Hydrazone-Tethered 5-(Pyridin-4-yl)-4H-1,2,4-triazole-3-thiol Hybrids: Synthesis, Characterisation, in silico ADME Studies, and in†vitro Antimycobacterial Evaluation and Cytotoxicity.

Compounds containing arylpyrrole-, 1,2,4-triazole- and hydrazone structural frameworks have been widely studied and demonstrated to exhibit a wide range of pharmacological properties. Herein, an exploratory series of new 1,2,4-triazole derivatives designed by amalgamation of arylpyrrole and 1,2,4-triazole structural units via a hydrazone linkage is reported. The synthesised compounds were tested in vitro for their potential activity against Mycobacterium tuberculosis (MTB) H37 Rv strain. The most promising compound 13 - the derivative without the benzene ring appended to the pyrrole unit displayed acceptable activity (MIC90 =3.99 µM) against MTB H37 Rv, while other compounds from the series exhibited modest to weak antimycobacterial activity with MIC90 values in the range between 7.0 and >125 µM. Furthermore, in silico results, predicated using the SwissADME web tool, show that the prepared compounds display desirable ADME profile with parameters within acceptable range.

Synthesis of 1,2,3-Triazole-Containing 2,3-Dihydrofuran Derivatives, Evaluation of Anticancer Activity and Molecular Docking Studies

A simple and convenient one-pot three-component method to synthesize 1,2,3-triazole-based 2,3-dihydrofuran derivatives from the condensation of 5,5-dimethylcyclohexane-1,3-dione, substituted phenacyl bromide, triethylamine and 1,2,3-triazole based benzaldehyde using a mixture of CH3CN/water as a reaction medium is described. The current protocol delivers numerous advantages such as good yield, short reaction time, easy work-up and simplicity in the procedure as it uses a green method and an eco-friendly catalyst. The target compounds are screened for their in-vitro anticancer activity and most of the compounds are found to exhibit promising activity compared to standard drug Doxorubicin. Molecular docking studies performed on caspase-3 and COVID-19 main protease revealed well defined binding interactions and docking scores.

Regioselective Synthesis and Molecular Docking Studies of 1,5-Disubstituted 1,2,3-Triazole Derivatives of Pyrimidine Nucleobases.

1,2,3-triazoles are versatile building blocks with growing interest in medicinal chemistry. For this reason, organic chemistry focuses on the development of new synthetic pathways to obtain 1,2,3-triazole derivatives, especially with pyridine moieties. In this work, a novel series of 1,5-disubstituted-1,2,3-triazoles functionalized with pyrimidine nucleobases were prepared via 1,3-dipolar cycloaddition reaction in a regioselective manner for the first time. The N1-propargyl nucleobases, used as an alkyne intermediate, were obtained in high yields (87-92%) with a new two-step procedure that selectively led to the monoalkylated compounds. Then, FeCl3 was employed as an efficient Lewis acid catalyst for 1,3-dipolar cycloaddition between different aryl and benzyl azides and the N1-propargyl nucleobases previously synthesized. This new protocol allows the synthesis of a series of new 1,2,3-triazole derivatives with good to excellent yields (82-92%). The ADME (Absorption, Distribution, Metabolism, and Excretion) analysis showed good pharmacokinetic properties and no violations of Lipinsky's rules, suggesting an appropriate drug likeness for these new compounds. Molecular docking simulations, conducted on different targets, revealed that two of these new hybrids could be potential ligands for viral and bacterial protein receptors such as human norovirus capsid protein, SARS-CoV-2 NSP13 helicase, and metallo-ß-lactamase.

Acute Kidney Injury Following Posaconazole for Mucormycosis: SARS-CoV-2 as a Back-Seat Driver.

Viruses have been implicated in the causation of several systemic illnesses, either directly or by immune modulation. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is not an exception. Due to altered immune regulation, it is often associated with novel clinical manifestations and complications which have not been reported before. SARS-CoV-2 induces a pro-inflammatory state which makes the patient vulnerable to developing a variety of previously unreported adverse reactions to medications. Coronavirus disease 2019 (COVID-19) and its treatment have provided a fertile ground for various opportunistic infections including mucormycosis. The standard treatment for mucormycosis is surgical debridement and liposomal amphotericin B. Triazole antifungals such as posaconazole and isavuconazonium are the second-line agents for those intolerant to first-line therapy. Posaconazole is safer than amphotericin B as far as renal adverse effects are concerned. We report the case of a 60-year-old lady with type 2 diabetes mellitus, hypertension, ischemic heart disease, and osteoarthritis. She had severe COVID-19 requiring non-invasive ventilation four months ago. She presented with right rhino-orbital swelling, diplopia, and serosanguinous discharge from the right nostril. She had right third, sixth, and seventh cranial nerve palsies. Magnetic resonance imaging revealed right maxillary, ethmoid, and frontal sinusitis. Biopsy from the right nostril confirmed mucormycosis. Having normal renal and liver functions, she was started on oral posaconazole as she had an allergic reaction to a test dose of 1 mg amphotericin B (non-liposomal) in 20 mL of 5% dextrose water infused over 30 minutes. On day five, she developed acute kidney injury requiring renal replacement therapy. Her posaconazole was stopped. As she was not improving with conservative treatment, an ultrasound-guided, percutaneous renal biopsy was performed from the left kidney. The renal biopsy revealed thrombotic microangiopathy. She was started on liposomal amphotericin B as decided by the multidisciplinary team. Her renal function improved, and she continued on liposomal amphotericin B. We conclude that thrombotic microangiopathy, in this case, was likely due to posaconazole. This is a novel adverse effect presumably of posaconazole. This case report will alert physicians to be vigilant of the renal adverse effects of posaconazole in patients who have had COVID-19. Patients who develop renal injury while on posaconazole should undergo an early renal biopsy to ascertain the exact histopathology.

Towards Covid-19 TMPRSS2 enzyme inhibitors and antimicrobial agents: Synthesis, antimicrobial potency, molecular docking, and drug-likeness prediction of thiadiazole-triazole hybrids.

1,3,4-Thiadiazole analogues 3 and 4 were synthesised via the reaction of 1-(5-methyl-1-(5-(methylthio)-1,3,4-thiadiazol-2-yl)-1H-1,2,3-triazol-4-yl)ethan-1one 2 with vanillin or thiophene-2-carboxaldhyde, respectively through chalcone reaction. Compounds 3 and 4 were submitted to react with thiosemicarbazide affording 5-(4­hydroxy-3-methoxyphenyl)-3-(5-methyl-1-(5-(methylthio)-1,3,4-thiadiazol-2-yl)-1H-1,2,3-triazol-4-yl)-4,5-dihydro-1H-pyrazole-1-carbothioamide (5) give 3-(5-methyl-1-(5-(methylthio)-1,3,4-thiadiazol-2-yl)-1H-1,2,3-triazol-4-yl)-5-(thiophen-2-yl)-4,5 dihydro-1H-pyrazole-1-carbothioamide (6), respectively. The letters were reacted with N-(4-chlorophenyl)-2-oxopropanehydrazonoyl chloride to give compounds 7 and 8. The chemical compositions of the novel compounds were affirmed by spectral and microanalytical data. Meanwhile, all the newly synthesized compounds have been screened for their ability to prevent the proliferation of different pathogens named Escherichia coli, Pseudomonas aeruginosa, Bacillus subtilis, Staphylococcus aureus, and Candida albicans in vitro. Additionally, the potency of the newly synthesized compounds to be anti-COVID-19 candidates was studied through a molecular docking study. The newly prepared molecules 2-8 were studied in silico against transmembrane serine protease 2 (TMPRSS2) to identify their potential therapeutic activity against Coronavirus. Moreover, the drug-likeness of the compounds was tested theoretically by ADMET studies. Compound 8 exhibited a better binding affinity (-9.1 kcal/mol) against the target enzyme TMPRSS2. Additionally, it respects Lipinski's rule of five and has acceptable ADMET properties, indicating that compound 8 could be interesting for the treatment of Covid-19.

Triazoles and Their Derivatives: Chemistry, Synthesis, and Therapeutic Applications.

Among the nitrogen-containing heterocyclic compounds, triazoles emerge with superior pharmacological applications. Structurally, there are two types of five-membered triazoles: 1,2,3-triazole and 1,2,4-triazole. Due to the structural characteristics, both 1,2,3- and 1,2,4-triazoles are able to accommodate a broad range of substituents (electrophiles and nucleophiles) around the core structures and pave the way for the construction of diverse novel bioactive molecules. Both the triazoles and their derivatives have significant biological properties including antimicrobial, antiviral, antitubercular, anticancer, anticonvulsant, analgesic, antioxidant, anti-inflammatory, and antidepressant activities. These are also important in organocatalysis, agrochemicals, and materials science. Thus, they have a broad range of therapeutic applications with ever-widening future scope across scientific disciplines. However, adverse events such as hepatotoxicity and hormonal problems lead to a careful revision of the azole family to obtain higher efficacy with minimum side effects. This review focuses on the structural features, synthesis, and notable therapeutic applications of triazoles and related compounds.

Expanding the chemical space of 3(5)-functionalized 1,2,4-triazoles.

An efficient approach to the gram-scale synthesis of 3(5)-substituted, 1,3- and 1,5-disubstituted 1,2,4-triazole-derived building blocks is described. The key synthetic precursors - 1,2,4-triazole-3(5)-carboxylates (20 examples, 35-89% yield) were prepared from readily available acyl hydrazides and ethyl 2-ethoxy-2-iminoacetate hydrochloride. Further transformations were performed following the convergent synthetic strategy and allowed the preparation of 1,3- and 1,5-disubstituted 1,2,4-triazole-derived esters (16 examples, 25-75% yield), 3(5)-substituted, 1,3- and 1,5-disubstituted carboxylate salts (18 examples, 78-93% yield), amides (5 examples, 82-93% yield), nitriles (5 examples, 30-85% yield), hydrazides (6 examples, 84-89% yield), and hydroxamic acids (3 examples, 73-78% yield). Considering wide applications of the 1,2,4-triazole motif in medicinal chemistry, these compounds are valuable building blocks for lead-oriented synthesis; they have also great potential for coordination chemistry. Supplementary Information: The online version contains supplementary material available at 10.1007/s10593-022-03064-z.

Synthesis of 1,3,4-Thiadiazole Derivatives Using Hydrazonoyl Bromide: Molecular Docking and Computational Studies

Alkyl phenylcarbamodithioates were reacted with hydrazonoyl bromide 1a, b in ethanol containing a catalytic amount of triethylamine solution to afford and 1,3,4-thiadiazole derevatives 5a, b, respectively. In the same manner, alkyl hydrazinecarbodithioate (6-10)a, b were reacted with the appropriate hydrazonoyl bromide (1a, b) in ethanol containing a catalytic amount of triethylamine solution to afford 1,3,4-thiadiazole derivatives (13-17), respectively. Moreover, hydrazonoyl bromide 1a or 1b was reacted with 5-phenyl-1,3,4-oxadiazole-2-thione 22A in refluxing chloroform containing triethylamine to give 1,3,4-thiadiazole derivatives 21a and b, respectively. Elemental analysis, spectral data, and an alternative synthetic route were used to confirm the structures of all the newly synthesized heterocyclic compounds. AutoDock was used to screen possible drugs. To screen potential medications, AutoDock was utilized. The antiviral medications chloroquine, hydroxychloroquine, and Lopinavir, as well as their synthesized components, were all tested. Confirmation comes from molecular docking and computational investigations. The results of a detailed exploration of the structural characterization of 5b and 13b using quantum chemistry methods calculated using the DFT (B3LYP) method with a 6-31 + g (d, p) basis set are presented in the computational study. The goal of this study was to investigate the molecular dynamics and structural characteristics that regulate chemical behavior, as well as to compare theoretical predictions with experimental results.

Drug repurposing of triazoles against mucormycosis using molecular docking: A short communication.

BACKGROUND: Mucormycosis, a fungal infection caused by Rhizopus species is on the rise in COVID-19 patients as a result of their suppressed immunity. The current therapies include systemic administration of Amphotericin B. HYPOTHESIS AND METHOD: We screened several triazole broad-spectrum antifungal agents against the therapeutic target in mucormycosis using computational techniques like molecular docking and compared them with isavuconazole, an approved drug. RESULT: The study concluded that 4 triazole drugs, pramiconazole, itraconazole, posaconazole and ketoconazole were strong candidates to be further evaluated and developed as a treatment for mucormycosis. CONCLUSION: Novel topical and oral therapies could be developed from these drug leads.

[Individualized antifungal therapy in critically ill patients with invasive fungal infection]. / Tratamiento antifúngico individualizado en el paciente crítico con infección fúngica invasora.

Invasive candidiasis (IC) is the most common invasive fungal infection (IFI) affecting critically ill patients, followed by invasive pulmonary aspergillosis (IPA). International guidelines provide different recommendations for a first-line antifungal therapy and, in most of them, echinocandins are considered the first-line treatment for IC, and triazoles are so for the treatment of IPA. However, liposomal amphotericinB (L-AmB) is still considered a second-line therapy for both clinical entities. Although in the last decade the management of IFI has improved, several controversies persist. The antifungal drugs currently available may have a suboptimal activity, or be wrongly used in certain IFI involving critically ill patients. The aim of this review is to analyze when to provide individualized antifungal therapy to critically ill patients suffering from IFI, emphasizing the role of L-AmB. Drug-drug interactions, the clinical status, infectious foci (peritoneal candidiasis is discussed), the fungal species involved, and the need of monitoring the concentration of the antifungal drug in the patient are considered.

Inhibitory effects of novel 1,4-disubstituted 1,2,3-triazole compounds on quorum-sensing of P. aeruginosa PAO1.

Quorum sensing (QS) inhibition is an essential strategy to combat bacterial infection. Previously, we have synthesized a series of thymidine derivatives bearing isoxazole and 1,2,3-triazole rings (TITL). Herein, the inhibitory effects of TITL on QS of Pseudomonas aeruginosa PAO1 were evaluated. In vitro results demonstrated that TITL effectively inhibited biofilm formation and reduced the virulence factors of P. aeruginosa PAO1. In combination with antibiotics, our TITL compounds significantly prolonged the lifespans of Caenorhabditis elegans N2 nematodes that were infected with P. aeruginosa PAO1 in vivo. In conclusion, TITL compounds are promising candidates for the treatment of antibiotic-resistant P. aeruginosa PAO1.

Advance of structural modification of nucleosides scaffold.

With Remdesivir being approved by FDA as a drug for the treatment of Corona Virus Disease 2019 (COVID-19), nucleoside drugs have once again received widespread attention in the medical community. Herein, we summarized modification of traditional nucleoside framework (sugar + base), traizole nucleosides, nucleoside analogues assembled by other drugs, macromolecule-modified nucleosides, and their bioactivity rules. 2'-"Ara"-substituted by -F or -CN group, and 3'-"ara" substituted by acetylenyl group can greatly influence their anti-tumor activities. Dideoxy dehydrogenation of 2',3'-sites can enhance antiviral efficiencies. Acyclic nucleosides and L-type nucleosides mainly represented antiviral capabilities. 5-F Substituted uracil analogues exihibit anti-tumor effects, and the substrates substituted by -I, -CF3, bromovinyl group usually show antiviral activities. The sugar coupled with 1-N of triazolid usually displays anti-tumor efficiencies, while the sugar coupled with 2-N of triazolid mainly represents antiviral activities. The nucleoside analogues assembled by cholesterol, polyethylene glycol, fatty acid and phospholipid would improve their bioavailabilities and bioactivities, or reduce their toxicities.