Two step one-pot synthesis of 7-azaindole linked 1,2,3-triazole hybrids: In-vitro and in-silico antimicrobial evaluation.

Herein, we report design, synthesis and characterization of a new library of 7-azaindole N-ethyl linked 1,2,3-triazoles containing ethylene as a spacer unit, and evaluation of all the synthesized compounds for their antimicrobial properties. Antibacterial potential was checked against two Gram positive (B. subtilis and S. aureus) and two Gram negative (E. coli and P. aeruginosa) bacterial strains while antifungal potential was assayed against two fungal strains (C. albicans and A. niger). All the tested compounds showed satisfactory antibacterial potency in comparison to reference drug ciprofloxacin with MIC values ranging from 0.0108 to 0.0432 µmol/mL. Interestingly, except two, all the target compounds showed better antifungal property as compared to the reference drug fluconazole with MIC values less than 0.0408 µmol/mL. One of the compounds exhibited two-fold better antifungal potential in comparison to fluconazole. Furthermore, in-silico ADMET and DFT studies reported drug likeness behavior and chemical reactivity parameters, respectively. The cytotoxicity results on substrate azide 3 and most potent 1,2,3-triazoles (5d and 5l) were found to be non-toxic.

Molecular Docking and Molecular Dynamics Simulations of Synthesized Thiazole-Isatin-1,2,3-triazole Hybrids as Promising Inhibitors for DNA Gyrase and 14α-Sterol Demethylase.

In the present work, a new class of thiazole-isatin-1,2,3-triazole hybrids (5a-5p) and precursor alkyne hybrids (6a-6d) has been reported with their in-silico studies. After structural identifications using different spectroscopic technique such as FTIR, 1H and 13C NMR and HRMS, the synthesized hybrids were explored for their biological potential using molecular docking and molecular dynamics calculations. Molecular docking results revealed that compound 5j showed maximum binding energy i.e. -10.3 and -12.6 kcal/mol against antibacterial and antifungal enzymes; 1KZN (E. coli) and 5TZ1 (C. albicans), respectively.Top of FormBottom of Form Molecular dynamics simulations for the best molecule (100 ns) followed by PBSA calculations  suggested a stable complex of 5j with 5TZ1 with binding energy of -118.760 kJ/mol as compared to 1KZN (-94.593 kJ/mol). The mean RMSD values for the 1KZN with 5j complex remained approximately 0.175 nm throughout all the time span of 100 ns in the production stages and is in the acceptable range.  Whereas, 5TZ1 with 5j complex, RMSD values exhibited variability within the range of 0.15 to 0.25 nm.

An updated review on 1,2,3-/1,2,4-triazoles: synthesis and diverse range of biological potential.

The synthesis of triazoles has attracted a lot of interest in the field of organic chemistry because of its versatile chemical characteristics and possible biological uses. This review offers an extensive overview of the different pathways used in the production of triazoles. A detailed analysis of recent research indicates that triazole compounds have a potential range of pharmacological activities, including the ability to inhibit enzymes, and have antibacterial, anticancer, and antifungal activities. The integration of computational and experimental methods provides a thorough understanding of the structure-activity connection, promoting sensible drug design and optimization. By including triazoles as essential components in drug discovery, researchers can further explore and innovate in the synthesis, biological assessment, and computational studies of triazoles as drugs, exploring the potential therapeutic significance of triazoles.

Pyrazoline Spiro-oxindole tethered 1,2,3-triazole hybrids: Design, synthesis, antimicrobial efficacy and molecular modelling studies.

Inspired from the important applications of spirocyclic compounds in medicinal chemistry, a new series of pyrazoline Spiro-oxindole tethered 1,2,3-triazole hybrids was reported via Cu(I)-catalyzed click reaction from isatin-pyrazoline linked terminal alkynes with in situ derived benzyl azides. Antimicrobial evaluation data showed that all hybrids exhibited promising efficacy towards the tested microbial strains. Antimicrobial screening as well as docking studies suggested that hybrid 6a was found to be most potent towards Aspergillus niger (MIC = 0.0122 µmol/mL) and Escherichia coli (MIC = 0.0061 µmol/mL). Molecular docking studies of 6a within the binding pockets of antibacterial and antifungal targets revealed good interactions with the binding energies of - 144.544 kcal/mol and - 154.364 kcal/mol against 1KZN (E. coli) and 3D3Z (A. niger), respectively. Further, MD simulations were performed to study the stability of the complexes formed at 300 K. Based on the RMSD trajectories, it is evident that 3D3Z-6a complex exhibits minimal deviation, whereas the 1KZN-6a complex displayed little more deviation compared to the protein but, both are in acceptable range. Moreover, 3D3Z-6a and 1KZN-6a showed maximum number of hydrogen bonds at 50 ns and 70 ns, respectively, thereby complementing the stability of these complexes.

Synthesis, Characterization, Antimicrobial and In Silico Studies of Isatin Schiff Base Linked 1,2,3-Triazole Hybrids.

A new series of isatin-Schiff base linked 1,2,3-triazole hybrids has been synthesized using CuAAC approach from (E)-3-(phenylimino)-1-(prop-2-yn-1-yl)indolin-2-one derivatives in high yield (73-91 %). These synthesized derivatives were characterized using FT-IR, 1H NMR, 13C NMR, 2D-NMR and HRMS spectral techniques. The in vitro antimicrobial activity assay demonstrated that most of the tested hybrids exhibited promising activity. Compound 5 j displayed significant antibacterial efficacy against P. aeruginosa and B. subtilis with MIC value of 0.0062 µmol/mL. While, 5 j also showed better antifungal potency against A. niger with MIC value of 0.0123 µmol/mL. The docking studies of most promising compounds were performed with the well-known antibacterial and antifungal targets i. e. 1KZ1, 5TZ1. Molecular modelling investigations demonstrated that hybrids 5 h and 5 l exhibited good interactions with 1KZN and 5TZ1, with binding energies of -9.6 and -11.0 kcal/mol, respectively. Further, molecular dynamics studies of the compounds showing promising binding interactions were also carried out to study the stability of complexes of these hybrids with both the targets.

Dehydroacetic acid a privileged medicinal scaffold: A concise review.

From the last decade, research on dehydroacetic acid (DHA) and its derivatives has increased immensely due to its significant role in various fields, including medicine, cosmetics, food industry, and so on. In the medicinal area, DHA plays an essential role in developing novel action-based drugs, which are helpful for treating various diseases. Besides its plethora of biological applications, its chelating ability offers the easiest synthetic route for synthesizing more active metal complexes. DHA derivatives along with their metal complexes show a number of biological activities and also exhibit various interactions with multiple biological targets. This article summarizes recent medicinal applications (2000-onwards) of DHA-based compounds and their analogs, along with their structure-activity relationship (SAR) analysis. Their interactions with different target enzymes are also discussed. This information derived from SAR analysis would be helpful for medicinal chemists working on the development of drugs based on heterocyclic frameworks, particularly those based on the DHA scaffold.

Nascent pharmacological advancement in adamantane derivatives.

The adamantane moiety has attracted significant attention since its discovery in 1933 due to its remarkable structural, chemical, and medicinal properties. This molecule has a notable impact in the therapeutic field because of its "add-on" lipophilicity to any pharmacophoric moieties. As in the case of molecular hybridization, in which one pharmacophore is attached to another one(s) with a probability of increasing the biological activity, adding an adamantane unit improves the absorption distribution, metabolism and excretion properties of the resultant hybrid molecule. This review summarizes various reports highlighting the biological activities of adamantane-based synthetic compounds and their structure-activity relationship study. The information presented in this review may open up possible dimensions for adamantane-based drug development and discovery in the pharmaceutical industry after proper structural modifications.

Antimicrobial, antibiofilm, docking, DFT and molecular dynamics studies on click-derived isatin-thiosemicarbazone-1,2,3-triazoles.

In an effort to develop new antimicrobial and antibiofilm agents, we have designed and synthesized a novel class of isatin-thiosemicarbazone-1,2,3-triazoles through the CuAAC approach. All the synthesized hybrids were characterized by several spectral techniques such as FTIR, 1H NMR, 13C NMR, 2D NMR and HRMS. All the derivatives were evaluated for their antimicrobial and antibiofilm efficacy towards various microbial species. Triazole hybrid 8d exhibited the highest efficacy towards E. coli (MIC = 0.0067 µmol/mL) and S. aureus (MIC = 0.0067 µmol/mL), whereas, compounds 8b, 8c, 8d, 8e, 9a and terminal alkyne (10) significantly inhibited biofilm formation against S. aureus, B. subtilis and E. coli. To find out the structure-activity relationship and binding interactions of synthesized hybrids with enzymes 1KZN and 5TZ1, molecular docking for all the synthesized hybrids was carried out. DFT calculations for all hybrids and the molecular dynamics studies for compounds 9e and 9f were also performed to support the biological behavior of these hybrids.Communicated by Ramaswamy H. Sarma.

Click synthesis, antimicrobial, DNA photocleavage and computational studies of oxindole-tethered 1H-1,2,3-triazoles.

Aim: To obtain new hybrids derived from isatin and triazole. Materials & methods: A series of oxindole-1-H-1,2,3-triazole hybrids (4a-l) were synthesized from 3-sulfenylated N-propargylated oxindoles and organic azides employing Cu(I)-catalyzed azide-alkyne cycloaddition. These compounds were evaluated in vitro for antimicrobial activity by the standard serial dilution method and DNA photocleavage activity. Results: Antimicrobial assay revealed that compounds 4l and 4f exhibited promising efficacy against Candida albicans and Rhizopus oryzae, respectively, with a minimum inhibitory concentration value of 0.0008 µmol/mL. Compounds 4h and 4k completely degraded plasmid DNA. Further molecular docking of compounds with 1KZN (4j and 4k) and 5TZ1 (4h and 4l) revealed good binding interactions. Conclusion: Results of the current research can help in the development of new antimicrobial agents with high efficacy.

A Mini Review on Pharmacological Significance of Isatin-1,2,3-Triazole Hybrids.

Molecular hybridization is one of the recent stratagems in medicinal chemistry to synthesize a novel hybrid molecule having better affinity and efficacy by combining two or more pharmacophoric moieties. Molecular hybridization, i.e., a linker or framework integration technique, can be used to connect the two pharmacophoric components. It has often been found that hybrid compounds perform more effectively and possess lower toxicity than their parent molecules. In order to create a new generation of effective and safe therapeutic candidates, such as anti-cancer, anti-viral, anti-HIV, antioxidant, and antibacterial, for a variety of frontline diseases, several articles have been published that discuss the molecular hybridization of preclinically or clinically proven compounds. Isatin and its derivatives have been studied extensively due to diversified biological activities, including antitumor, antimicrobial, anti-inflammatory, analgesic, antiviral, antioxidant, anticonvulsant, etc. Similarly, 1,2,3-triazoles have received significant interest as a bio-isostere in medicinal chemistry for generating a large number of pharmaceutically significant molecules. As it possesses diversified physiochemical properties, such as hydrogen bond formation capacity, ease of synthesis, moderate dipole moment, stability towards acidic/basic hydrolysis, inertness towards oxidizing/ reducing agents, and good binding potential with several biological targets, triazole is an important choice of the medicinal chemists for the novel medication development. The aim of the current review is to summarize the research articles showing the pharmacological significance of hybrid molecules containing isatin and 1,2,3-triazole moieties. The present review may assist chemists in designing and synthesizing isatin-1,2,3-triazole hybrids with better efficacy and low cytotoxicity.

Synthesis, antimicrobial, antibiofilm and computational studies of isatin-semicarbazone tethered 1,2,3-triazoles.

In present era, heterocyclic compounds containing two or three nitrogen atoms play a vital role in drug discovery. In this context, a new class of isatin-semicarbazone tethered 1,2,3-triazole hybrids was synthesized via Cu(I)-mediated azide alkyne cycloaddition reaction. Structural characteristics of the newly derived compounds were identified by various spectral techniques like FTIR, 1H NMR, 13C NMR, HRMS and single crystal X-ray crystallography. Synthesized derivatives were also screened for in vitro antimicrobial and antibiofilm activity against different microbial species. Triazole hybrid 7e showed significant efficacy towards E. coli having MIC of 0.0063 µmol/mL, whereas 6a, 6b, 7a, 7c, 7e, and 7f showed highest percentage of biofilm inhibition against P. aeruginosa. Bioassay results suggested that these triazole hybrids could act as biomaterial for antimicrobial and antibiofilm applications and may constitute a new promising class of antimicrobial and antibiofilm agents. These results were further supported by in silico docking, DFT calculations and ADME studies.

Urea-thiazole/benzothiazole hybrids with a triazole linker: synthesis, antimicrobial potential, pharmacokinetic profile and in silico mechanistic studies.

Some urea-thiazole/benzothiazole hybrids with a triazole linker were synthesized via Cu(I)-catalysed click reaction. After successfully analysed by various spectral techniques including FTIR, NMR and HRMS, antimicrobial screening of the synthesized hybrids along with their precursors was carried out against two Gram (+) bacteria (Staphylococcus aureus and Bacillus endophyticus), two Gram (-) bacteria (Escherichia coli and Pseudomonas fluorescens) and two fungi (Candida albicans and Rhizopus oryzae). All the synthesized compounds (4a-4l) displayed better biological response than the standard fluconazole against both of the tested fungi. Compounds 4h and 4j were found to be the most active compounds against R. oryzae and C. albicans, respectively. Molecular docking of hybrid 4j and its alkyne precursor 1b in the active site of C. albicans target sterol 14-α demethylase was also performed and was also supported by molecular dynamics studies. In silico ADME prediction of synthesized urea-thiazole/benzothiazole hybrids with a triazole linker and their alkyne precursors was also predicted.

Recent Progress in 1H-1,2,3-triazoles as Potential Antifungal Agents.

The need to overcome ever-increasing cases of antifungal resistance and circumvent side effects and drug interactions related to currently available drugs has impelled the demand to expedite the drug discovery and the development of novel antifungals. 1,4-disubstituted 1,2,3-triazole has gained tremendous interest in the last two decades mainly because of its ease of synthesis via copper( I)-catalyzed azide-alkyne cycloaddition (CuAAC) and its broad spectrum of chemotherapeutic potential. 1,2,3-Triazole is an excellent pharmacophore that has been used as a bioisostere for obtaining libraries of new medicinally important scaffolds. The present review focuses on the recent advances (2016-2021) in 1,2,3-triazole derivatives obtained by CuAAC as potential antifungal agents that may facilitate the triazole-based antifungal development process.

Antimicrobial Screening, in Silico Studies and QSAR of Chalcone-based 1,4-disubstituted 1,2,3-triazole Hybrids.

The in vitro antimicrobial properties of some chalcones (1A-1C: ) and chalcone tethred 1,4-disubstituted 1,2,3-triazoles (2A-2U: ) towards different microbial strains viz. Staphylococcus aureus, Bacillus subtilis, Escherichia coli, Pseudomonas aeruginosa, Aspergillus niger and Candida albicans are reported. Compounds 2G: and 2U: exhibited better potency than the standard Fluconazole with MIC values of 0.0063 µmol/mL and 0.0068 µmol/mL, respectively. Furthermore, molecular docking was performed to investigate the binding modes of two potent compounds 2Q: and 2G: with E. coli topoisomerase II DNA gyrase B and C. albicans lanosterol 14α-demethylase, respectively. Based on these results, a statistically significant quantitative structure activity relationship (QSAR) model was successfully summarized for antibacterial activity against B. subtilis.

Synthesis, antimicrobial potency with in silico study of Boc-leucine-1,2,3-triazoles.

A library of N-Boc protected Leucine-linked 1,4-disubstituted 1,2,3-triazoles was synthesized and fully characterized, in high yield via copper-catalyzed alkyne-azide cycloaddition (CuAAC) reaction. In vitro antibacterial activity showed that compound 4h found to be more potent than the reference drug Ciprofloxacin (MIC: 0.0196 µmol/mL) against tested bacterial strains S. entrica, B. subtilis, S. aureus, E. coli and P. auroginosa with MIC: 0.0148, 0.0074, 0.0148, 0.0074, and 0.0074 µmol/mL, respectively and antifungal activity with MIC: 0.0148 µmol/mL as compared to reference drug Fluconazole (MIC: 0.0102 µmol/mL) against A. niger and C. albicans fungal strains. Further, the molecular docking study on 4h and its predecessor alkyne 3 by choosing E. coli topoisomerase II, DNA Gyrase (PDB ID: 1KZN) showed better binding with triazole than alkyne and these results were supported by DFT study using B3LYP/6-311G(d,p) basis set.

Oxazolone-1,2,3-Triazole Hybrids: Design, Synthesis and Antimicrobial Evaluation.

BACKGROUND: Oxazolones and 1,2,3-triazoles are among the extensively studied heterocycles in medicinal chemistry. Both of these moieties are reported to possess a broad spectrum of biological activity including antimicrobial. OBJECTIVE: The objective of the current work is to design, synthesize and antimicrobial evaluation of some new oxazolone-1,2,3-triazole hybrids. METHODS: The designed oxazolone-1,2,3-triazole hybrids were synthesized using copper(I)-catalyzed azide-alkyne cycloaddition. The antimicrobial evaluation was carried out using serial dilution method. RESULTS: Most of the synthesized hybrids showed significant antimicrobial properties. Some of the compounds were found to be possessing better or comparable activity to that of the standards used. The docking simulations results are also in agreement with the antimicrobial activity data. CONCLUSION: Sixteen new hybrids were synthesized and tested in vitro for their antimicrobial activity. Some of the tested compounds exhibited promising antimicrobial activity and could be utilized for the development of the lead compounds for new and more potent antimicrobial drugs.

Synthesis, crystal structure and antimicrobial potential of some fluorinated chalcone-1,2,3-triazole conjugates.

A simple and green synthesis of some fluorinated chalcone-triazole hybrids from propargylated chalcones and organic azides catalyzed by cellulose supported copper nanoparticles click reaction is reported. All the synthesized compounds were well characterized by various analytical and spectroscopic methods. The X-rays crystallographic study of compounds 6k revealed the self assembling properties. The antimicrobial screening results of all the synthesized compounds revealed that most of the triazole hybrids exhibited significant efficacy against tested bacterial and fungal strains. The activity results showed the synergistic effect of biological activity when two pharmacophoric units, i.e. chalcone and 1,2,3-triazole are conjugated. Further, docking simulation of the most active compounds 6p into Escherichia coli topoisomerase II DNA Gyrase B was also carried out.

Design, synthesis, characterization, antimicrobial evaluation and molecular modeling studies of some dehydroacetic acid-chalcone-1,2,3-triazole hybrids.

A series of new dehydroacetic acid chalcone-1,2,3-triazole hybrids as potential antimicrobial agents was designed, synthesized and characterized by FTIR, NMR and HRMS spectral techniques. All the synthesized compounds were screened in vitro against four bacterial strains (Staphylococcus epidermidis, Bacillus subtilis, Escherichia coli and Pseudomonas aeruginosa) and two fungal strains (Aspergillus niger and Candida albicans). The antimicrobial results indicated that some of the compounds showed remarkable activities comparable to the standard drugs. Most of the compounds exhibited better efficacy compared to the DHA, which is itself an antimicrobial agent. The synergistic effect in biological activity was observed when DHA, chalcone and 1,2,3-triazole are conjugated. The molecular modeling studies of compound 5j into E. coli topoisomerase II DNA gyrase B were also performed.

Recent Advancements in 1,4-Disubstituted 1H-1,2,3-Triazoles as Potential Anticancer Agents.

Cancer is a class of formidable disease with high degree of mortality. Despite much progress in chemotherapy, the problem of drug resistance has led to the search for newer leads with superior efficacy. 1,2,3- Triazoles are among a vast number of nitrogen containing heterocycles studied extensively as pharmacologically important scaffolds. Recently developed copper(I)-catalyzed cycloaddition reaction between organic azides and terminal alkynes yielding 1,4-disubstituted 1,2,3-triazoles has attracted considerable attention because it allows the construction of a vast array of 1,2,3-triazoles with significant potential in pharmaceutical chemistry. In this article, an attempt to summarize the wide range of anticancer agents derived from copper(I)-catalyzed azide alkyne cycloaddition reported by the authors worldwide, has been made. This review includes articles published from 2010 onwards and summarizes the recent progress on the development of 1,4-disubstituted 1H-1,2,3-triazoles as novel anticancer chemotypes with high therapeutic indices.

Green synthesis and anticancer potential of chalcone linked-1,2,3-triazoles.

A series of chalcone linked-1,2,3-triazoles was synthesized via cellulose supported copper nanoparticle catalyzed click reaction in water. The structures of all the compounds were analyzed by IR, NMR and Mass spectral techniques. All the synthesized products were subjected to 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyltetrazolium bromide (MTT) cytotoxicity assay against a panel of four human cancer cell lines (MCF-7, MIA-Pa-Ca-2, A549, HepG2) to check their anticancer potential. Compound 6h was found to be most active against all the tested cancer cell lines with IC50 values in the range of 4-11 µM and showed better or comparable activity to the reference drug against all the tested cell lines. Cell cycle analysis revealed that compound 6h induces apoptosis and G2/S arrest in MIA-Pa-Ca-2 cells. Compound 6h triggers mitochondrial potential loss in pancreatic cancer MIA-Pa-Ca-2 cells. Further, Compound 6h also triggers caspase-3 and PARP-1 cleavage, which increases in dose dependent manner.