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A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: closed (30 September 2020) | Viewed by 49106

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Dr. Antonio Carta

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Surgical and Experimental Medical Sciences, Università degli Studi di Sassari, Sassari, Italy
Interests: antiviral drug discovery
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Several viruses are pathogenic and cause clinically significant diseases in humans and animals. Viruses are obligate intracellular parasites that borrow cellular metabolic pathways. They encode proteins resembling cellular proteins and force their host cell to produce progeny virions. Thus, inhibiting a viral protein without affecting its cellular equivalent is very challenging. For this reason, most compounds inhibiting viral replication are also toxic to the host. The aim of this Special Issue is to collect original research papers and reviews focused on the antiviral activity, synthesis, and mechanism of action of new small organic molecules, metal complexes, and natural products, as well as on the study of mechanisms of drug resistance and on in silico design of antiviral agents. Furthermore, studies on antiviral target validation are welcome.

Prof. Dr. Antonio Carta
Guest Editor

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Keywords

Antiviral agents
Antiviral drug discovery and synthesis
Antiviral target validation
Mechanisms of action of antiviral agents
Antiviral drug resistance and mechanisms
In silico drug design
Phenotype screening
Biochemistry studies

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Published Papers (10 papers)

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12 pages, 1393 KiB

Open AccessArticle

Validated Reversed-Phase Liquid Chromatographic Method with Gradient Elution for Simultaneous Determination of the Antiviral Agents: Sofosbuvir, Ledipasvir, Daclatasvir, and Simeprevir in Their Dosage Forms

by Essam Ezzeldin, Nisreen F. Abo-Talib, Marwa H. Tammam, Yousif A. Asiri, Abd El-Galil E. Amr and Abdulrahman A. Almehizia

Molecules 2020, 25(20), 4611; https://doi.org/10.3390/molecules25204611 - 10 Oct 2020

Cited by 10 | Viewed by 3303

Abstract

A simple, rapid, sensitive, and precise reversed-phase liquid chromatographic method was developed and validated for the simultaneous determination of four direct-acting antivirals, sofosbuvir (SF), ledipasvir (LD), declatasvir (DC), and simeprevir (SM), in their respective pharmaceutical formulations. Effective chromatographic separation was achieved on an Agilent Eclipse plus C8 column (250 mm × 4.6 mm, 5 µm) at 40 °C with gradient elution using a mobile phase composed of acetonitrile:phosphate buffer (pH 6.5). The quantification of SF and DC was based on peak area measurements at 260 nm, while the quantification of LD and SM was achieved at 330 nm. The linearity was acceptable from 1.0 to 20.0 μg/mL for the studied drugs, with correlation coefficients >0.999. The analytical performance of the newly proposed HPLC procedure was thoroughly validated according to ICH guidelines in terms of linearity, precision (RSD%, 0.39–1.57), accuracy (98.05–101.90%), specificity, limit of detection (LOD) (0.022–0.039 μg/mL), limit of quantification (LOQ) (0.067–0.118 μg/mL), and robustness. The validated HPLC method was successfully used to analyze the abovementioned drugs in their pure and dosage forms without interference from common excipients present in commercial formulations. Full article

(This article belongs to the Special Issue Antiviral Agents)

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28 pages, 9545 KiB

Open AccessArticle

In Silico Identification of Potential Natural Product Inhibitors of Human Proteases Key to SARS-CoV-2 Infection

by R.P. Vivek-Ananth, Abhijit Rana, Nithin Rajan, Himansu S. Biswal and Areejit Samal

Molecules 2020, 25(17), 3822; https://doi.org/10.3390/molecules25173822 - 22 Aug 2020

Cited by 48 | Viewed by 8930

Abstract

Presently, there are no approved drugs or vaccines to treat COVID-19, which has spread to over 200 countries and at the time of writing was responsible for over 650,000 deaths worldwide. Recent studies have shown that two human proteases, TMPRSS2 and cathepsin L, play a key role in host cell entry of SARS-CoV-2. Importantly, inhibitors of these proteases were shown to block SARS-CoV-2 infection. Here, we perform virtual screening of 14,011 phytochemicals produced by Indian medicinal plants to identify natural product inhibitors of TMPRSS2 and cathepsin L. AutoDock Vina was used to perform molecular docking of phytochemicals against TMPRSS2 and cathepsin L. Potential phytochemical inhibitors were filtered by comparing their docked binding energies with those of known inhibitors of TMPRSS2 and cathepsin L. Further, the ligand binding site residues and non-covalent interactions between protein and ligand were used as an additional filter to identify phytochemical inhibitors that either bind to or form interactions with residues important for the specificity of the target proteases. This led to the identification of 96 inhibitors of TMPRSS2 and 9 inhibitors of cathepsin L among phytochemicals of Indian medicinal plants. Further, we have performed molecular dynamics (MD) simulations to analyze the stability of the protein-ligand complexes for the three top inhibitors of TMPRSS2 namely, qingdainone, edgeworoside C and adlumidine, and of cathepsin L namely, ararobinol, (+)-oxoturkiyenine and 3α,17α-cinchophylline. Interestingly, several herbal sources of identified phytochemical inhibitors have antiviral or anti-inflammatory use in traditional medicine. Further in vitro and in vivo testing is needed before clinical trials of the promising phytochemical inhibitors identified here. Full article

(This article belongs to the Special Issue Antiviral Agents)

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20 pages, 18093 KiB

Open AccessArticle

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

by Olujide O. Olubiyi, Maryam Olagunju, Monika Keutmann, Jennifer Loschwitz and Birgit Strodel

Molecules 2020, 25(14), 3193; https://doi.org/10.3390/molecules25143193 - 13 Jul 2020

Cited by 66 | Viewed by 6476

Abstract

We use state-of-the-art computer-aided drug design (CADD) techniques to identify prospective inhibitors of the main protease enzyme, 3CL^pro of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causing COVID-19. From our screening of over one million compounds including approved drugs, investigational drugs, natural products, and organic compounds, and a rescreening protocol incorporating enzyme dynamics via ensemble docking, we have been able to identify a range of prospective 3CL^pro inhibitors. Importantly, some of the identified compounds had previously been reported to exhibit inhibitory activities against the 3CL^pro enzyme of the closely related SARS-CoV virus. The top-ranking compounds are characterized by the presence of multiple bi- and monocyclic rings, many of them being heterocycles and aromatic, which are flexibly linked allowing the ligands to adapt to the geometry of the 3CL^pro substrate site and involve a high amount of functional groups enabling hydrogen bond formation with surrounding amino acid residues, including the catalytic dyad residues H41 and C145. Among the top binding compounds we identified several tyrosine kinase inhibitors, which include a bioflavonoid, the group of natural products that binds best to 3CL^pro. Another class of compounds that decently binds to the SARS-CoV-2 main protease are steroid hormones, which thus may be endogenous inhibitors and might provide an explanation for the age-dependent severity of COVID-19. Many of the compounds identified by our work show a considerably stronger binding than found for reference compounds with in vitro demonstrated 3CL^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. Full article

(This article belongs to the Special Issue Antiviral Agents)

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15 pages, 3290 KiB

Open AccessCommunication

Composition and Orientation of the Core Region of Novel HIV-1 Entry Inhibitors Influences Metabolic Stability

by Rama Karadsheh, Megan E. Meuser and Simon Cocklin

Molecules 2020, 25(6), 1430; https://doi.org/10.3390/molecules25061430 - 21 Mar 2020

Cited by 13 | Viewed by 3230

Abstract

Fostemsavir/temsavir is an investigational HIV-1 entry inhibitor currently in late-stage clinical trials. Although it holds promise to be a first-in-class Env-targeted entry inhibitor for the clinic, issues with bioavailability relegate its use to salvage therapies only. As such, the development of a small molecule HIV-1 entry inhibitor that can be used in standard combination antiretroviral therapy (cART) remains a longstanding goal for the field. We previously demonstrated the ability of extending the chemotypes available to this class of inhibitor as the first step towards this overarching goal. In addition to poor solubility, metabolic stability is a crucial determinant of bioavailability. Therefore, in this short communication, we assess the metabolic stabilities of five of our novel chemotype entry inhibitors. We found that changing the piperazine core region of temsavir alters the stability of the compound in human liver microsome assays. Moreover, we identified an entry inhibitor with more than twice the metabolic stability of temsavir and demonstrated that the orientation of the core replacement is critical for this increase. This work further demonstrates the feasibility of our long-term goal—to design an entry inhibitor with improved drug-like qualities—and warrants expanded studies to achieve this. Full article

(This article belongs to the Special Issue Antiviral Agents)

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18 pages, 2183 KiB

Open AccessCommunication

The Evolution of Pleconaril: Modified O-Alkyl Linker Analogs Have Biological Activity towards Coxsackievirus B3 Nancy

by Alexandrina Volobueva, Anna Egorova, Anastasia Galochkina, Sean Ekins, Vladimir Zarubaev and Vadim Makarov

Molecules 2020, 25(6), 1345; https://doi.org/10.3390/molecules25061345 - 16 Mar 2020

Cited by 6 | Viewed by 3514

Abstract

Coxsackieviruses type B are one of the most common causes of mild upper respiratory and gastrointestinal illnesses. At the time of writing, there are no approved drugs for effective antiviral treatment for Coxsackieviruses type B. We used the core-structure of pleconaril, a well-known antienteroviral drug candidate, for the synthesis of novel compounds with O-propyl linker modifications. Some original compounds with 4 different linker patterns, such as sulfur atom, ester, amide, and piperazine, were synthesized according to five synthetic schemes. The cytotoxicity and bioactivity of 14 target compounds towards Coxsackievirus B3 Nancy were examined. Based on the results, the values of 50% cytotoxic dose (CC₅₀), 50% virus-inhibiting dose (IC₅₀), and selectivity index (SI) were calculated for each compound. Several of the novel synthesized derivatives exhibited a strong anti-CVB3 activity (SI > 20 to > 200). These results open up new possibilities for synthesis of further new selective anticoxsackievirus compounds. Full article

(This article belongs to the Special Issue Antiviral Agents)

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16 pages, 2261 KiB

Open AccessArticle

Quinolinecarboxamides Inhibit the Replication of the Bovine Viral Diarrhea Virus by Targeting a Hot Spot for the Inhibition of Pestivirus Replication in the RNA-Dependent RNA Polymerase

by Simone Musiu, Yunierkis Perez Castillo, Alexandra Muigg, Gerhard Pürstinger, Pieter Leyssen, Mathy Froeyen, Johan Neyts and Jan Paeshuyse

Molecules 2020, 25(6), 1283; https://doi.org/10.3390/molecules25061283 - 12 Mar 2020

Cited by 8 | Viewed by 2845

Abstract

The bovine viral diarrhea virus (BVDV), a pestivirus from the family of Flaviviridae is ubiquitous and causes a range of clinical manifestations in livestock, mainly cattle. Two quinolinecarboxamide analogues were identified in a CPE-based screening effort, as selective inhibitors of the in vitro bovine viral diarrhea virus (BVDV) replication, i.e., TO505-6180/CSFCI (average EC₅₀ = 0.07 µM, SD = 0.02 µM, CC₅₀ > 100 µM) and TO502-2403/CSFCII (average EC₅₀ = 0.2 µM, SD = 0.06 µM, CC₅₀ > 100 µM). The initial antiviral activity observed for both hits against BVDV was corroborated by measuring the inhibitory effect on viral RNA synthesis and the production of infectious virus. Modification of the substituents on the quinolinecarboxamide scaffold resulted in analogues that proved about 7-fold more potent (average EC₅₀ = 0.03 with a SD = 0.01 µM) and that were devoid of cellular toxicity, for the concentration range tested (SI = 3333). CSFCII resistant BVDV variants were selected and were found to carry the F224P mutation in the viral RNA-dependent RNA polymerase (RdRp), whereas CSFCI resistant BVDV carried two mutations in the same region of the RdRp, i.e., N264D and F224Y. Likewise, molecular modeling revealed that F224P/Y and N264D are located in a small cavity near the fingertip domain of the pestivirus polymerase. CSFC-resistant BVDV proved to be cross-resistant to earlier reported pestivirus inhibitors (BPIP, AG110, LZ37, and BBP) that are known to target the same region of the RdRp. CSFC analogues did not inhibit the in vitro activity of recombinant BVDV RdRp but inhibited the activity of BVDV replication complexes (RCs). CSFC analogues likely interact with the fingertip of the pestivirus RdRp at the same position as BPIP, AG110, LZ37, and BBP. This indicates that this region is a “hot spot” for the inhibition of pestivirus replication. Full article

(This article belongs to the Special Issue Antiviral Agents)

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17 pages, 4681 KiB

Open AccessArticle

Design, Synthesis, and Bioactivity Evaluation of Novel Isoxazole-Amide Derivatives Containing an Acylhydrazone Moiety as New Active Antiviral Agents

by Zai-Bo Yang, Pei Li and Yin-Ju He

Molecules 2019, 24(20), 3766; https://doi.org/10.3390/molecules24203766 - 19 Oct 2019

Cited by 19 | Viewed by 2833

Abstract

As a continuation of our efforts to discover and develop “me-better” active molecules, in this study, a series of novel isoxazole-amide derivatives containing an acylhydrazone moiety were synthesized and evaluated for their antiviral activities against tobacco mosaic virus (TMV) and cucumber mosaic virus (CMV). Antiviral bioassays indicated that some of the target compounds exhibited better in vivo antiviral activities against TMV and CMV than those of Ningnanmycin (NNM). Especially, the compound 7t exhibited the best curative, protection, and inactivation activities against TMV and CMV which were superior to those of NNM. Meanwhile, our present work also revealed that compound 7t could enhance the defense-related enzyme activity and increase the chlorophyll content in tobacco leaves to induce resistance and enhance plant tolerance to TMV infection. Full article

(This article belongs to the Special Issue Antiviral Agents)

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11 pages, 1474 KiB

Open AccessArticle

Synthesis and Biological Evaluation of NH₂-Sulfonyl Oseltamivir Analogues as Influenza Neuraminidase Inhibitors

by Yaping Hu, Binfeng Chen, Zaiqiang Lei, Hongqian Zhao, Hongxi Zhu, Peng Quan and Yongshou Tian

Molecules 2019, 24(11), 2176; https://doi.org/10.3390/molecules24112176 - 10 Jun 2019

Cited by 7 | Viewed by 3690

Abstract

A series of NH₂-sulfonyl oseltamivir analogues were designed, synthesized, and their inhibitory activities against neuraminidase from H5N1 subtype evaluated. The results indicated that the IC₅₀ value of compound 4a, an oseltamivir analogue via methyl sulfonylation of C5-NH₂, was 3.50 μM. Molecular docking simulations suggested that 4a retained most of the interactions formed by oseltamivir carboxylate moieties and formed an additional hydrogen bond with the methylsulfonyl group. Meanwhile, 4a showed high stability towards human liver microsomes. More importantly, 4a without basic moieties is not a zwitterion as reported on the general structure of neuraminidase inhibitors. This research will provide valuable reference for the research of new types of neuraminidase inhibitors. Full article

(This article belongs to the Special Issue Antiviral Agents)

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Review

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25 pages, 5281 KiB

Open AccessReview

Recent Advances in HIV-1 Gag Inhibitor Design and Development

by Alexej Dick and Simon Cocklin

Molecules 2020, 25(7), 1687; https://doi.org/10.3390/molecules25071687 - 7 Apr 2020

Cited by 17 | Viewed by 7479

Abstract

Acquired Immune Deficiency Syndrome (AIDS) treatment with combination antiretroviral therapy (cART) has improved the life quality of many patients since its implementation. However, resistance mutations and the accumulation of severe side effects associated with cART remain enormous challenges that need to be addressed with the continual design and redesign of anti-HIV drugs. In this review, we focus on the importance of the HIV-1 Gag polyprotein as the master coordinator of HIV-1 assembly and maturation and as an emerging drug target. Due to its multiple roles in the HIV-1 life cycle, the individual Gag domains are attractive but also challenging targets for inhibitor design. However, recent encouraging developments in targeting the Gag domains such as the capsid protein with highly potent and potentially long-acting inhibitors, as well as the exploration and successful targeting of challenging HIV-1 proteins such as the matrix protein, have demonstrated the therapeutic viability of this important protein. Such Gag-directed inhibitors have great potential for combating the AIDS pandemic and to be useful tools to dissect HIV-1 biology. Full article

(This article belongs to the Special Issue Antiviral Agents)

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22 pages, 9722 KiB

Open AccessReview

Synthetic Compounds with 2-Amino-1,3,4-Thiadiazole Moiety Against Viral Infections

by Georgeta Serban

Molecules 2020, 25(4), 942; https://doi.org/10.3390/molecules25040942 - 19 Feb 2020

Cited by 42 | Viewed by 5970

Abstract

Viral infections have resulted in millions of victims in human history. Although great efforts have been made to find effective medication, there are still no drugs that truly cure viral infections. There are currently approximately 90 drugs approved for the treatment of human viral infections. As resistance toward available antiviral drugs has become a global threat to health, there is an intrinsic need to identify new scaffolds that are useful in discovering innovative, less toxic and highly active antiviral agents. 1,3,4-Thiadiazole derivatives have been extensively studied due to their pharmacological profile, physicochemical and pharmacokinetic properties. This review provides an overview of the various synthetic compounds containing the 2-amino-1,3,4-thiadiazole moiety that has been evaluated for antiviral activity against several viral strains and could be considered possible prototypes for the development of new antiviral drugs. Full article

(This article belongs to the Special Issue Antiviral Agents)

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