Current Topics in Medicinal Chemistry - Volume 20, Issue 24, 2020

Multidrug resistance in microbes poses a major health crisis and demands for the discovery of novel antimicrobial agents. The recent pandemic of SARS-CoV-2 has raised a public health emergency in almost all the countries of the world. Unlike viruses, a bacterium plays a significant role in various environmental issues such as bioremediation. Furthermore, biosurfactants produced by various bacterial species have an edge over traditionally produced chemical surfactants for its biodegradability, low toxicity and better interfacial activity with various applications in agriculture and industry. This special issue focuses on the global perspective of drug discovery for various antimicrobial, antiviral, and antifungal agents for infectious diseases. The issue also emphasizes the ongoing developments and the role of microbes in environmental remediation. We wish the articles published in this issue will enhance the current understanding in microbiology among the readers, and serve as the "seed of an idea" for drug development for ongoing COVID-19 pandemic.

Background: The emergence of a new coronavirus (CoV), named 2019-nCoV, as an outbreak originated in the city of Wuhan, China, has resulted in the death of more than 3,400 people this year alone and has caused worldwide an alarming situation, particularly following previous CoV epidemics, including the Severe Acute Respiratory Syndrome (SARS) in 2003 and the Middle East Respiratory Syndrome (MERS) in 2012. Currently, no exists for infections caused by CoVs; however, some natural products may represent potential treatment resources, such as those that contain diterpenes. Objective: This study aimed to use computational methods to perform a virtual screening (VS) of candidate diterpenes with the potential to act as CoV inhibitors. Methods: 1,955 diterpenes, derived from the Nepetoideae subfamily (Lamiaceae), were selected using the SistematX tool (https://sistematx.ufpb.br), which were used to make predictions. From the ChEMBL database, 3 sets of chemical structures were selected for the construction of predictive models. Results: The chemical structures of molecules with known activity against SARS CoV, two of which were tested for activity against specific viral proteins and one of which was tested for activity against the virus itself, were classified according to their pIC50 values [-log IC50 (mol/l)]. Conclusion: In the consensus analysis approach, combining both ligand- and structure-based VSs, 19 compounds were selected as potential CoV inhibitors, including isotanshinone IIA (01), tanshinlactone (02), isocryptotanshinone (03), and tanshinketolactone (04), which did not present toxicity within the evaluated parameters.

Background: The vast geographical expansion of novel coronavirus and an increasing number of COVID-19 affected cases have overwhelmed health and public health services. Artificial Intelligence (AI) and Machine Learning (ML) algorithms have extended their major role in tracking disease patterns, and in identifying possible treatments. Objective: This study aims to identify potential COVID-19 protease inhibitors through shape-based Machine Learning assisted by Molecular Docking and Molecular Dynamics simulations. Methods: 31 Repurposed compounds have been selected targeting the main coronavirus protease (6LU7) and a machine learning approach was employed to generate shape-based molecules starting from the 3D shape to the pharmacophoric features of their seed compound. Ligand-Receptor Docking was performed with Optimized Potential for Liquid Simulations (OPLS) algorithms to identify highaffinity compounds from the list of selected candidates for 6LU7, which were subjected to Molecular Dynamic Simulations followed by ADMET studies and other analyses. Results: Shape-based Machine learning reported remdesivir, valrubicin, aprepitant, and fulvestrant as the best therapeutic agents with the highest affinity for the target protein. Among the best shape-based compounds, a novel compound identified was not indexed in any chemical databases (PubChem, Zinc, or ChEMBL). Hence, the novel compound was named 'nCorv-EMBS'. Further, toxicity analysis showed nCorv-EMBS to be suitable for further consideration as the main protease inhibitor in COVID-19. Conclusion: Effective ACE-II, GAK, AAK1, and protease 3C blockers can serve as a novel therapeutic approach to block the binding and attachment of the main COVID-19 protease (PDB ID: 6LU7) to the host cell and thus inhibit the infection at AT2 receptors in the lung. The novel compound nCorv- EMBS herein proposed stands as a promising inhibitor to be evaluated further for COVID-19 treatment.

Background: Methicillin-resistant and vancomycin-resistant Staphylococcus aureus are pathogens causing severe infectious diseases that pose real public health threats problems worldwide. In S. aureus, the most efficient multidrug-resistant system is the NorA efflux pump. For this reason, it is critical to identify efflux pump inhibitors. Objective: In this paper, we present an update of the new natural and synthetic compounds that act as modulators of antibiotic resistance through the inhibition of the S. aureus NorA efflux pump. Results: Several classes of compounds capable of restoring the antibiotic activity have been identified against resistant-S. aureus strains, acting as NorA efflux pump inhibitors. The most promising classes of compounds were quinolines, indoles, pyridines, phenols, and sulfur-containing heterocycles. However, the substantial degree structural diversity of these compounds makes it difficult to establish good structure- activity correlations that allow the design of compounds with more promising activities and properties. Conclusion: Despite substantial efforts put forth in the search for new antibiotic adjuvants that act as efflux pump inhibitors, and despite several promising results, there are currently no efflux pump inhibitors authorized for human or veterinary use, or in clinical trials. Unfortunately, it appears that infection control strategies have remained the same since the discovery of penicillin, and that most efforts remain focused on discovering new classes of antibiotics, rather than trying to prolong the life of available antibiotics, and simultaneously fighting mechanisms of bacterial resistance.

Background: Resistance to antimicrobial agents is a major public health problem, being Staphylococcus aureus prevalent in infections in hospital and community environments and, admittedly, related to biofilm formation in biotic and abiotic surfaces. Biofilms form a complex and structured community of microorganisms surrounded by an extracellular matrix adhering to each other and to a surface that gives them even more protection from and resistance against the action of antimicrobial agents, as well as against host defenses. Methods: Aiming to control and solve these problems, our study sought to evaluate the action of 1,2,3- triazoles against a Staphylococcus aureus isolate in planktonic and in the biofilm form, evaluating the activity of this triazole through Minimum Inhibitory Concentration (MIC) and Minimum Bactericidal Concentration (MBC) tests. We have also performed cytotoxic evaluation and Scanning Electron Microscopy (SEM) of the biofilms under the treatment of the compound. The 1,2,3-triazole DAN 49 showed bacteriostatic and bactericidal activity (MIC and MBC 128 μg/mL). In addition, its presence interfered with the biofilm formation stage (1/2 MIC, p <0.000001) and demonstrated an effect on young preformed biofilm (2 MICs, p <0.05). Results: Scanning Electron Microscopy images showed a reduction in the cell population and the appearance of deformations on the surface of some bacteria in the biofilm under treatment with the compound. Conclusion: Therefore, it was possible to conclude the promising anti-biofilm potential of 1,2,3-triazole, demonstrating the importance of the synthesis of new compounds with biological activity.

Background: From the literature it is known that many derivatives of fused thienopyrimidines and furopyrimidines possess broad spectrum of biological activity. Objectives: The current studies describe the synthesis and evaluation of antimicrobial activity of some new N-1,3-thiazol-2-ylacetamides of pyrido[3',2':4,5]furo(thieno)[3,2-d]pyrimidines. Methods: By cyclocondensation of ethyl 1-aminofuro(thieno)[2,3-b]pyridine-2-carboxylates 1with formamide were converted to the pyrido[3',2':4,5]furo(thieno)[3,2-d]pyrimidin-7(8)-ones 2.Alkylation of compound 2 with 2-chloro-N-1,3-thiazol-2-ylacetamide led to the aimed N-1,3-thiazol-2-ylaceta-mides of pyrido[3',2':4,5]furo(thieno)[3,2-d]pyrimidines 3. Starting from compound 2 the relevant S-alkylated derivatives of pyrido[3',2':4,5]furo(thieno)[3,2-d]pyrimidines 6 were also synthesized. Results: All the compounds showed antibacterial activity to non-resistant strains. Compounds 3a-3m showed antibacterial activity with MIC/MBC at 0.08-2.31 mg/mL/0.11-3.75 mg/mL .The two most active compounds, 3j and 6b, appeared to be more active towards MRSA than the reference drugs. Half of the tested compounds appeared to be equipotent/more potent than ketoconazole and more potent than bifonazole. The docking analysis provided useful information about the interactions occurring between the tested compounds and the different enzymes. Conclusion: Gram-negative and Gram-positive bacteria and fungi showed different response towards tested compounds, indicating that different substituents may lead to different modes of action or that the metabolism of some bacteria/fungi was better able to overcome the effect of the compounds or adapt to it.

World Health Organization declared coronavirus disease (COVID-19) caused by SARS coronavirus-2 (SARS-CoV-2) as pandemic. Its outbreak started in China in Dec 2019 and rapidly spread all over the world. SARS-CoV-2 has infected more than 800,000 people and caused about 35,000 deaths so far, moreover, no approved drugs are available to treat COVID-19. Several investigations have been carried out to identify potent drugs for COVID-19 based on drug repurposing, potential novel compounds from ligand libraries, natural products, short peptides, and RNAseq analysis. This review is focused on three different aspects; (i) targets for drug design (ii) computational methods to identify lead compounds and (iii) drugs for COVID-19. It also covers the latest literature on various hit molecules proposed by computational methods and experimental techniques.

Background: Bioremediation has taken its call for removing pollutants for years. The oilcontaminated surroundings are majorly hazardous for sustaining life, but a great contribution to nature in the form of microorganisms. The complex carbon-hydrogen chain has served as classic raw material to chemical industries, which has perked up the hydrocarbon waste. Microbial remediation has been thus, focused to deal with the lacuna, where the new addition to this category is Microbacterium species. Objectives: The identification and characterization of lipopeptide biosurfactant producing Microbacterium spp. isolated from brackish river water. Methods: The strain was isolated from an oil-contaminated lake. The strain was tested with all the other isolated species for oil degradation using screening protocols such as haemolysis, oil spread assay, BATH, E24, etc. The produced biosurfactant was extracted by acid precipitation, followed by solvent recovery. The strain with maximum potential was sequenced and was subjected to phylogeny assessment using in silico tools. Results: Novel Microbacterium species produce the extracellular biosurfactant. The surface tension of Microbacterium was found to be 32mN/m, indicates its powerful surface tension-reducing property. The strain was optimized for the production of biosurfactant and the best results were obtained with sucrose (2%) and yeast extract (3%) medium at 7 pH and 40°C temperature. Conclusion: The isolate was confirmed to be a novel Microbacterium species that could produce 0.461 gm biosurfactant in 100 ml of the medium throughout a life cycle and novel strain of isolate was deposited to NCBI as Microbacterium spp. ANSKSLAB01 using an accession number: KU179507.

Over the past decades, a tremendous rise in invasive fungal infection diseases attributed to the yeast Candida albicans in immunocompromised individuals poses a seriously challenging issue. Another concern is the emergence of multi-drug resistant pathogens to the existing medicines due to their overuse and misuse. It was recently reported that 25-55% of the mortality rate is caused by invasive infection. Despite a large variety of drugs being available to treat invasive candidiasis, only two of them contain a 1,2,4-triazole core, namely Fluconazole and itraconazole, which are efficient in treating infection induced by fungal Candida species. Moreover, long-term therapy associated with azole medications has led to an increase in azole resistance as well as a high risk of toxicity. Despite numerous outstanding achievements in antifungal drug discovery, development of novel, safer and potent antifungal agents while overcoming the resistance problem associated with the current drugs is becoming the main focus of medicinal chemists. Therefore, this review outlines the breakthroughs in medicinal chemistry research regarding 1,2,4- triazole-based derivatives as potential antifungal agents in the past decade. In addition, the structureactivity relationship of these compounds is also discussed.