In vitro and in silico investigation of effects of antimicrobial peptides from Solanaceae plants against rice sheath blight pathogen Rhizoctinia solani.

Rhizoctonia solani, the causative agent of sheath blight disease in rice, poses a significant threat to agricultural productivity. Traditional management approaches involving chemical fungicides have been effective but come with detrimental consequences for the ecosystem. This study aimed to investigate sustainable alternatives in the form of antifungal peptides derived from Solanaceous plant species as potential agents against R. solani. Peptide extracts were obtained using an optimized antimicrobial peptide (AMP) extraction method and desalted using the solid-phase extraction technique. The antifungal potential of peptide-rich extracts from Solanum tuberosum and Capsicum annum was assessed through in vitro tests employing the agar well diffusion method. Furthermore, peptide-protein docking analysis was performed on HPEPDOCK and HDOCK server; and molecular dynamics simulations (MDS) of 100 ns period were performed using the Gromacs 2020.4. The results demonstrated significant inhibition zones for both extracts at concentrations of 100 mg/mL. Additionally, the extracts of Solanum tuberosum and Capsicum annum had minimum inhibitory concentrations of 50 mg/mL and 25 mg/mL, respectively with minimum fungicidal concentrations of 25 mg/mL. Insights into the potential mechanisms of key peptides inhibiting R. solani targets were gleaned from in-silico studies. Notably, certain AMPs exhibited favorable free energy of binding against pathogenicity-related targets, including histone demethylase, sortin nexin, and squalene synthase, in protein-peptide docking simulations. Extended molecular dynamics simulations lasting 100 ns and MM-PBSA calculations were performed on select protein-peptide complexes. AMP10 displayed the most favorable binding free energy against all target proteins, with AMP3, AMP12b, AMP6, and AMP15 also exhibiting promising results against specific targets of R. solani. These findings underscore the potential of peptide extracts from S. tuberosum and C. annum as effective antifungal agents against rice sheath blight caused by R. solani.

Exploring antibiofilm potential of some new imidazole analogs against C. albicans: synthesis, antifungal activity, molecular docking and molecular dynamics studies.

A series of 1, 2, 4, 5-tetrasubstituted imidazole derivatives were synthesized and their antibiofilm potential against Candida albicans was evaluated in vitro. Two of the synthesized derivatives 5e (IC50 = 25 µg/mL) and 5m (IC50 = 6 µg/mL),displayed better antifungal and antibiofilm potential than the standard drug Fluconazole (IC50 = 40 µg/mL) against C. albicans. Based on the in vitro results, we escalated the real time polymerase chain reaction (RT-PCR) analysis to gain knowledge of the enzymes expressed in the generation and maintenance of biofilms and the mechanism of biofilm inhibition by the synthesized analogues. We then investigated the possible interactions of the synthesized compounds in inhibiting agglutinin-like proteins, namely Als3, Als4 and Als6 were prominently down-regulated using in-silico molecular docking analysis against the previously available crystal structure of Als3 and constructed structure of Als4 and Als6 using the SWISS-MODEL server. The stability and energy of the agglutinin-like proteins-ligand complexes were evaluated using molecular dynamics simulations (MDS). According to the 100 ns MDS, all the compounds remained stable, formed a maximum of 3, and on average 2 hydrogen bonds, and Gibb's free energy landscape analysis suggested greater affinity of the compounds 5e and 5m toward Als4 protein.Communicated by Ramaswamy H. Sarma.

Green synthesis of biogenic selenium nanoparticles functionalized with ginger dietary extract targeting virulence factor and biofilm formation in Candida albicans.

To treat the systemic infections caused by Candida albicans (C. albicans), various drugs have been used, however, infections still persisted due to virulence factors and increasing antifungal resistance. As a solution to this problem, we synthesized selenium nanoparticles (SeNPs) by using Bacillus cereus bacteria. This is the first study to report a higher (70 %) reduction of selenite ions into SeNPs in under 6 h. The as-synthesized, biogenic SeNPs were used to deliver bioactive constituents of aqueous extract of ginger for inhibiting the growth and biofilm (virulence factors) in C. albicans. UV-visible spectroscopy revealed a characteristic absorption at 280 nm, and Raman spectroscopy showed a characteristic peak shift at 253 cm-1 for the biogenic SeNPs. The synthesized SeNPs are spherical with 240-250 nm in size as determined by electron microscopy. Fourier transform infrared spectroscopy confirmed the functionalization of antifungal constituents of ginger over the SeNPs (formation of Ginger@SeNPs nanoconjugates). In contrast to biogenic SeNPs, nanoconjugates were active against C. albicans for inhibiting growth and biofilm formation. In order to reveal antifungal mechanism of nanoconjugates', real-time polymerase chain reaction (RT-PCR) analysis was performed, according to RT-PCR analysis, the nanoconjugates target virulence genes involved in C. albicans hyphae and biofilm formation. Nanoconjugates inhibited 25 % growth of human embryonic kidney (HEK) 293 cell line, indicating moderate cytotoxicity of active nanoconjugates in an in-vitro cytotoxicity study. Therefore, biogenic SeNPs conjugated with ginger dietary extract may be a potential antifungal agent and drug carrier for inhibiting C. albicans growth and biofilm formation.

Antifungal Properties of Biogenic Selenium Nanoparticles Functionalized with Nystatin for the Inhibition of Candida albicans Biofilm Formation.

In the present study, biogenic selenium nanoparticles (SeNPs) have been prepared using Paenibacillus terreus and functionalized with nystatin (SeNP@PVP_Nystatin nanoconjugates) for inhibiting growth, morphogenesis, and a biofilm in Candida albicans. Ultraviolet-visible spectroscopy analysis has shown a characteristic absorption at 289, 303, and 318 nm, and X-ray diffraction analysis has shown characteristic peaks at different 2θ values for SeNPs. Electron microscopy analysis has shown that biogenic SeNPs are spherical in shape with a size in the range of 220-240 nm. Fourier transform infrared spectroscopy has confirmed the functionalization of nystatin on SeNPs (formation of SeNP@PVP_Nystatin nanoconjugates), and the zeta potential has confirmed the negative charge on the nanoconjugates. Biogenic SeNPs are inactive; however, nanoconjugates have shown antifungal activities on C. albicans (inhibited growth, morphogenesis, and a biofilm). The molecular mechanism for the action of nanoconjugates via a real-time polymerase chain reaction has shown that genes involved in the RAS/cAMP/PKA signaling pathway play an important role in antifungal activity. In cytotoxic studies, nanoconjugates have inhibited only 12% growth of the human embryonic kidney cell line 293 cells, indicating that the nanocomposites are not cytotoxic. Thus, the biogenic SeNPs produced by P. terreus can be used as innovative and effective drug carriers to increase the antifungal activity of nystatin.

Insilico structure based drug design approach to find potential hits in ventilator-associated pneumonia caused by Pseudomonas aeruginosa.

Tetraacyldisaccharide 4'-kinase (LpxK) is the prime enzyme responsible for the biosynthesis of lipid A. LpxK is a key antibacterial drug target, but it is less exploitation in Pseudomonas aeruginosa and other bacterial species limits its therapeutic use. Pseudomonas aeruginosa is responsible for severe infections like pneumonia and urinary tract infections. The precautionary measures of Pseudomonas aeruginosa infections are decisive as it results in extensive drug resistance, systemic bacteremia, and ventilator-associated pneumonia. The current rational approach highlights exploiting the use of computer-aided drug design approaches to counter Pseudomonas aeruginosa specific LpxK. The various approaches used were exploring the metabolic pathway database (Metacyc), drug target validation using DEG, protein modeling, ligand docking, e-pharmacophore assisted virtual screening, physicochemical and Toxicity profile prediction studies, and molecular simulations in spotting out novel potential hits compounds. The virtual hits which have highly ranked in the study were STOCK4S-16119, STOCK1S -60869, STOCK6S -43621, STOCK6S -3328, and STOCKS-39892 which can act as a scaffold for the establishment of new hits against LpxK and can result in control of Pseudomonas aeruginosa infectivity.

Biofilm inhibition in Candida albicans with biogenic hierarchical zinc-oxide nanoparticles.

The present study demonstrates lignin (L), fragments of lignin (FL), and oxidized fragmented lignin (OFL) as templates for the synthesis of zinc oxide nanoparticles (ZnO NPs) viz., lignin-ZnO (L-ZnO), hierarchical FL-ZnO, and OFL-ZnO NPs. The X-ray diffraction patterns confirmed the formation of phase pure ZnO NPs with a hexagonal wurtzite structure. Electron microscopy confirmed the hierarchical structures with one-dimensional arrays of ZnO NPs with an average particle diameter of 40 nm. The as-synthesized L-ZnO, FL-ZnO, and OFL-ZnO NPs were tested in-vitro for growth and virulence inhibition (morphogenesis and biofilm) in Candida albicans. L-ZnO, FL-ZnO, and OFL-ZnO NPs all inhibited growth and virulence. Growth and virulence inhibitions were highest (more than 90%, respectively at 125, 31.2, and 62.5 µg/mL) in presence of FL-ZnO NPs, indicating that the hierarchical FL-ZnO NPs were potent growth and virulence inhibiting agent than non-hierarchical ZnO NPs. Furthermore, the real-time polymerase chain (RT-PCR) was used to study the virulence inhibition molecular mechanisms of L-ZnO, FL-ZnO, and OFL-ZnO NPs. RT-PCR results showed that the downregulation of phr1, phr2, efg1, hwp1, ras1, als3 and als4, and the upregulation of bcy1, nrg1, and tup1 genes inhibited the virulence in C. albicans. Lastly, we also performed in-vitro test cell cytotoxicity on the cell line, mouse embryo 3T3L1, and in-vivo toxicity on Rats, which showed that FL-ZnO NPs were biocompatible and nontoxic.

New 1,2,3-Triazole-Appended Bis-pyrazoles: Synthesis, Bioevaluation, and Molecular Docking.

The present work describes design of a small library of new 1,2,3-triazole-appended bis-pyrazoles by using a molecular hybridization approach, and the synthesized hybrids were evaluated for their antifungal activity against different fungal strains, namely, Candida albicans, Cryptococcus neoformans, Candida glabrata, Candida tropicalis, Aspergillus niger, and Aspergillus fumigatus. All the compounds exhibited broad-spectrum activity against the tested fungal strains with excellent minimum inhibitory concentration values. The molecular docking study against sterol 14α-demethylase (CYP51) could provide valuable insights into the binding modes and affinity of these compounds. Furthermore, these compounds were also evaluated for their antioxidant activity, which also resulted in promising data.

One pot synthesis, in silico study and evaluation of some novel flavonoids as potent topoisomerase II inhibitors.

A library of novel flavonoid derivatives with diverse heterocyclic groups was designed and efficiently synthesized. Structures of the newly synthesized compounds 4a-i and 8a-l have been characterized by 1H NMR, 13C NMR, MS and elemental analysis. Anticancer activities were evaluated against MCF-7, A549, HepG2 and MCF-10A by MTT based assay. Compared with the positive control Adriamycin, compounds 4a, 4b, 4c, 4d, 8d, 8e and 8j were found to be most active anti-proliferative compounds against human cancer cell line. We found that compounds 4a and 4c exhibited inhibition of enzyme topoisomerase II with IC50 values 10.28 and 12.38 µM, respectively. In silico docking study of synthesized compounds showed that compounds 4a and 4c have good binding affinity toward topoisomerase IIα enzyme and have placed in between DNA base pair at active site of enzyme. In silico ADME prediction results that flavonoid coumarin analogues 4a-i could be exploited as an oral drug candidate.

Development of novel, biocompatible, polyester amines for microglia-targeting gene delivery.

Recent progress in personalized medicine and gene delivery has created exciting opportunities in therapeutics for central nervous system (CNS) disorders. Despite the interest in gene-based therapies, successful delivery of nucleic acids for treatment of CNS disorders faces major challenges. Here we report the facile synthesis of a novel, biodegradable, microglia-targeting polyester amine (PEA) carrier based on hydrophilic triethylene glycol dimethacrylate (TG) and low-molecular weight polyethylenimine (LMW-PEI). This nanocarrier, TG-branched PEI (TGP), successfully condensed double-stranded DNA into a size smaller than 200 nm. TGP nanoplexes were nontoxic in primary mixed glial cells and showed elevated transfection efficiency compared with PEI-25K and lipofector-EZ. After intrathecal and intracranial administration, PEA nanoplexes delivered genes specifically to microglia in the spinal cord and brain, respectively, proposing TGP as a novel microglia-specific gene delivery nanocarrier. The microglia-specific targeting of the TGP nanocarrier offers a new therapeutic strategy to modulate CNS disorders involving aberrant microglia activation while minimizing off-target side effects.

Application of Carbon Nanotubes In Drug Delivery of Non-cancerous Diseases: A Review.

Carbon Nanotubes (CNT) are the allotropes of carbon in nanosize dimension and are popular in medicinal field. These nano-based technologies are gaining high interest in the recent years for the treatment of diseases that are previously considered to be impossible to cure. CNTs have gained significance in the treatment of the majority of disorders such as Malaria, Alzheimer's disease, Infectious disease, and Asthma. Moreover, patient's responsiveness also increased in cardiovascular and pulmonary diseases. To date, a number of reviews are available in the literature covering applications of CNT in cancer. However, the purpose of this review is to focus on the use of CNTs in drug delivery of non-cancerous diseases. The novelty of this review is that it is focused on the applicability of CNT in the various non-cancerous diseases. Detailed information was collected from the literature which will guide and encourage researchers to explore the applicability of CNT in various non-cancerous diseases in the future.

Rapid Construction of Substituted Dihydrothiophene Ureidoformamides at Room Temperature Using Diisopropyl Ethyl Ammonium Acetate: A Green Perspective.

An economic, sustainable, and straightforward environmentally friendly synthesis of highly diversified polyfunctional dihydrothiophenes is successfully achieved via diisopropyl ethyl ammonium acetate as a room-temperature ionic liquid. Multicomponent synthesis contains domino processes; the benefit of this present protocol is highlighted by its readily available starting materials, superior functional group tolerance, purity of synthesized compounds was checked by high-performance liquid chromatography results in up to 99.7% purity for the synthesized compounds, reaction mass efficiency, effective mass yield, and excellent atom economy. In addition, a series of 2-(N-carbamoyl acetamide)-substituted 2,3-dihydrothiophene analogs were synthesized, and selected samples were chosen for testing their in vitro antibacterial and antifungal activities. Furthermore, a molecular docking study against sterol 14α-demethylase could provide valuable insight into the mechanism of antifungal action providing an opportunity for structure-based lead optimization.

Insights of tankyrases: A novel target for drug discovery.

Tankyrases are the group of enzymes belonging to a class of Poly (ADP-ribose) polymerase (PARP) recently named ADP-ribosyltransferase (ARTD). The two isoforms of tankyrase i.e. tankyrase1 (TNKS1) and tankyrase2 (TNKS2) were abundantly expressed in various biological functions in telomere regulation, Wnt/ß-catenin signaling pathway, viral replication, endogenous hormone regulation, glucose transport, cherubism disease, erectile dysfunction, and apoptosis. The structural analysis, mechanistic information, in vitro and in vivo studies led identification and development of several classes of tankyrase inhibitors under clinical phases. In the nutshell, this review will drive future research on tankyrase as it enlighten the structural and functional features of TNKS 1 and TNKS 2, different classes of inhibitors with their structure-activity relationship studies, molecular modeling studies, as well as past, current and future perspective of the different class of tankyrase inhibitors.

New N-phenylacetamide-linked 1,2,3-triazole-tethered coumarin conjugates: Synthesis, bioevaluation, and molecular docking study.

A series of new 1,2,3-triazole-tethered coumarin conjugates linked by N-phenylacetamide was efficiently synthesized via the click chemistry approach in excellent yields. The synthesized conjugates were evaluated for their in vitro antifungal and antioxidant activities. Antifungal activity determination was carried out against fungal strains such as Candida albicans, Fusarium oxysporum, Aspergillus flavus, Aspergillus niger and Cryptococcus neoformans. Compounds 7b, 7d, 7e, 8b and 8e displayed higher potency than the standard drug miconazole, with lower minimum inhibitory concentration values. Also, compound 7a exhibited potential radical scavenging activity as compared with the standard antioxidant butylated hydroxytoluene. In addition, a molecular docking study of the newly synthesized compounds was carried out, and the results showed a good binding mode at the active site of the fungal (C. albicans) P450 cytochrome lanosterol 14α-demethylase enzyme. Furthermore, the synthesized compounds were also tested for ADME properties, and they demonstrated potential as good candidates for oral drugs.

Pyridine and Benzoisothiazole Decorated Vanillin Chalcones: Synthesis, Antimicrobial, Antioxidant, Molecular Docking Study and ADMET Properties.

BACKGROUND: The search for new antimicrobial drugs is a never-ending task due to microbial resistance to the existing drugs. Antioxidants are essential to prevent free radical reactions which lead to chronic diseases to humankind. OBJECTIVE: The present studies were aimed at synthesis, characterization, antimicrobial and antioxidant activities of pyridine and benzoisothiazole decorated chalcones. MATERIALS AND METHODS: FTIR spectra were recorded using KBr pellets on Shimadzu FT-IR spectrophotometer. 1H and 13C NMR spectra were recorded on Bruker 400 MHz spectrometer. Antimicrobial activity of the synthesized chalcones was found to be good against different bacterial and fungal strains. Antioxidant activity was studied in terms of 2,2-diphenyl-1-picrylhydrazyl, hydroxyI and superoxide radical scavenging activities. Molecular docking was studied using Discovery Studio Visualizer Software, version 16 whereas Autodock Vina program was used to predict the toxicity profile of the compounds using FAFDrugs2 predictor. RESULTS AND DISCUSSION: The compounds 5c, 5d & 6c showed good antioxidant activities. The insilico molecular docking study supports the experimental results and demonstrated that the chalcones 5d, 6a and 7a are the most active among the synthesized derivatives. CONCLUSION: Prediction of pharmacokinetic parameters and molecular docking studies suggest that the synthesized chalcones have good pharmacokinetic properties to act as lead molecules in the drug discovery process.

SGLT inhibitors as antidiabetic agents: a comprehensive review.

Diabetes is one of the most common disorders that substantially contributes to an increase in global health burden. As a metabolic disorder, diabetes is associated with various medical conditions and diseases such as obesity, hypertension, cardiovascular diseases, and atherosclerosis. In this review, we cover the scientific studies on sodium/glucose cotransporter (SGLT) inhibitors published during the last decade. Our focus on providing an exhaustive overview of SGLT inhibitors enabled us to present their chemical classification for the first time.

Pharmacoinformatics approaches to identify potential hits against tetraacyldisaccharide 4'-kinase (LpxK) of Pseudomonas aeruginosa.

Pseudomonas aeruginosa infection can cause pneumonia and urinary tract infection and the management of Pseudomonas aeruginosa infection is critical in multidrug resistance, hospital-acquired bacteremia and ventilator-associated pneumonia. The key enzymes of lipid A biosynthesis in Pseudomonas aeruginosa are promising drug targets. However, the enzyme tetraacyldisaccharide 4'-kinase (LpxK) has not been explored as a drug target so far. Several pharmacoinformatics tools such as comparative metabolic pathway analysis (Metacyc), data mining from a database of essential genes (DEG), homology modeling, molecular docking, pharmacophore based virtual screening, ADMET prediction and molecular dynamics simulation were used in identifying novel lead compounds against this target. The top virtual hits STOCK6S-33288, 43621, 39892, 37164 and 35740 may serve as the templates for the design and synthesis of potent LpxK inhibitors in the management of serious Pseudomonas aeruginosa infection.

Organocatalyzed Domino Synthesis of New Thiazole-Based Decahydroacridine-1,8-diones and Dihydropyrido[2,3-d : 6,5-d']- dipyrimidines in Water as Antimicrobial Agents.

Organopromoter, 2-aminoethanesulfonic acid was used to catalyze the synthesis of a series of structurally intriguing new hybrids thiazolyl acridine-1,8(2H,5H)-diones and dihydropyrido[2,3-d : 6,5-d']dipyrimidine-2,4,6,8(1H,3H,5H,7H)-tetraones for the first time. 2-Aminoethanesulfonic acid is a biobased organopromoter, used to generate four new bonds for the synthesis of new coupled thiazole-based decahydroacridine-1,8-diones. Superior green credentials, operational simplicity, easy work-up and recyclability of the catalyst are the key strengths of this method. The broad substrate scope, mild reaction conditions, short reaction time, cost effectiveness, high atom economy and good to excellent yields make the present method a distinct improvement over existing methods. Spectral (IR, 1 H-NMR,13 C-NMR, Mass) data and elemental analyses confirmed the structures of the titled products. A series of thiazolyl acridine-1,8(2H,5H)-diones and dihydropyrido[2,3-d : 6,5-d']dipyrimidine-2,4,6,8(1H,3H,5H,7H)-tetraones were screened for their antimicrobial activity against four bacterial and three fungal strains.

Quinoline Based Monocarbonyl Curcumin Analogs as Potential Antifungal and Antioxidant Agents: Synthesis, Bioevaluation and Molecular Docking Study.

In search for new fungicidal and free radical scavenging agents, we synthesized a focused library of 2-chloroquinoline based monocarbonyl analogs of curcumin (MACs). The synthesized MACs were evaluated for in vitro antifungal and antioxidant activity. The antifungal activity was evaluated against five different fungal strains such as Candida albicans, Fusarium oxysporum, Aspergillus flavus, Aspergillus niger, and Cryptococcus neoformans, respectively. Most of the synthesized MACs displayed promising antifungal activity compared to the standard drug Miconazole. Furthermore, molecular docking study on a crucial fungal enzyme sterol 14α-demethylase (CYP51) could provide insight into the plausible mechanism of antifungal activity. MACs were also screened for in vitro radical scavenging activity using butylated hydroxytoluene (BHT) as a standard. Almost all MACs exhibited better antioxidant activity compared to BHT.

Synthesis and biological activity of structurally diverse phthalazine derivatives: A systematic review.

Phthalazine, a structurally and pharmacologically versatile nitrogen-containing heterocycle, has gained more attention from medicinal chemists in the design and synthesis of novel drugs owing to its pharmacological potential. In particular, phthalazine scaffold appeared as a pharmacophoric feature numerous drugs exhibiting pharmacological activities, in particular, antidiabetic, anticancer, antihypertensive, antithrombotic, anti-inflammatory, analgesic, antidepressant and antimicrobial activities. This review presents a summary of updated and detailed information on phthalazine as illustrated in both patented and non-patented literature. The reported literature have described the optimal pharmacological characteristics of phthalazine derivatives and highlighted the applicability of phthalazine, as potent scaffold in drug discovery.