervous System Coccidioidomycosis

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00999-18 ◽

2018 ◽

Vol 62 (9) ◽

Cited By ~ 11

Author(s):

Nathan P. Wiederhold ◽

Laura K. Najvar ◽

Rosie Jaramillo ◽

Marcos Olivo ◽

Michael Birch ◽

...

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Oral Therapy ◽

Vehicle Control ◽

Coccidioides Immitis ◽

Central Nervous System Infections ◽

Content Type ◽

Highly Active

ABSTRACT Olorofim (formerly F901318) is an advanced analog of the orotomide class that inhibits fungal pyrimidine biosynthesis. We evaluated the in vitro and in vivo activities of olorofim against Coccidioides species. In vitro activity was assessed against 59 clinical Coccidioides isolates. Central nervous system infections were established in mice via intracranial inoculation with Coccidioides immitis arthroconidia. Oral therapy began 48 h postinoculation and consisted of vehicle control, olorofim daily doses of 20 mg/kg (6.67 mg/kg three times daily or 10 mg/kg twice daily) or 40 mg/kg (13.3 mg/kg three times daily or 20 mg/kg twice daily), or fluconazole (25 mg/kg twice daily). Treatment continued for 7 and 14 days in the fungal burden and survival arms, respectively. Fungal burdens were assessed by CFU counts in brains. Olorofim demonstrated potent in vitro activity (MIC range, ≤0.008 to 0.06 μg/ml). Survival was significantly enhanced in mice treated with olorofim. Reductions in brain tissue fungal burdens were also observed on day 9 in the olorofim-treated groups. Improvements in survival and reductions in fungal burdens also occurred with fluconazole. More frequent dosing of olorofim was associated with enhanced survival and greater reductions in fungal burdens. In the group treated with 13.3 mg/kg olorofim three times daily, fungal burdens remained low on day 30 (15 days after treatment was stopped), with undetectable levels in 7 of 10 mice. In contrast, fungal burdens rebounded in all other groups after therapy stopped. Olorofim was highly active in vitro and in vivo against Coccidioides. These results demonstrate that olorofim may have a role in the treatment of coccidioidomycosis.

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Crystal products of lamotrigine-citric acid for improvement of in vitro drug release in simulated gastric fluid

Journal of the Serbian Chemical Society ◽

10.2298/jsc200705049s ◽

2020 ◽

pp. 49-49

Author(s):

Bhabani Satapathy ◽

Asuprita Patel ◽

Rudra Sahoo ◽

Subrata Mallick

Keyword(s):

Citric Acid ◽

Drug Release ◽

Crystal Engineering ◽

Oral Absorption ◽

Gastric Fluid ◽

In Vivo Studies ◽

Simulated Gastric Fluid ◽

Drug Development Research

Crystal engineering is an integral part of the drug development research. Crystal forms can modify the physicochemical properties of the parent drug molecule. The present work was aimed at the synthesis and characterization of crystalline product of lamotrigine (LT), a FDA approved anti-epileptic drug, with citric acid (CA) to improve its release in gastric region and oral absorption. The crystalline products of LT-CA were developed by solvent evaporation method using ethanol-water as the solvent system. Appearance of new charac-teristic peaks in the FTIR spectra for the crystal products indicated formation of new crystal state. In DSC thermogram, melting point of the experimental crystal products was different than that of the pure drug. Further, formation of new crystalline phase was confirmed from XRD data through the identification of new sharp peaks for the selected crystal products. A higher cumulative percen-tage of drug release was observed for the crystal products than the free drug within 60 min of drug release in simulated gastric fluid. However, in vivo studies are warranted for the future technology transfer of the product at industrial scale.

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