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4 pages, 224 KiB

Open AccessEditorial

Special Issue “Drug Candidates for the Treatment of Infectious Diseases”

by Chung Man Chin and Jean Leandro Dos Santos

Pharmaceuticals 2023, 16(9), 1257; https://doi.org/10.3390/ph16091257 - 6 Sep 2023

Viewed by 1039

Abstract

Infectious diseases encompass a range of conditions stemming from parasites [...] Full article

(This article belongs to the Special Issue Drug Candidates for the Treatment of Infectious Diseases)

Research

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24 pages, 2769 KiB

Open AccessArticle

In Silico Prediction of Anti-Infective and Cell-Penetrating Peptides from Thalassophryne nattereri Natterin Toxins

by Gabrielle Lupeti De Cena, Bruna Vitória Scavassa and Katia Conceição

Pharmaceuticals 2022, 15(9), 1141; https://doi.org/10.3390/ph15091141 - 13 Sep 2022

Cited by 9 | Viewed by 3505

Abstract

The therapeutic potential of venom-derived peptides, such as bioactive peptides (BAPs), is determined by specificity, stability, and pharmacokinetics properties. BAPs, including anti-infective or antimicrobial peptides (AMPs) and cell-penetrating peptides (CPPs), share several physicochemical characteristics and are potential alternatives to antibiotic-based therapies and drug [...] Read more.

The therapeutic potential of venom-derived peptides, such as bioactive peptides (BAPs), is determined by specificity, stability, and pharmacokinetics properties. BAPs, including anti-infective or antimicrobial peptides (AMPs) and cell-penetrating peptides (CPPs), share several physicochemical characteristics and are potential alternatives to antibiotic-based therapies and drug delivery systems, respectively. This study used in silico methods to predict AMPs and CPPs derived from natterins from the venomous fish Thalassophryne nattereri. Fifty-seven BAPs (19 AMPs, 8 CPPs, and 30 AMPs/CPPs) were identified using the web servers CAMP, AMPA, AmpGram, C2Pred, and CellPPD. The physicochemical properties were analyzed using ProtParam, PepCalc, and DispHred tools. The membrane-binding potential and cellular location of each peptide were analyzed using the Boman index by APD3, and TMHMM web servers. All CPPs and two AMPs showed high membrane-binding potential. Fifty-four peptides were located in the plasma membrane. Peptide immunogenicity, toxicity, allergenicity, and ADMET parameters were evaluated using several web servers. Sixteen antiviral peptides and 37 anticancer peptides were predicted using the web servers Meta-iAVP and ACPred. Secondary structures and helical wheel projections were predicted using the PEP-FOLD3 and Heliquest web servers. Fifteen peptides are potential lead compounds and were selected to be further synthesized and tested experimentally in vitro to validate the in silico screening. The use of computer-aided design for predicting peptide structure and activity is fast and cost-effective and facilitates the design of potent therapeutic peptides. The results demonstrate that toxins form a natural biotechnological platform in drug discovery, and the presence of CPP and AMP sequences in toxin families opens new possibilities in toxin biochemistry research. Full article

(This article belongs to the Special Issue Drug Candidates for the Treatment of Infectious Diseases)

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16 pages, 2065 KiB

Open AccessArticle

Siccanin Is a Dual-Target Inhibitor of Plasmodium falciparum Mitochondrial Complex II and Complex III

by Keisuke Komatsuya, Takaya Sakura, Kazuro Shiomi, Satoshi Ōmura, Kenji Hikosaka, Tomoyoshi Nozaki, Kiyoshi Kita and Daniel Ken Inaoka

Pharmaceuticals 2022, 15(7), 903; https://doi.org/10.3390/ph15070903 - 21 Jul 2022

Cited by 10 | Viewed by 4387

Abstract

Plasmodium falciparum contains several mitochondrial electron transport chain (ETC) dehydrogenases shuttling electrons from the respective substrates to the ubiquinone pool, from which electrons are consecutively transferred to complex III, complex IV, and finally to the molecular oxygen. The antimalarial drug atovaquone inhibits complex [...] Read more.

Plasmodium falciparum contains several mitochondrial electron transport chain (ETC) dehydrogenases shuttling electrons from the respective substrates to the ubiquinone pool, from which electrons are consecutively transferred to complex III, complex IV, and finally to the molecular oxygen. The antimalarial drug atovaquone inhibits complex III and validates this parasite’s ETC as an attractive target for chemotherapy. Among the ETC dehydrogenases from P. falciparum, dihydroorotate dehydrogenase, an essential enzyme used in de novo pyrimidine biosynthesis, and complex III are the two enzymes that have been characterized and validated as drug targets in the blood-stage parasite, while complex II has been shown to be essential for parasite survival in the mosquito stage; therefore, these enzymes and complex II are considered candidate drug targets for blocking parasite transmission. In this study, we identified siccanin as the first (to our knowledge) nanomolar inhibitor of the P. falciparum complex II. Moreover, we demonstrated that siccanin also inhibits complex III in the low-micromolar range. Siccanin did not inhibit the corresponding complexes from mammalian mitochondria even at high concentrations. Siccanin inhibited the growth of P. falciparum with IC₅₀ of 8.4 μM. However, the growth inhibition of the P. falciparum blood stage did not correlate with ETC inhibition, as demonstrated by lack of resistance to siccanin in the yDHODH-3D7 (EC₅₀ = 10.26 μM) and Dd2-ELQ300 strains (EC₅₀ = 18.70 μM), suggesting a third mechanism of action that is unrelated to mitochondrial ETC inhibition. Hence, siccanin has at least a dual mechanism of action, being the first potent and selective inhibitor of P. falciparum complexes II and III over mammalian enzymes and so is a potential candidate for the development of a new class of antimalarial drugs. Full article

(This article belongs to the Special Issue Drug Candidates for the Treatment of Infectious Diseases)

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18 pages, 2869 KiB

Open AccessArticle

4-Substituted Thieno[3,2-d]pyrimidines as Dual-Stage Antiplasmodial Derivatives

by Prisca Lagardère, Romain Mustière, Nadia Amanzougaghene, Sébastien Hutter, Jean-François Franetich, Nadine Azas, Patrice Vanelle, Pierre Verhaeghe, Nicolas Primas, Dominique Mazier, Nicolas Masurier and Vincent Lisowski

Pharmaceuticals 2022, 15(7), 820; https://doi.org/10.3390/ph15070820 - 1 Jul 2022

Cited by 5 | Viewed by 2051

Abstract

Malaria remains one of the major health problems worldwide. The increasing resistance of Plasmodium to approved antimalarial drugs requires the development of novel antiplasmodial agents that can effectively prevent and/or treat this disease. Based on the structure of Gamhepathiopine, a 2-tert-butylaminothieno[3,2- [...] Read more.

Malaria remains one of the major health problems worldwide. The increasing resistance of Plasmodium to approved antimalarial drugs requires the development of novel antiplasmodial agents that can effectively prevent and/or treat this disease. Based on the structure of Gamhepathiopine, a 2-tert-butylaminothieno[3,2-d]pyrimidin-4(3H)-one hit, active on the sexual and asexual stages of the parasite and thanked for the introduction of various substituents at position 4 of the thienopyrimidine core by nucleophilic aromatic substitution and pallado-catalyzed coupling reactions, a series of 4-substituted thieno[3,2-d]pyrimidines were identified as displaying in vitro activities against both the erythrocytic stage of P. falciparum and the hepatic stage of P. berghei. Among the 28 compounds evaluated, the chloro analogue of Gamhepathiopine showed good activity against the erythrocytic stage of P. falciparum, moderate toxicity on HepG2, and better activity against hepatic P. berghei parasites, compared to Gamhepathiopine. Full article

(This article belongs to the Special Issue Drug Candidates for the Treatment of Infectious Diseases)

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21 pages, 3735 KiB

Open AccessArticle

Synthesis, Structure–Activity Relationships, and Parasitological Profiling of Brussonol Derivatives as New Plasmodium falciparum Inhibitors

by Camila S. Barbosa, Anees Ahmad, Sarah El Chamy Maluf, Igor M. R. Moura, Guilherme E. Souza, Giovanna A. H. Guerra, Roberto R. Moraes Barros, Marcos L. Gazarini, Anna C. C. Aguiar, Antonio C. B. Burtoloso and Rafael V. C. Guido

Pharmaceuticals 2022, 15(7), 814; https://doi.org/10.3390/ph15070814 - 30 Jun 2022

Cited by 1 | Viewed by 2339

Abstract

Malaria is a parasitic disease caused by protozoan parasites from the genus Plasmodium. Plasmodium falciparum is the most prevalent species worldwide and the causative agent of severe malaria. The spread of resistance to the currently available antimalarial therapy is a major concern. [...] Read more.

Malaria is a parasitic disease caused by protozoan parasites from the genus Plasmodium. Plasmodium falciparum is the most prevalent species worldwide and the causative agent of severe malaria. The spread of resistance to the currently available antimalarial therapy is a major concern. Therefore, it is imperative to discover and develop new antimalarial drugs, which not only treat the disease but also control the emerging resistance. Brussonol is an icetexane derivative and a member of a family of diterpenoids that have been isolated from several terrestrial plants. Here, the synthesis and antiplasmodial profiling of a series of brussonol derivatives are reported. The compounds showed inhibitory activities in the low micromolar range against a panel of sensitive and resistant P. falciparum strains (IC₅₀s = 5–16 μM). Moreover, brussonol showed fast-acting in vitro inhibition and an additive inhibitory behavior when combined with the antimalarial artesunate (FIC_index~1). The mode of action investigation indicated that brussonol increased the cytosolic calcium levels within the parasite. Hence, the discovery of brussonol as a new scaffold endowed with antiplasmodial activity will enable us to design derivatives with improved properties to deliver new lead candidates for malaria. Full article

(This article belongs to the Special Issue Drug Candidates for the Treatment of Infectious Diseases)

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12 pages, 2214 KiB

Open AccessArticle

Linearolactone Induces Necrotic-like Death in Giardia intestinalis Trophozoites: Prediction of a Likely Target

by Raúl Argüello-García, Fernando Calzada, Bibiana Chávez-Munguía, Audifás-Salvador Matus-Meza, Elihú Bautista, Elizabeth Barbosa, Claudia Velazquez, Marta Elena Hernández-Caballero, Rosa Maria Ordoñez-Razo and José Antonio Velázquez-Domínguez

Pharmaceuticals 2022, 15(7), 809; https://doi.org/10.3390/ph15070809 - 29 Jun 2022

Cited by 4 | Viewed by 2067

Abstract

Linearolactone (LL) is a neo-clerodane type diterpene that has been shown to exert giardicidal effects; however, its mechanism of action is unknown. This work analyzes the cytotoxic effect of LL on Giardia intestinalis trophozoites and identifies proteins that could be targeted by [...] Read more.

Linearolactone (LL) is a neo-clerodane type diterpene that has been shown to exert giardicidal effects; however, its mechanism of action is unknown. This work analyzes the cytotoxic effect of LL on Giardia intestinalis trophozoites and identifies proteins that could be targeted by this active natural product. Increasing concentrations of LL and albendazole (ABZ) were used as test and reference drugs, respectively. Cell cycle progression, determination of reactive oxygen species (ROS) and apoptosis/necrosis events were evaluated by flow cytometry (FCM). Ultrastructural alterations were analyzed by transmission electron microscopy (TEM). Ligand–protein docking analyses were carried out using the LL structure raised from a drug library and the crystal structure of an aldose reductase homologue (GdAldRed) from G. intestinalis. LL induced partial arrest at the S phase of trophozoite cell cycle without evidence of ROS production. LL induced pronecrotic death in addition to inducing ultrastructural alterations as changes in vacuole abundances, appearance of perinuclear and periplasmic spaces, and deposition of glycogen granules. On the other hand, the in silico study predicted that GdAldRed is a likely target of LL because it showed a favored change in Gibbs free energy for this complex. Full article

(This article belongs to the Special Issue Drug Candidates for the Treatment of Infectious Diseases)

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26 pages, 6808 KiB

Open AccessArticle

Design and Synthesis of Hepatitis B Virus (HBV) Capsid Assembly Modulators and Evaluation of Their Activity in Mammalian Cell Model

by Karina Spunde, Brigita Vigante, Unda Nelda Dubova, Anda Sipola, Irena Timofejeva, Anna Zajakina, Juris Jansons, Aiva Plotniece, Karlis Pajuste, Arkadij Sobolev, Ruslan Muhamadejev, Kristaps Jaudzems, Gunars Duburs and Tatjana Kozlovska

Pharmaceuticals 2022, 15(7), 773; https://doi.org/10.3390/ph15070773 - 22 Jun 2022

Cited by 7 | Viewed by 3909

Abstract

Capsid assembly modulators (CAMs) have emerged as a promising class of antiviral agents. We studied the effects of twenty-one newly designed and synthesized CAMs including heteroaryldihydropyrimidine compounds (HAPs), their analogs and standard compounds on hepatitis B virus (HBV) capsid assembly. Cytoplasmic expression of [...] Read more.

Capsid assembly modulators (CAMs) have emerged as a promising class of antiviral agents. We studied the effects of twenty-one newly designed and synthesized CAMs including heteroaryldihydropyrimidine compounds (HAPs), their analogs and standard compounds on hepatitis B virus (HBV) capsid assembly. Cytoplasmic expression of the HBV core (HBc) gene driven by the exogenously delivered recombinant alphavirus RNA replicon was used for high level production of the full-length HBc protein in mammalian cells. HBV capsid assembly was assessed by native agarose gel immunoblot analysis, electron microscopy and inhibition of virion secretion in HepG2.2.15 HBV producing cell line. Induced fit docking simulation was applied for modelling the structural relationships of the synthesized compounds and HBc. The most efficient were the HAP class compounds—dihydropyrimidine 5-carboxylic acid n-alkoxyalkyl esters, which induced the formation of incorrectly assembled capsid products and their accumulation within the cells. HBc product accumulation in the cells was not detected with the reference HAP compound Bay 41-4109, suggesting different modes of action. A significant antiviral effect and substantially reduced toxicity were revealed for two of the synthesized compounds. Two new HAP compounds revealed a significant antiviral effect and a favorable toxicity profile that allows these compounds to be considered promising leads and drug candidates for the treatment of HBV infection. The established alphavirus based HBc expression approach allows for the specific selection of capsid assembly modulators directly in the natural cell environment. Full article

(This article belongs to the Special Issue Drug Candidates for the Treatment of Infectious Diseases)

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29 pages, 2416 KiB

Open AccessArticle

Synthesis of Coumarin and Homoisoflavonoid Derivatives and Analogs: The Search for New Antifungal Agents

by Alana R. Ferreira, Danielle da N. Alves, Ricardo D. de Castro, Yunierkis Perez-Castillo and Damião P. de Sousa

Pharmaceuticals 2022, 15(6), 712; https://doi.org/10.3390/ph15060712 - 3 Jun 2022

Cited by 15 | Viewed by 3170

Abstract

A set of twenty-four synthetic derivatives, with coumarin and homoisoflavonoid cores and structural analogs, were submitted for evaluation of antifungal activity against various species of Candida. The broth microdilution test was used to determine the Minimum Inhibitory Concentration (MIC) of the compounds and [...] Read more.

A set of twenty-four synthetic derivatives, with coumarin and homoisoflavonoid cores and structural analogs, were submitted for evaluation of antifungal activity against various species of Candida. The broth microdilution test was used to determine the Minimum Inhibitory Concentration (MIC) of the compounds and to verify the possible antifungal action mechanisms. The synthetic derivatives were obtained using various reaction methods, and six new compounds were obtained. The structures of the synthesized products were characterized by FTIR spectroscopy: ¹H-NMR, ¹³C-NMR, and HRMS. The coumarin derivative 8 presented the best antifungal profile, suggesting that the pentyloxy substituent at the C-7 position of coumarin ring could potentiate the bioactivity. Compound 8 was then evaluated against the biofilm of C. tropicalis ATCC 13803, which showed a statistically significant reduction in biofilm at concentrations of 0.268 µmol/mL and 0.067 µmol/mL, when compared to the growth control group. For a better understanding of their antifungal activity, compounds 8 and 21 were submitted to a study of the mode of action on the fungal cell wall and plasma membrane. It was observed that neither compound interacted directly with ergosterol present in the fungal plasma membrane or with the fungal cell wall. This suggests that their bioactivity was due to interaction involving other pharmacological targets. Compound 8 was also subjected to a molecular modeling study, which showed that its antifungal action mechanism occurred mainly through interference in the redox balance of the fungal cell, and by compromising the plasma membrane; not by direct interaction, but by interference in ergosterol synthesis. Another important finding was the antifungal capacity of homoisoflavonoids 23 and 24. Derivative 23 presented slightly higher antifungal activity, possibly due to the presence of the methoxyl substituent in the meta position in ring B. Full article

(This article belongs to the Special Issue Drug Candidates for the Treatment of Infectious Diseases)

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15 pages, 1859 KiB

Open AccessArticle

Novel High-Throughput Fluorescence-Based Assay for the Identification of Nematocidal Compounds That Target the Blood-Feeding Pathway

by Anthony Marchand, Joyce W. M. Van Bree, Aya C. Taki, Mati Moyat, Gerardo Turcatti, Marc Chambon, Adam Alexander Thil Smith, Rory Doolan, Robin B. Gasser, Nicola Laraine Harris and Tiffany Bouchery

Pharmaceuticals 2022, 15(6), 669; https://doi.org/10.3390/ph15060669 - 27 May 2022

Cited by 1 | Viewed by 3198

Abstract

Hookworm infections cause a neglected tropical disease (NTD) affecting ~740 million people worldwide, principally those living in disadvantaged communities. Infections can cause high morbidity due to their impact on nutrient uptake and their need to feed on host blood, resulting in a loss [...] Read more.

Hookworm infections cause a neglected tropical disease (NTD) affecting ~740 million people worldwide, principally those living in disadvantaged communities. Infections can cause high morbidity due to their impact on nutrient uptake and their need to feed on host blood, resulting in a loss of iron and protein, which can lead to severe anaemia and impaired cognitive development in children. Currently, only one drug, albendazole is efficient to treat hookworm infection and the scientific community fears the rise of resistant strains. As part of on-going efforts to control hookworm infections and its associated morbidities, new drugs are urgently needed. We focused on targeting the blood-feeding pathway, which is essential to the parasite survival and reproduction, using the laboratory hookworm model Nippostrongylus brasiliensis (a nematode of rodents with a similar life cycle to hookworms). We established an in vitro-drug screening assay based on a fluorescent-based measurement of parasite viability during blood-feeding to identify novel therapeutic targets. A first screen of a library of 2654 natural compounds identified four that caused decreased worm viability in a blood-feeding-dependent manner. This new screening assay has significant potential to accelerate the discovery of new drugs against hookworms. Full article

(This article belongs to the Special Issue Drug Candidates for the Treatment of Infectious Diseases)

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18 pages, 4736 KiB

Open AccessArticle

A Combination of Pharmacophore-Based Virtual Screening, Structure-Based Lead Optimization, and DFT Study for the Identification of S. epidermidis TcaR Inhibitors

by Srimai Vuppala, Jaeyoung Kim, Bo-Sun Joo, Ji-Myung Choi and Joonkyung Jang

Pharmaceuticals 2022, 15(5), 635; https://doi.org/10.3390/ph15050635 - 21 May 2022

Cited by 6 | Viewed by 2197

Abstract

The transcriptional regulator (TcaR) enzyme plays an important role in biofilm formation. Prevention of TcaR-DNA complex formation leads to inhibit the biofilm formation is likely to reveal therapeutic ways for the treatment of bacterial infections. To identify the novel ligands for TcaR and [...] Read more.

The transcriptional regulator (TcaR) enzyme plays an important role in biofilm formation. Prevention of TcaR-DNA complex formation leads to inhibit the biofilm formation is likely to reveal therapeutic ways for the treatment of bacterial infections. To identify the novel ligands for TcaR and to provide a new idea for drug design, two efficient drug design methods, such as pharmacophore modeling and structure-based drug design, were used for virtual screening of database and lead optimization, respectively. Gemifloxacin (FDA-approved drug) was considered to generate the pharmacophore model for virtual screening of the ZINC database, and five hits, namely ZINC77906236, ZINC09550296, ZINC77906466, ZINC09751390, and ZINC01269201, were identified as novel inhibitors of TcaR with better binding energies. Using structure-based drug design, a set of 7a–7p inhibitors of S. epidermidis were considered, and Mol34 was identified with good binding energy and high fitness score with improved pharmacological properties. The active site residues ARG110, ASN20, HIS42, ASN45, ALA38, VAL63, VAL68, ALA24, VAL43, ILE57, and ARG71 are playing a promising role in inhibition process. In addition, we performed DFT simulations of final hits to understand the electronic properties and their significant role in driving the inhibitor to adopt apposite bioactive conformations in the active site. Conclusively, the newly identified and designed hits from both the methods are promising inhibitors of TcaR, which can hinder biofilm formation. Full article

(This article belongs to the Special Issue Drug Candidates for the Treatment of Infectious Diseases)

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12 pages, 1636 KiB

Open AccessArticle

Microbiological Evaluation of Novel Bis-Quaternary Ammonium Compounds: Clinical Strains, Biofilms, and Resistance Study

by Nikita Frolov, Elena Detusheva, Nadezhda Fursova, Irina Ostashevskaya and Anatoly Vereshchagin

Pharmaceuticals 2022, 15(5), 514; https://doi.org/10.3390/ph15050514 - 22 Apr 2022

Cited by 21 | Viewed by 3029

Abstract

This work is devoted to the investigation of biocidal properties of quaternary ammonium compounds (QACs) based on pyridine structures with aromatic spacers, and their widely known analogs, against clinically significant microorganisms. This study is focused on investigating their antimicrobial activity (minimum inhibitory concentrations [...] Read more.

This work is devoted to the investigation of biocidal properties of quaternary ammonium compounds (QACs) based on pyridine structures with aromatic spacers, and their widely known analogs, against clinically significant microorganisms. This study is focused on investigating their antimicrobial activity (minimum inhibitory concentrations (MICs) and minimum bactericidal concentrations (MBCs)), antibiofilm properties (minimum biofilm inhibitory concentrations (MBICs) and minimum biofilm eradication concentrations (MBECs)), synergetic effect with different alcohols in antiseptic formulations, and bacterial resistance development. It was shown that all combined analogue preparations had a higher level of antibacterial activity against the tested bacterial strains, with a 16- to 32-fold reduction in MICs and MBCs compared to previously used antiseptic preparations. Moreover, hit-QACs demonstrated a stable effect against Gram-negative E. coli, K. pneumoniae, and A. baumannii within a month of incubation. Overall results indicated a high level of antibacterial activity of pyridine-based QACs. Full article

(This article belongs to the Special Issue Drug Candidates for the Treatment of Infectious Diseases)

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12 pages, 5784 KiB

Open AccessArticle

Camostat Does Not Inhibit the Proteolytic Activity of Neutrophil Serine Proteases

by Akmaral Assylbekova, Anuar Zhanapiya, Renata Grzywa, Marcin Sienczyk, Christian Schönbach and Timo Burster

Pharmaceuticals 2022, 15(5), 500; https://doi.org/10.3390/ph15050500 - 20 Apr 2022

Cited by 4 | Viewed by 2663

Abstract

Coronavirus disease 2019 (COVID-19) can lead to multi-organ failure influenced by comorbidities and age. Binding of the severe acute respiratory syndrome coronavirus 2 spike protein (SARS-CoV-2 S protein) to angiotensin-converting enzyme 2 (ACE2), along with proteolytic digestion of the S protein by furin [...] Read more.

Coronavirus disease 2019 (COVID-19) can lead to multi-organ failure influenced by comorbidities and age. Binding of the severe acute respiratory syndrome coronavirus 2 spike protein (SARS-CoV-2 S protein) to angiotensin-converting enzyme 2 (ACE2), along with proteolytic digestion of the S protein by furin and transmembrane protease serine subtype 2 (TMPRSS2), provokes internalization of SARS-CoV-2 into the host cell. Productive infection occurs through viral replication in the cytosol and cell-to-cell transmission. The catalytic activity of TMPRSS2 can be blocked by the trypsin-like serine protease inhibitor camostat, which impairs infection by SARS-CoV-2. At the site of infection, immune cells, such as neutrophils, infiltrate and become activated, releasing neutrophil serine proteases (NSPs), including cathepsin G (CatG), neutrophil elastase (NE), and proteinase 3 (PR3), which promote the mounting of a robust immune response. However, NSPs might be involved in infection and the severe outcome of COVID-19 since the uncontrolled proteolytic activity is responsible for many complications, including autoimmunity, chronic inflammatory disorders, cardiovascular diseases, and thrombosis. Here, we demonstrate that camostat does not inhibit the catalytic activity of CatG, NE, and PR3, indicating the need for additional selective serine protease inhibitors to reduce the risk of developing severe COVID-19. Full article

(This article belongs to the Special Issue Drug Candidates for the Treatment of Infectious Diseases)

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14 pages, 4776 KiB

Open AccessArticle

Targeting Viral Ion Channels: A Promising Strategy to Curb SARS-CoV-2

by Anamika Singh and Isaiah T. Arkin

Pharmaceuticals 2022, 15(4), 396; https://doi.org/10.3390/ph15040396 - 24 Mar 2022

Cited by 6 | Viewed by 2748

Abstract

SARS-CoV-2 is the etiological agent COVID-19, one of the most impactful health crises afflicting humanity in recent decades. While research advances have yielded several treatment and prevention options, the pandemic is slow to abate, necessitating an expansion of our treatment arsenal. As a [...] Read more.

SARS-CoV-2 is the etiological agent COVID-19, one of the most impactful health crises afflicting humanity in recent decades. While research advances have yielded several treatment and prevention options, the pandemic is slow to abate, necessitating an expansion of our treatment arsenal. As a member of the coronaviridae, SARS-CoV-2 contains several ion channels, of which E and 3a are the best characterized. Since ion channels as a family are excellent drug targets, we sought to inhibit both viroporins as a means to curb infectivity. In a previous targeted study, we identified several blockers to each channel from an extensive drug repurposing library. Herein, we examined the ability of said compounds on the whole virus in cellulo. Gratifyingly, many of the blockers exhibited antiviral activity in a stringent assay examining protection from viral-driven death. In particular, darapladib and flumatinib, both 3a blockers, displayed potent antiviral activity. Furthermore, appreciable synergism between flumatinib and several E blockers was identified in a concentration regime in which the compounds are present in human plasma following oral administration. Taken together, targeting ion channels represents a promising approach to both augment and complement our antiviral arsenal against COVID-19. Full article

(This article belongs to the Special Issue Drug Candidates for the Treatment of Infectious Diseases)

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15 pages, 1524 KiB

Open AccessArticle

A High-Throughput Phenotypic Screen of the ‘Pandemic Response Box’ Identifies a Quinoline Derivative with Significant Anthelmintic Activity

by Harrison T. Shanley, Aya C. Taki, Joseph J. Byrne, Abdul Jabbar, Tim N. C. Wells, Kirandeep Samby, Peter R. Boag, Nghi Nguyen, Brad E. Sleebs and Robin B. Gasser

Pharmaceuticals 2022, 15(2), 257; https://doi.org/10.3390/ph15020257 - 21 Feb 2022

Cited by 12 | Viewed by 3350

Abstract

Parasitic nematodes cause diseases in livestock animals and major economic losses to the agricultural industry worldwide. Nematodes of the order Strongylida, including Haemonchus contortus, are particularly important. The excessive use of anthelmintic compounds to treat infections and disease has led to widespread [...] Read more.

Parasitic nematodes cause diseases in livestock animals and major economic losses to the agricultural industry worldwide. Nematodes of the order Strongylida, including Haemonchus contortus, are particularly important. The excessive use of anthelmintic compounds to treat infections and disease has led to widespread resistance to these compounds in nematodes, such that there is a need for new anthelmintics with distinctive mechanisms of action. With a focus on discovering new anthelmintic entities, we screened 400 chemically diverse compounds within the ‘Pandemic Response Box’ (from Medicines for Malaria Venture, MMV) for activity against H. contortus and its free-living relative, Caenorhabditis elegans—a model organism. Using established phenotypic assays, test compounds were evaluated in vitro for their ability to inhibit the motility and/or development of H. contortus and C. elegans. Dose-response evaluations identified a compound, MMV1581032, that significantly the motility of H. contortus larvae (IC₅₀ = 3.4 ± 1.1 μM) and young adults of C. elegans (IC₅₀ = 7.1 ± 4.6 μM), and the development of H. contortus larvae (IC₅₀ = 2.2 ± 0.7 μM). The favourable characteristics of MMV1581032, such as suitable physicochemical properties and an efficient, cost-effective pathway to analogue synthesis, indicates a promising candidate for further evaluation as a nematocide. Future work will focus on a structure-activity relationship investigation of this chemical scaffold, a toxicity assessment of potent analogues and a mechanism/mode of action investigation. Full article

(This article belongs to the Special Issue Drug Candidates for the Treatment of Infectious Diseases)

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17 pages, 3107 KiB

Open AccessArticle

Synthesis and Biological Evaluation of Novel Cinnamic Acid-Based Antimicrobials

by Marina Mingoia, Carmela Conte, Annalisa Di Rienzo, Marilisa Pia Dimmito, Lorella Marinucci, Gloria Magi, Hasan Turkez, Maria Concetta Cufaro, Piero Del Boccio, Antonio Di Stefano and Ivana Cacciatore

Pharmaceuticals 2022, 15(2), 228; https://doi.org/10.3390/ph15020228 - 15 Feb 2022

Cited by 19 | Viewed by 3562

Abstract

The main antimicrobial resistance (AMR) nosocomial strains (ESKAPE pathogens such as Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter spp.) are the most widespread bacteria in cutaneous infections. In this work we report the [...] Read more.

The main antimicrobial resistance (AMR) nosocomial strains (ESKAPE pathogens such as Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter spp.) are the most widespread bacteria in cutaneous infections. In this work we report the synthesis, in silico skin permeability prediction, antimicrobial, antibiofilm, and wound healing properties of novel cinnamic acid-based antimicrobials (DM1–11) as novel antibacterial drugs for the treatment of ESKAPE-related skin infections. Antimicrobial and wound healing scratch assays were performed to evaluate the antibacterial properties of DM1–11. In silico skin permeability capabilities of DM1–11 were evaluated using Swiss-ADME online database. Cytotoxicity assays were performed on keratinocytes and fibroblasts. DM2, bearing a catechol group on the aromatic ring of the cinnamic portion of the molecule, possesses a significant antibacterial activity against S. aureus (MIC range 16–64 mg/L) and contrasts the biofilm-mediated S. epidermidis infection at low concentrations. Wound healing assays showed that wound closure in 48 h was observed in DM2-treated keratinocytes with a better healing pattern at all the used concentrations (0.1, 1.0, and 10 µM). A potential good skin permeation for DM2, that could guarantee its effectiveness at the target site, was also observed. Cytotoxicity studies revealed that DM2 may be a safe compound for topical use. Taking together all these data confirm that DM2 could represent a safe wound-healing topical agent for the treatment of skin wound infections caused by two of main Gram-positive bacteria belonging to ESKAPE microorganisms. Full article

(This article belongs to the Special Issue Drug Candidates for the Treatment of Infectious Diseases)

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12 pages, 2690 KiB

Open AccessArticle

Understanding the Anti-Diarrhoeal Properties of Incomptines A and B: Antibacterial Activity against Vibrio cholerae and Its Enterotoxin Inhibition

by Fernando Calzada, Elihu Bautista, Sergio Hidalgo-Figueroa, Normand García-Hernández, Claudia Velázquez, Elizabeth Barbosa, Miguel Valdes and Jesús Iván Solares-Pascasio

Pharmaceuticals 2022, 15(2), 196; https://doi.org/10.3390/ph15020196 - 3 Feb 2022

Cited by 4 | Viewed by 2142

Abstract

Incomptines A (IA) and B (IB) are two sesquiterpene lactones with antiprotozoal, antibacterial, cytotoxic, antitumor, spermicidal, and phytotoxic properties. The antibacterial activity of IA and IB against bacteria causing diarrhoea have been reported; however, no information is available regarding [...] Read more.

Incomptines A (IA) and B (IB) are two sesquiterpene lactones with antiprotozoal, antibacterial, cytotoxic, antitumor, spermicidal, and phytotoxic properties. The antibacterial activity of IA and IB against bacteria causing diarrhoea have been reported; however, no information is available regarding their antibacterial activity on Vibrio cholerae. In this work, both compounds were evaluated for their anti-diarrhoeal potential using the bacterium V. cholerae, sodium dodecyl sulphate–polyacrylamide gel electrophoresis (SDS-PAGE) analysis on cholera toxin, and a cholera toxin-induced diarrhoea model in male Balb/c mice. In addition, a molecular docking study was carried out to understand the interaction of IA and IB with cholera toxin. In terms of antibacterial activity, IB was three times more active than IA on V. cholerae. In the case of SDS-PAGE analysis and the in silico study, IA was most effective, revealing its potential binding mode at a molecular level. In terms of anti-diarrhoeal activity, IA was 10 times more active than IB and racecadotril, an antisecretory drug used as positive control; the anti-diarrheal activity of IB was also closer than racecadotril. The results obtained from in vitro, in vivo, and computational studies on V. cholerae and cholera toxin support the potential of IA and IB as new anti-diarrhoeal compounds. Full article

(This article belongs to the Special Issue Drug Candidates for the Treatment of Infectious Diseases)

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26 pages, 2328 KiB

Open AccessArticle

Synthesis and Characterization of Novel 2-Acyl-3-trifluoromethylquinoxaline 1,4-Dioxides as Potential Antimicrobial Agents

by Galina I. Buravchenko, Dmitry A. Maslov, Md Shah Alam, Natalia E. Grammatikova, Svetlana G. Frolova, Aleksey A. Vatlin, Xirong Tian, Ivan V. Ivanov, Olga B. Bekker, Maxim A. Kryakvin, Olga A. Dontsova, Valery N. Danilenko, Tianyu Zhang and Andrey E. Shchekotikhin

Pharmaceuticals 2022, 15(2), 155; https://doi.org/10.3390/ph15020155 - 27 Jan 2022

Cited by 7 | Viewed by 3642

Abstract

The emergence of drug resistance in pathogens leads to a loss of effectiveness of antimicrobials and complicates the treatment of bacterial infections. Quinoxaline 1,4-dioxides represent a prospective scaffold for search of new compounds with improved chemotherapeutic characteristics. Novel 2-acyl-3-trifluoromethylquinoxaline 1,4-dioxides with alteration of [...] Read more.

The emergence of drug resistance in pathogens leads to a loss of effectiveness of antimicrobials and complicates the treatment of bacterial infections. Quinoxaline 1,4-dioxides represent a prospective scaffold for search of new compounds with improved chemotherapeutic characteristics. Novel 2-acyl-3-trifluoromethylquinoxaline 1,4-dioxides with alteration of substituents at position 2 and 6 were synthesized via nucleophilic substitution with piperazine moiety and evaluated against a broad panel of bacteria and fungi by measuring their minimal inhibitory concentrations. Their mode of action was assessed by whole-genomic sequencing of spontaneous drug-resistant Mycobacterium smegmatis mutants, followed by comparative genomic analysis, and on an original pDualrep2 system. Most of the 2-acyl-3-trifluoromethylquinoxaline 1,4-dioxides showed high antibacterial properties against Gram-positive strains, including mycobacteria, and the introduction of a halogen atom in the position 6 of the quinoxaline ring further increased their activity, with 13c being the most active compound. The mode of action studies confirmed the DNA-damaging nature of the obtained quinoxaline 1,4-dioxides, while drug-resistance may be provided by mutations in redox homeostasis genes, encoding enzymes potentially involved in the activation of the compounds. This study extends views about the antimicrobial and antifungal activities of the quinoxaline 1,4-dioxides and can potentially lead to the discovery of new antibacterial drugs. Full article

(This article belongs to the Special Issue Drug Candidates for the Treatment of Infectious Diseases)

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47 pages, 8209 KiB

Open AccessArticle

Computational and Biological Evaluation of β-Adrenoreceptor Blockers as Promising Bacterial Anti-Virulence Agents

by Ahmad J. Almalki, Tarek S. Ibrahim, Sameh S. Elhady, Wael A. H. Hegazy and Khaled M. Darwish

Pharmaceuticals 2022, 15(2), 110; https://doi.org/10.3390/ph15020110 - 18 Jan 2022

Cited by 36 | Viewed by 3166

Abstract

Bacterial resistance to antibiotics is an increasing public health threat as it has the potential to affect people at any stage of life, as well as veterinary. Various approaches have been proposed to counteract the bacterial resistance development. Tackling bacterial virulence is one [...] Read more.

Bacterial resistance to antibiotics is an increasing public health threat as it has the potential to affect people at any stage of life, as well as veterinary. Various approaches have been proposed to counteract the bacterial resistance development. Tackling bacterial virulence is one of the most promising approaches that confer several merits. The bacterial virulence is mainly regulated by a communication system known as quorum sensing (QS) system. Meanwhile, bacteria can sense the adrenergic hormones and eavesdrops on the host cells to establish their infection, adrenergic hormones were shown to enhance the bacterial virulence. In this study, β-adrenoreceptor blockers were proposed not only to stop bacterial espionage on our cells but also as inhibitors to the bacterial QS systems. In this context, a detailed in silico study has been conducted to evaluate the affinities of twenty-two β-blockers to compete on different structural QS receptors. Among the best docked and thermodynamically stable β-blockers; atenolol, esmolol, and metoprolol were subjected to further in vitro and in vivo investigation to evaluate their anti-QS activities against Chromobacterium violaceum, Pseudomonas aeruginosa and Salmonella typhimurium. The three tested β-blockers decreased the production of QS-controlled C. violaceum, and the formation of biofilm by P. aeruginosa and S. typhimurium. Additionally, the tested β-blockers down-regulated the P. aeruginosa QS-encoding genes and S. typhimurium sensor kinase encoding genes. Furthermore, metoprolol protected mice against P. aeruginosa and S. typhimurium. Conclusively, these investigated β-blockers are promising anti-virulence agents antagonizing adrenergic hormones induced virulence, preventing bacterial espionage, and blocking bacterial QS systems. Full article

(This article belongs to the Special Issue Drug Candidates for the Treatment of Infectious Diseases)

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20 pages, 3014 KiB

Open AccessCommunication

Design and Synthesis of Hybrid Compounds as Epigenetic Modifiers

by Juliana Romano Lopes, Igor Muccilo Prokopczyk, Max Gerlack, Chung Man Chin and Jean Leandro Dos Santos

Pharmaceuticals 2021, 14(12), 1308; https://doi.org/10.3390/ph14121308 - 15 Dec 2021

Cited by 3 | Viewed by 3006

Abstract

Epigenetic modifiers acting through polypharmacology mechanisms are promising compounds with which to treat several infectious diseases. Histone deacetylase (HDAC) enzymes, mainly class I, and extra-terminal bromodomains (BET) are involved in viral replication and the host response. In the present study, 10 compounds were [...] Read more.

Epigenetic modifiers acting through polypharmacology mechanisms are promising compounds with which to treat several infectious diseases. Histone deacetylase (HDAC) enzymes, mainly class I, and extra-terminal bromodomains (BET) are involved in viral replication and the host response. In the present study, 10 compounds were designed, assisted by molecular docking, to act against HDAC class I and bromodomain-4 (BRD4). All the compounds were synthesized and characterized by analytical methods. Enzymatic assays were performed using HDAC-1, -4, and -11 and BRD4. Compounds (2–10) inhibited both HDAC class I, mainly HDAC-1 and -2, and reduced BRD4 activity. For HDAC-1, the inhibitory effect ranged from 8 to 95%, and for HDAC-2, these values ranged from 10 to 91%. Compounds (2–10) decreased the BRD4 activity by up to 25%. The multi-target effects of these compounds show desirable properties that could help to combat viral infections by acting through epigenetic mechanisms. Full article

(This article belongs to the Special Issue Drug Candidates for the Treatment of Infectious Diseases)

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15 pages, 3211 KiB

Open AccessArticle

Naphthyridine Derivatives Induce Programmed Cell Death in Naegleria fowleri

by Aitor Rizo-Liendo, Iñigo Arberas-Jiménez, Endika Martin-Encinas, Ines Sifaoui, María Reyes-Batlle, Javier Chao-Pellicer, Concepción Alonso, Francisco Palacios, José E. Piñero and Jacob Lorenzo-Morales

Pharmaceuticals 2021, 14(10), 1013; https://doi.org/10.3390/ph14101013 - 1 Oct 2021

Cited by 2 | Viewed by 2355

Abstract

Primary amoebic encephalitis (PAM) caused by the opportunistic pathogen Naegleria fowleri is characterized as a rapid and lethal infection of the brain which ends in the death of the patient in more than 90% of the reported cases. This amoeba thrives in warm [...] Read more.

Primary amoebic encephalitis (PAM) caused by the opportunistic pathogen Naegleria fowleri is characterized as a rapid and lethal infection of the brain which ends in the death of the patient in more than 90% of the reported cases. This amoeba thrives in warm water bodies and causes infection after individuals perform risky activities such as splashing or diving, mostly in non-treated water bodies such as lakes and ponds. Moreover, the infection progresses very fast and no fully effective molecules have currently been found to treat PAM. In this study, naphthyridines fused with chromenes or chromenones previously synthetized by the group were tested in vitro against the trophozoite stage of two strains of N. fowleri. In addition, the most active molecule was evaluated in order to check the induction of programmed cell death (PCD) in the treated amoebae. Compound 3 showed good anti-Naegleria activity (61.45 ± 5.27 and 76.61 ± 10.84 µM, respectively) against the two different strains (ATCC^® 30808 and ATCC^® 30215) and a good selectivity compared to the cytotoxicity values (>300 µM). In addition, it was able to induce PCD, causing DNA condensation, damage at the cellular membrane, reduction in mitochondrial membrane potential and ATP levels, and ROS generation. Hence, naphthyridines fused with chromenes or chromenones could be potential therapeutic agents against PAM in the near future. Full article

(This article belongs to the Special Issue Drug Candidates for the Treatment of Infectious Diseases)

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19 pages, 4308 KiB

Open AccessSystematic Review

Resveratrol and Curcumin for Chagas Disease Treatment—A Systematic Review

by Carlos Henrique Lima Imperador, Cauê Benito Scarim, Priscila Longhin Bosquesi, Juliana Romano Lopes, Augusto Cardinalli Neto, Jeanine Giarolla, Elizabeth Igne Ferreira, Jean Leandro dos Santos and Chung Man Chin

Pharmaceuticals 2022, 15(5), 609; https://doi.org/10.3390/ph15050609 - 15 May 2022

Cited by 8 | Viewed by 2833

Abstract

Chagas disease (CD) is a neglected protozoan infection caused by Trypanosoma cruzi, which affects about 7 million people worldwide. There are two available drugs in therapeutics, however, they lack effectiveness for the chronic stage—characterized mainly by cardiac (i.e., cardiomyopathy) and digestive manifestations [...] Read more.

Chagas disease (CD) is a neglected protozoan infection caused by Trypanosoma cruzi, which affects about 7 million people worldwide. There are two available drugs in therapeutics, however, they lack effectiveness for the chronic stage—characterized mainly by cardiac (i.e., cardiomyopathy) and digestive manifestations (i.e., megaesophagus, megacolon). Due to the involvement of the immuno-inflammatory pathways in the disease’s progress, compounds exhibiting antioxidant and anti-inflammatory activity seem to be effective for controlling some clinical manifestations, mainly in the chronic phase. Resveratrol (RVT) and curcumin (CUR) are natural compounds with potent antioxidant and anti-inflammatory properties and their cardioprotective effect have been proposed to have benefits to treat CD. Such effects could decrease or block the progression of the disease’s severity. The purpose of this systematic review is to analyze the effectiveness of RVT and CUR in animal and clinical research for the treatment of CD. The study was performed according to PRISMA guidelines and it was registered on PROSPERO (CDR42021293495). The results did not find any clinical study, and the animal research was analyzed according to the SYRCLES risk of bias tools and ARRIVE 2.0 guidelines. We found 9 eligible reports in this study. We also discuss the potential RVT and CUR derivatives for the treatment of CD as well. Full article

(This article belongs to the Special Issue Drug Candidates for the Treatment of Infectious Diseases)

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