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.

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.

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.

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, biological evaluations and computational studies of N-(3-(-2-(7-Chloroquinolin-2-yl)vinyl) benzylidene)anilines as fungal biofilm inhibitors.

In the present investigation, new chloroquinoline derivatives bearing vinyl benzylidene aniline substituents at 2nd position were synthesized and screed for biofilm inhibitory, antifungal and antibacterial activity. The result of biofilm inhibition of C. albicans suggested that compounds 5j (IC50 value = 51.2 µM) and 5a (IC50 value = 66.2 µM) possess promising antibiofilm inhibition when compared with the standard antifungal drug fluconazole (IC50 = 40.0 µM). Two compounds 5a (MIC = 94.2 µg/mL) and 5f (MIC = 98.8 µg/mL) also exhibited good antifungal activity comparable to standard drug fluconazole (MIC = 50.0 µg/mL). The antibacterial screening against four strains of bacteria viz. E. coli, P. aeruginosa, B. subtilis, and S. aureus suggested their potential antibacterial activity and especially all the compounds except 5g were found more active than the standard drug ciprofloxacin against B. subtilis. To further gain insights into the possible mechanism of these compounds in biofilm inhibition through the agglutinin like protein (Als), molecular docking and molecular dynamics simulation studies were carried out. Molecular modeling studies suggested the clear role in inhibition of this protein and the resulting biofilm inhibitory activity.

New N-phenylacetamide-incorporated 1,2,3-triazoles: [Et3NH][OAc]-mediated efficient synthesis and biological evaluation.

A facile, highly efficient, and greener method for the synthesis of new 1,4-disubstituted-1,2,3-triazoles was conducted using [Et3NH][OAc] as a medium by the implementation of ultrasound irradiation via click chemistry, affording excellent yields. The present synthetic method exhibited numerous advantages such as mild reaction conditions, excellent product yields, minimal chemical waste, operational simplicity, shorter reaction time, and a wide range of substrate scope. The synthesized compounds were further evaluated for in vitro antifungal activity against five fungal strains, and some of the compounds displayed equivalent or greater potency than the standard drug. A molecular docking study against the modelled three-dimensional structure of cytochrome P450 lanosterol 14α-demethylase was also performed to understand the binding affinity and binding interactions of the enzyme. Furthermore, the synthesized compounds were evaluated for DPPH radical scavenging activity and antitubercular activity against Mycobacterium tuberculosis H37Rv strain.

Novel Benzylidenehydrazide-1,2,3-Triazole Conjugates as Antitubercular Agents: Synthesis and Molecular Docking.

BACKGROUND & OBJECTIVE: Novel 1,2,3-triazole based benzylidenehydrazide derivatives were synthesized and evaluated for antitubercular activity against Mycobacterium tuberculosis (MTB) H37Ra, M. bovis BCG and cytotoxic activity. Most of the derivatives exhibited promising in vitro potency against MTB characterized by lower MIC values. METHODS: Among all the synthesized derivatives, compound 6a and 6j were the most active against active and dormant MTB H37Ra, respectively. Compound 6d was significantly active against dormant and active M. bovis BCG. RESULTS: The structure activity relationship has been explored on the basis of anti-tubercular activity data. The active compounds were also tested against THP-1, A549 and Panc-1 cell lines and showed no significant cytotoxicity. Further, the synthesized compounds were found to have potential antioxidant with IC50 range = 11.19-56.64 µg/mL. The molecular docking study of synthesized compounds was performed against DprE1 enzyme of MTB to understand the binding interactions. CONCLUSION: Furthermore, synthesized compounds were also analysed for ADME properties and the potency of compounds indicated that, this series can be considered as a starting point for the developement of novel and more potent anti-tubercular agents in future.

New 2-Oxoindolin Phosphonates as Novel Agents to Treat Cancer: A Green Synthesis and Molecular Modeling.

The work reports the facile synthesis of novel α-aminophosphonate derivatives coupled with indole-2,3-dione moieties, namely the diethyl(substituted phenyl/heteroaryl)(2-(2-oxoindolin-3-ylidene)hydrazinyl)methylphosphonates derivatives 4(a⁻n). One-pot three component Kabachnik-Fields reactions were used to synthesize these derivatives. The reaction was carried out at room temperature by stirring in presence of ceric ammonium nitrate (CAN) as a green catalyst. The structures of the synthesized compounds were established by spectral studies. The synthesized derivatives 4(a⁻n) were evaluated for their in vitro anticancer activity against six human cancer cell lines by the SRB assay method. The cancer cell lines used in this research work are SK-MEL-2 (melanoma), MCF-7 (breast cancer), IMR-32 (neuroblastoma) MG-63 (human osteosarcoma), HT-29 (human colon cancer) and Hep-G2 (human hepatoma). All the synthesized derivatives inhibited the cell proliferation. Importantly, all the target compounds showed no cytotoxicity towards normal tissue cells (GI50 > 250 µM). A docking study was performed to predict the mode of action. Docking results indicate that the compounds have good binding with the enzyme tyrosine kinase as well as with microtubules, which makes them dual inhibitors. The result of in-silico bioavailability studies suggests that the compounds from the present series have good oral drug-like properties and are non-toxic in nature. In vivo acute oral toxicity study results indicate that the compounds can be considered safe, and therefore could be developed in the future as good anticancer agents or as leads for the design and synthesis of novel anticancer agents.

Ultrasound Assisted Synthesis of 4-(Benzyloxy)-N-(3-chloro-2-(substitutedphenyl)-4-oxoazetidin-1-yl) Benzamide as Challenging Anti-Tubercular Scaffold.

A series of ten novel derivatives of 4-(benzyloxy)-N-(3-chloro-2-(substituted phenyl)-4-oxoazetidin-1-yl) benzamide 6a⁻j were synthesized in good yield from the key compound 4-(benzyloxy)-N'-(substituted benzylidene) benzo hydrazide, called Schiff 's bases 5a⁻j, by Staudinger reaction ([2 + 2] ketene-imine cycloaddition reaction) with chloro acetyl chloride in the presence of catalyst tri ethylamine and solvent dimethyl formamide (DMF), by using ultra-sonication as one of the green chemistry tools. All the synthesised compounds were evaluated for in vitro anti-tubercular activity against Mycobacterium tuberculosis (MTB) and most of them showed promising activity with an IC50 value of less than 1 µg/mL. To establish the safety, all the synthesized compounds were further tested for cytotoxicity against the human cancer cell line HeLa and all 6a⁻j compounds were found to be non-cytotoxic in nature. The molecular docking study was carried out with essential enzyme InhA (FabI/ENR) of Mycobacterium responsible for cell wall synthesis which suggests that 6a and 6e are the most active derivatives of the series. The theoretical evaluation of cell permeability based on Lipinski's rule of five has helped to rationalize the biological results and hence the synthesized azetidinone derivatives 6a⁻j were also analyzed for physicochemical evaluation that is, absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties and the results showed that all the derivatives could comply with essential features required for a potential lead in the anti-tubercular drug discovery process.

Ultrasound Promoted Green Synthesis, Docking Study of Indole Spliced Thiadiazole, α-amino Phosphonates as Anticancer Agents and Antityrosinase Agents.

BACKGROUND: Regardless of recent advances in the development of clinically authorized anticancer agents the number of deaths due to cancer is increasing day by day all over the world. The aim of this research work is to synthesis novel anticancer agents. METHOD: In this work, a new series of diethyl ((1H-indole-3-yl)((5-phenyl-1,3,4-thiadiazole-2-yl)amino) methyl)phosphonate derivatives 6(a-j) were designed and synthesized in Ultrasound by green protocol using Kabachnik-Fields reaction. The structures of the synthesized compounds were confirmed by spectral analysis such as elemental analyses, IR, 1H NMR, 13C NMR, 31P NMR and mass spectra. The synthesized compounds 6(a-j) were appraised for their in vitro anticancer activity against human cancer cell lines such as SK-MEL-2 (melanoma), IMR-32 (Neuroblastoma), HT-29(Colon) and also on normal murine embryonic fibroblast NIH/3T3 by Sulforhodamine B (SRB) assay, using Adriamycin as a standard drug. RESULT: The treatment of SK-MEL-2 cancer cells with 6i showed apoptosis and morphological changes like cell shrinkage, cell wall deformation and reduced number of viable cells. The synthesized derivatives were also evaluated for their anti-tyrosinase effect. Nearly all the tested derivatives have been found to be potent tyrosinase inhibitors. CONCLUSION: Nearly all the compounds were tested, the docking study was performed and indicates that the compounds have good binding interactions with tyrosine kinase enzyme. Absorption, Distribution, Metabolism and Elimination (ADME) properties of the synthesized compounds were also analyzed which manifested their potentiality to thrive as good oral drug candidates.

Structural insights of dipeptidyl peptidase-IV inhibitors through molecular dynamics-guided receptor-dependent 4D-QSAR studies.

Dipeptidyl peptidase-IV (DPP-IV) inhibitors are promising antidiabetic agents. Currently, several DPP-IV inhibitors have been approved for therapeutic use in diabetes mellitus. Receptor-dependent 4D-QSAR is comparatively a new approach which uses molecular dynamics simulations to generate conformational ensemble profiles of compounds representing a dynamic state of compounds at a target's binding site. This work describes a receptor-dependent 4D-QSAR study on triazolopiperazine derivatives. QSARINS multiple linear regression method was adopted to generate 4D-QSAR models. A model with 9 variables was found to have better predictive accuracy with [Formula: see text], [Formula: see text] (leave-one-out) = 0.592 and [Formula: see text] predicted = 0.597. The location of these 9 variables at the binding site of DPP-IV revealed the importance of the residues Val711, Tyr662, Tyr666, Val202, Asp200 and Thr199 in making critical interactions with DPP-IV inhibitors. The study of these critical interactions revealed the structural features required in DPP-IV inhibitors. Thus, in this study the importance of a halogen substituent on a phenyl ring, the extent of substitution on the triazolopiperazine ring, the presence of an ionizable amino group and the presence of a hydrophobic substituent that can bind deeper in binding pocket of DPP-IV were revealed.