Azole Derivatives Research Articles

Highly Active, Entirely Biobased Antimicrobial Pickering Emulsions.

We present the development of surfactant-free, silica-free and fully biobased oil-in-water antimicrobial Pickering emulsions, based on the self-assembly of β-cyclodextrin and phytoantimicrobial oils (terpinen-4-ol or carvacrol). Undecylenic acid (UA), derived from castor oil, can be used as bio-based drug to treat fungal infection, but is less effective than petroleum-based drugs as azole derivatives. To maximize its antifungal potential, we have incorporated UA in fully biobased Pickering emulsions. These emulsions are effective against fungi, Gram-positive and Gram-negative bacteria. The carvacrol emulsion charged with UA is +390 % and +165 % more potent against methicillin-resistant S. aureus (MRSA), compared to UA and azole-based commercial formulations. Moreover, this emulsion is up to +480 % more efficient that UA ointment against C. albicans. Finally, remarkable eradication of E. coli and MRSA biofilms was obtained with this environmental-friendly emulsion.

Design and In silico Studies of 2,5-Disubstituted 1,2,4-Triazole and 1,3,4-Thiadiazole Derivatives as Pteridine Reductase 1 Inhibitors

Aims: Design and in silico studies of 2,5-disubstituted triazole and thiadiazole derivatives as Pteridine Reductase 1 inhibitors. With a view to develop effective agents against Leishmaniasis, 2-substituted-5-[(1H-benzimidazol-2yl) methyl] azole derivatives (A1-A12) were designed against the target enzyme Pteridine reductase 1.
 Methodology: The series was designed by targeting Pteridine reductase 1 which is an enzyme responsible for folate and pterin metabolism. Based on thorough study of the enzyme structure and structural features of ligands required for optimum interaction with the enzyme, a series of 12 compounds consisting of 2,5-disubstituted 1,2,4-triazole and 1,3,4-thiadiazole derivatives was designed. In silico studies were carried out which included docking studies (using V Life software) to understand binding of the compounds with enzyme PTR1, ADMET studies, drug likeness studies for physicochemical properties and bioactivity studies to understand the possible mechanism of action of the compounds. These studies were undertaken using online softwares, molinspiration and admetSAR web servers.
 Results: Compounds A10 and A12 gave the best docking scores of -59.9765 and -60.4373 respectively that were close to dihydrobiopterin (original substrate). All the compounds complied with Lipinski’s rule of five. Most of the compounds displayed favorable ADMET properties.
 Conclusion: The 2,5-disubstituted 1,2,4-triazole and 1,3,4-thiadiazole derivatives exhibited good binding affinity for PTR1 enzyme (PDB code: 1E92). The docking scores indicated that enzyme binding may be governed by the nature and size of the substituents on the azole ring. The compounds display well-defined drug-like and pharmacokinetic properties based on Lipinski’s rule of five with additional physicochemical and ADMET parameters. Bioactivity studies suggested the possible drug mechanism as enzyme inhibition. Hence, this study provides evidence for consideration of valuable ligands in 2,5-disubstituted 1,2,4-triazole and 1,3,4-thiadiazole derivatives as potential pteridine reductase 1 inhibitor and further in vitro and in vivo investigations may prove its therapeutic potential.

Association of azole antifungals with survival in patients with non-small cell lung cancer receiving immunotherapy.

e18777 Background: Preclinical data suggest certain azole derivatives may have antitumor efficacy and modulate responses to immune checkpoint inhibitors (ICIs). Clinical evidence of synergy can support ongoing research that is investigating the role of repurposing current FDA-approved azole medications to improve outcomes in people with non-small cell lung cancer (NSCLC). We evaluated the association of concomitant azole drugs in a population of NSCLC patients treated with ICI within the Veterans Health Administration. Methods: We conducted a retrospective cohort study of veterans diagnosed with NSCLC between 2010-2018 who were treated with ICI. Receipt of azole drugs was defined as taking a systemic azole within 90 days of ICI therapy. Overall survival (OS) was measured from the start of ICI therapy using Cox-Proportional Hazard (PH) multivariable regression. Patients whose earliest azole administration occurred more than 30 days after initiation of ICI were excluded. Results: We identified 3,413 Veterans treated with ICI; of these, 324 (9.5%) were treated with an azole, most commonly clotrimazole (3.0%) and fluconazole (2.5%). Patients had predominantly stage IV disease (40.8%) at initial diagnosis, followed by stage III (27.1%), stage I-II (19.9%), and unknown stage (12.1%). There was no significant difference in OS multivariable analysis (HR = 0.93 [0.81-1.06]; p = 0.28). Propensity score-matched analysis with 324 patients in each cohort also did not measure a significant difference in OS (HR = 0.89 [0.75-1.06]; p = 0.18) between patients who received any azole versus those who did not. When evaluating specific azole agents on multivariable analysis, there was an association of higher OS with receipt of clotrimazole (HR = 0.72 [0.56 – 0.92]; p = 0.009) and more than one azole (HR = 0.71 [0.53-0.96]; p = 0.026) when compared with no azole. There was an association of shorter OS with miconazole (HR = 1.92 [1.30-2.832]; p = 0.001) and no association with itraconazole (p = 0.08), fluconazole (p = 0.20), or ketoconazole (p = 0.87). In the matched analysis of 102 clotrimazole patients versus no azole, OS was longer in patients who received clotrimazole (HR = 0.76; 95% CI 0.55 – 1.04; p = 0.087), although this effect was not statistically significant. Conclusions: This analysis demonstrated a trend towards longer survival with concomitant clotrimazole and ICI for advanced NSCLC. This association was not seen for other azole mediations.

Design and synthesis of new 4-methylthiazole derivatives: In vitro and in silico studies of antimicrobial activity

The development of resistance against antimicrobial drugs has become a world-wide issue. It is predicted that some or perhaps all the antimicrobial drugs used in clinics will be out of the treatment protocols soon. Therefore, researchers pay more attention to the development of new antimicrobial drugs. For this purpose, we designed and synthesized new 4-methylthiazole-(benz)azole derivatives. The structural elucidation of the compounds was performed by 1H-NMR, 13C-NMR, HSQC, NOESY, HMBC and LC/MS-IT-TOF spectral and elemental analyses. Then, their antimicrobial activity against bacteria and fungi strains was tested. The antibacterial effect of the compounds was found valuable as compared with their anticandidal activity. By combining the findings with molecular docking results, structure-activity relationship (SAR) was explained. Thus, in the development of new antimicrobial agents which can be used as DNA gyrase inhibitors, SAR showed that the products might be used in the discovery of new antimicrobials where their activity is owed to the allosteric effect. Although the effect of compound 3f was modest compared to the reference compound, it was better than the other synthesized compounds. Also, compound 3f has a better allosteric effect and might be a good lead candidate to synthesize new and better active hits. In addition, it was observed that all the synthesized compounds showed half potency against P. aeruginosa compared to the reference drug. On the other hand, no significant difference was seen between compounds against gram-positive or gram-negative bacteria. Briefly, meaningful data to correlate the SAR with thiazole-(benz)azole hybridized compounds were presented in this study. In future projects, the mentioned ideas can be used to synthesize new compounds having better antibacterial activity, particularly against resistant organisms.

Structural Analysis, Antifungal Activity and Molecular Docking Study of a Compound Isolated from Streptomyces species

Background: The emergence of drug resistance is the biggest threat; consequently, novel antimicrobial agents from natural sources is the need of the hour. This study was designed to isolate and evaluate a bioactive compound from actinomycete against human pathogens. Methods: In search of a new antimicrobial compound with enhanced potency, several actinomycetes were isolated and screened for their anidermatophytic acitivity. The bioactive compound was extracted and purified by chromatographic technique. The structure of the extracted bio active compound was elucidated by mass and NMR data. The synthesized bioactive compound was further tested for its antidermatophytic activity by the micro broth dilution method. Results: Streptomyces ARITM 03 was isolated that exhibited antifungal activity against human pathogenic fungi by primary and secondary screening methods. The MIC of bioactive compound was found to be 1250, 312.5 and 2500 μg/ml against tested fungal pathogens A. niger, C. albicans and M. canis, respectively. Chromatography analysis of active metabolite showed a single spot having Rf value of 0.74 and FT-IR spectrum displaying the presence of OH, CO=NH2 functional amide group, and C=O keto groups in the structure. The mass and NMR spectra revealed the molecular formula C26H44N4O6 of bioactive compound. The azole derivative showed an acceptable docking score and exhibited a greater zone of inhibition in comparison to the other compounds. Conclusion: The results presented in this paper provided an insight into the capability of Streptomyces sp. ARITM03 as a potential source of bioactive secondary metabolites compound a molecule to develop other azoles, to be used clinically to overcome adverse effects like gynecomastia and hepatotoxicity due to extensive use of current azole antifungal agents.

Synthesis and Antibacterial Activity of New Azole, Diazole and Triazole Derivatives Based on p-Aminobenzoic Acid.

The p-aminobenzoic acid was applied for the synthesis of substituted 1-phenyl-5-oxopyrrolidine derivatives containing benzimidazole, azole, oxadiazole, triazole, dihydrazone, and dithiosemicarbazide moieties in the structure. All the obtained compounds were evaluated for their in vitro antimicrobial activity against Staphylococcus aureus, Bacillus cereus, Listeria monocytogenes, Salmonella enteritidis, Escherichia coli, and Pseudomonas aeruginosa by using MIC and MBC assays. This study showed a good bactericidal activity of γ-amino acid and benzimidazoles derivatives. The antimicrobial activity of the most promising compounds was higher than ampicillin. Furthermore, two benzimidazoles demonstrated good antimicrobial activity against L. monocytogenes (MIC 15.62 µg/mL) that was four times more potent than ampicillin (MIC 65 µg/mL). Further studies are needed to better understand the mechanism of the antimicrobial activity as well as to generate antimicrobial compounds based on the 1-phenyl-5-oxopyrrolidine scaffold.

A High Rate of Recurrent Vulvovaginal Candidiasis and Therapeutic Failure of Azole Derivatives Among Iranian Women.

Recurrent vulvovaginal candidiasis (RVVC) is one of the most prevalent fungal infections in humans, especially in developing countries; however, it is underestimated and regarded as an easy-to-treat condition. RVVC may be caused by dysbiosis of the microbiome and other host-, pathogen-, and antifungal drug-related factors. Although multiple studies on host-related factors affecting the outcome have been conducted, such studies on Candida-derived factors and their association with RVVC are lacking. Thus, fluconazole-tolerant (FLZT) isolates may cause fluconazole therapeutic failure (FTF), but this concept has not been assessed in the context of Candida-associated vaginitis. Iran is among the countries with the highest burden of RVVC; however, comprehensive studies detailing the clinical and microbiological features of this complication are scarce. Therefore, we conducted a 1-year prospective study with the aim to determine the RVVC burden among women referred to a gynecology hospital in Tehran, the association of the previous exposure to clotrimazole and fluconazole with the emergence of FLZT and fluconazole-resistant (FLZR) Candida isolates, and the relevance of these phenotypes to FTF. The results indicated that about 53% of the patients (43/81) experienced RVVC. Candida albicans and C. glabrata constituted approximately 90% of the yeast isolates (72 patients). Except for one FLZT C. tropicalis isolate, FLZR and FLZT phenotypes were detected exclusively in patients with RVVC; among them, 27.9% (12/43) harbored FLZR strains. C. albicans constituted 81.2% of FLZR (13/16) and 100% of the FLZT (13/13) isolates, respectively, and both phenotypes were likely responsible for FTF, which was also observed among patients with RVVC infected with fluconazole-susceptible isolates. Thus, FTF could be due to host-, drug-, and pathogen-related characteristics. Our study indicates that FLZT and FLZR isolates may arise following the exposure to over-the-counter (OTC) topical azole (clotrimazole) and that both phenotypes can cause FTF. Therefore, the widespread use of OTC azoles can influence fluconazole therapeutic success, highlighting the necessity of controlling the use of weak topical antifungals among Iranian women.

DNA-Encoded Libraries: Hydrazide as a Pluripotent Precursor for On-DNA Synthesis of Various Azole Derivatives.

DNA-encoded combinatorial chemical library (DEL) technology, an approach that combines the power of genetics and chemistry, has emerged as an invaluable tool in drug discovery. Skeletal diversity plays a fundamental importance in DEL applications, and relies heavily on novel DNA-compatible chemical reactions. We report herein a phylogenic chemical transformation strategy using DNA-conjugated benzoyl hydrazine as a common versatile precursor in azole chemical expansion of DELs. DNA-compatible reactions deriving from the common benzoyl hydrazine precursor showed excellent functional group tolerance with exceptional efficiency in the synthesis of various azoles, including oxadiazoles, thiadiazoles, and triazoles, under mild reaction conditions. The phylogenic chemical transformation strategy provides DELs a facile way to expand into various unique chemical spaces with privileged scaffolds and pharmacophores.

Synthesis, structure and computational study of 5-[(prop-2-en-1-yl)sulfanyl]-1,3,4-thiadiazol-2-amine (Pesta) and its heterometallic π,σ-complex [Cu2FeCl2(Pesta)4][FeCl4

Copper(I) π-coordination compounds with allyl derivatives of azoles are an interesting subject of current research, but CuI π-complexes with other transition-metal ions incorporated in the structure have been virtually uninvestigated. The present work is directed toward the synthesis and structural characterization of the novel heterometallic CuI/FeII π-complex di-μ2-chlorido-1:2κ2Cl;2:3κ2Cl-tetrakis[μ2-5-(prop-2-en-1-ylsulfanyl)-1,3,4-thiadiazol-2-amine]-1:2κ2N4:N3;1(η2),κN4:2κN3;2:3κ2N3:N4;2κN3:3(η2),κN4-dicopper(I)iron(II) tetrachloridoferrate(II), [Cu2FeCl2(C5H7N3S2)4][FeCl4] (1). The structure of the 5-[(prop-2-en-1-yl)sulfanyl]-1,3,4-thiadiazol-2-amine (Pesta, C5H7N3S2) ligand is also presented. The cationic substructure in 1 consists of one FeII and two CuI ions bridged by two chloride ions along with two σ,σ- and two π,σ-coordinated ligands, whereas the anionic part is built of isolated tetrahedral [FeCl4]2- ions. π-Coordination of the Pesta allyl group to the CuI ions prevents agglomeration of the inorganic Cu-Cl-Fe-Cl-Cu part into infinate chains. An energy framework computational analysis was performed for Pesta.

Cytoskeletal Alteration Is an Early Cellular Response in Pulmonary Epithelium Infected with Aspergillus fumigatus Rather than Scedosporium apiospermum.

Invasive aspergillosis and scedosporiosis are life-threatening fungal infections with similar clinical manifestations in immunocompromised patients. Contrarily, Scedosporium apiospermum is susceptible to some azole derivative but often resistant to amphotericin B. Histopathological examination alone cannot diagnose these two fungal species. Pathogenesis studies could contribute to explore candidate protein markers for new diagnosis and treatment methods leading to a decrease in mortality. In the present study, proteomics was conducted to identify significantly altered proteins in A549 cells infected with or without Aspergillus fumigatus and S. apiospermum as measured at initial invasion. Protein validation was performed with immunogold labelling alongside immunohistochemical techniques in infected A549 cells and lungs from murine models. Further, cytokine production was measured, using the Bio-Plex-Multiplex immunoassay. The cytoskeletal proteins HSPA9, PA2G4, VAT1, PSMA2, PEX1, PTGES3, KRT1, KRT9, CLIP1 and CLEC20A were mainly changed during A. fumigatus infection, while the immunologically activated proteins WNT7A, GAPDH and ANXA2 were principally altered during S. apiospermum infection. These proteins are involved in fungal internalisation and structural destruction leading to pulmonary disorders. Interleukin (IL)-21, IL-1α, IL-22, IL-2, IL-8, IL-12, IL-17A, interferon-γ and tumour necrosis factor-α were upregulated in both aspergillosis and scedosporiosis, although more predominately in the latter, in accordance with chitin synthase-1 and matrix metalloproteinase levels. Our results demonstrated that during invasion, A. fumigatus primarily altered host cellular integrity, whereas S. apiospermum chiefly induced and extensively modulated host immune responses.

Azole-triphenylphosphonium conjugates combat antifungal resistance and alleviate the development of drug-resistance

Azole antifungals are commonly used to treat fungal infections but have resulted in the occurrence of drug resistance. Therefore, developing azole derivatives (AZDs) that can both combat established drug-resistant fungal strains and evade drug resistance is of great importance. In this study, we synthesized a series of AZDs with a fluconazole (FLC) skeleton conjugated with a mitochondria-targeting triphenylphosphonium cation (TPP+). These AZDs displayed potent activity against both azole-sensitive and azole-resistant Candida strains without eliciting obvious resistance. Moreover, two representative AZDs, 20 and 25, exerted synergistic antifungal activity with Hsp90 inhibitors against C. albicans strains resistant to the combination treatment of FLC and Hsp90 inhibitors. AZD 25, which had minimal cytotoxicity, was effective in preventing C. albicans biofilm formation. Mechanistic investigation revealed that AZD 25 inhibited the biosynthesis of the fungal membrane component ergosterol and interfered with mitochondrial function. Our findings provide an alternative approach to address fungal resistance problems.

Correlation of Trichosporon asahii Genotypes with Anatomical Sites and Antifungal Susceptibility Profiles: Data Analyses from 284 Isolates Collected in the Last 22 Years across 24 Medical Centers.

Trichosporon asahii is an opportunistic fungal pathogen that can cause severe infections with high mortality rates. Azole derivatives are the best-targeted therapy for T. asahii invasive infections, but azole-resistant isolates have been reported. To investigate peculiarities in the antifungal susceptibility profile (ASP) of T. asahii clinical isolates, we analyzed the genotype distribution, isolation sources, and ASP of 284 strains collected from 1997 to 2019 in different Brazilian medical centers. Species identification and genotype characterization were performed by analysis of the intergenic spacer (IGS1) region of the ribosomal DNA (rDNA). Antifungal susceptibility testing (AST) for amphotericin B and azoles was with the CLSI M27, 4th edition, microdilution broth method. Trends in the ASP of Brazilian T. asahii isolates were investigated using epidemiological cutoff values. Five different genotypes were found among the 284 isolates tested (G1, 76%; G3, 10%; G4, 3%; G5, 7%; and G7, 4%). The isolates were collected mainly from urine (55%) and blood/catheter tip samples (25%) where G1 was the most frequent genotype found (P < 0.05). The G7 isolates exhibited the highest MIC90 values for azoles compared to those for the other genotypes (P < 0.05). Genotype 7 isolates also contributed to the increasing rates of voriconazole non-wild-type isolates found in recent years (P = 0.02). No significant differences were found among the AST results generated by isolates cultured from different anatomical sites. Monitoring T. asahii genotype distributions and antifungal susceptibility profiles is warranted to prevent the spread of azole-resistant isolates.

Chebulinic Acid for Alternative Treatment of Vulvovaginal Candidiasis by Targeting Agglutinin-Like Sequence Protein 3 in Candida albicans: In silico Approach

Chebulinic acid, a chemotaxonamic marker of Terminalia chebula has been described in Ayurveda, Unani and homeopathy traditional medicinal system for the treatment of various fungal diseases. Almost 70-80 % of women are currently affected from vulvovaginal candidiasis and the overgrowth of Candida albicans is the major reason behind it. The aim of the present study was to determine the efficacy of chebulinic acid in inhibiting adhesion as well as growth of Candida albicans inside the host in comparison with currently available azole derivatives in the market. The inhibitory effect of chebulinic acid was determined by spectrophotometric growth curve analysis reflecting 10 % lower minimum inhibitory concentration value of fluconazole, ketaconazole, itraconazole and chebulinic acid. Virtual docking study was carried out at catalytic domain of agglutinin-like sequence protein 3 chain A and B respectively, to determine the binding affinity and its active binding sites. Chebulinic acid exhibited high sensitivity against Candida albicans with minimum inhibitory concentration of (0.025 μg/ml) followed by ketaconazole (0.05), itraconazole (0.048) and fluconazole (1.5). An extended lag phase and a decline in overall growth were observed in Candida albicans when compared to control when grown in presence of chebulinic acid. At ASN22, TYR23, TRP224, ASP169, TYR166, ASP162, ASN225 GLY297, ARG294 and ASP162, ASN160, ASP169, THR168, TYR166, TYR226, chebulinic acid binds with agglutinin-like sequence protein 3 chain A and B respectively with binding affinity of -10.4 and -9.8 kcal/mol. Our present study strengthens the evidences which stand in support of the fact that chebulinic acid can be used as potent inhibitor of Candida albicans than other commercially available synthetic anti-fungal drugs.

Inhibitory effect of new azole derivative in the corrosion of aluminum in acidic medium: common electrochemical and electrochemical noise investigation

Inhibitory effect of new azole derivative in the corrosion of aluminum in acidic medium: common electrochemical and electrochemical noise investigation

Antifungal activity and mechanism of action of 2-chloro-N -phenylacetamide: a new molecule with activity against strains of Aspergillus flavus.

Aspergillus genus causes many diseases, and the species Aspergillus flavus is highly virulent. Treatment of aspergillosis involves azole derivatives such as voriconazole and polyenes such as amphotericin B. Due to an increase in fungal resistance, treatments are now less effective; the search for new compounds with promising antifungal activity has gained importance. The aims of this study were to evaluate the effects of the synthetic amide 2-chloro-N-phenylacetamide (A1Cl) against strains of Aspergillus flavus and to elucidate its mechanism of action. Thus, the minimum inhibitory concentration, minimum fungicidal concentration, conidial germination, associations with antifungal agents, cell wall activities, membrane activities and molecular docking were evaluated. A1Cl presented antifungal activity against Aspergillus flavus strains with a minimum inhibitory concentration of between 16 and 256 μg/mL and a minimum fungicidal concentration between 32 and 512 μg/mL. The minimum inhibitory concentration of A1Cl also inhibited conidial germination, but when associated with amphotericin B and voriconazole, it promoted antagonistic effects. Binding to ergosterol on the fungal plasma membrane is the likely mechanism of action, along with possible inhibition of DNA synthesis through the inhibition of thymidylate synthase. It is concluded that the amide 2-chloro-N-phenylacetamide has promising antifungal potential.

Synthesis, characterization and antimicrobial screening of new pyrazolyl-1,2,3-triazolyl-thiazolyl-ethanol derivatives

Novel 2-{4-[3-aryl-1-phenylpyrazol-4-yl]-1,2,3-triazol-1-yl}-1-(4-methyl-2-aryl-1,3-thiazol-5-yl)ethanol derivatives, (5a-l) are synthesized by applying click reaction between 4-ethynyl-1,3-diphenyl-1H-pyrazole, (2a-c) and 2-azido-1-(4-methyl-2-arylthiazol-5-yl)ethanone (3a-d) followed by reduction of carbonyl with sodiumborohydride. The starting compounds 4-ethynyl-3-aryl-1-phenyl-1H-pyrazole (2a-c) were synthesized in good yield from 3-aryl-1-phenyl-1H-pyrazole-4-carbaldehyde (1a-c) using Bestmann-Ohira reagents.The newly synthesized azole derivatives (5a-l) were screened for in vitro antimicrobial activity against Proteus mirabilis (NCIM2388), Escherichia coli (NCIM2065), Bacillus subtilis (NCIM2063), Staphylococcus albus (NCIM 2178) and in vitro antifungal activity against Candida albicans (NCIM 3100), Aspergillus niger (ATCC 504). 2-{4-[3-(4-Methoxyphenyl)-1-phenylpyrazol-4-yl]-1,2,3-triazol-1-yl}-1-(4-methyl-2-phenyl-1,3-thiazol-5-yl)ethanol, (5a) 2-{4-[3-(4-fluorophenyl)-1-phenylpyrazol-4-yl]-1,2,3-triazol-1-yl}-1-[4-methyl-2-(4-methylphenyl)-1,3-thiazol-5-yl]ethanol, (5 h) 2-{4-[3-(4-bromophenyl)-1-phenylpyrazol-4-yl]-1,2,3-triazol-1-yl}-1-(4-methyl-2-phenyl-1,3-thiazol-5-yl)ethanol, (5i) 2-{4-[3-(4-bromophenyl)-1-phenylpyrazol-4-yl]-1,2,3-triazol-1-yl}-1-[2-(4-chlorophenyl)-4-methyl-1,3-thiazol-5-yl]ethanol (5j) and 2-{4-[3-(4-bromophenyl)-1-phenylpyrazol-4-yl]-1,2,3-triazol-1-yl}-1-[2-(4-fluorophenyl)-4-methyl-1,3-thiazol-5-yl]ethanol, (5k) reportedgoodantifungal activity against A. niger with MIC 31.25-62.5 µg/mL. Most of the compounds showed moderate activity against bacterial strains. The antifungal activity of pyrazolyl-1,2,3-triazolyl-thiazolylethanol derivatives suggested that these derivatives could lead to compounds for treatment against fungal infection.

Adsorption of 2-mercaptobenzimidazole Corrosion Inhibitor on Copper: DFT Study on Model Oxidized Interfaces

High corrosion inhibition efficiency of the 2-mercaptobenzimidazole (MBI) molecule for copper in different aqueous solutions is well established. We propose a first principle DFT study of the surface chemistry of the adsorption of MBI on preoxidized Cu(111). For both thione (MBIH) and thiolate (MBI◦) species, the formation of a full monolayer (ML) is favored over low coverage adsorption. At the ML coverage, the molecules adopt a perpendicular orientation with respect to the surface. MBI◦ interaction with the surface is stronger than MBIH one. MBIH and MBI◦ bond to the surface forming a S–Cu bond; for MBIH, the NH moiety forms a H-bond with a surface oxygen atom; for MBI◦, a N–Cu bond is formed. For MBI◦ at low coverage, a Cu–C bond is also formed. The charge analyses show a charge transfer between the surface and the molecule. Comparing the MBIH/MBI◦ adsorption energies with that of water/OH, we find that MBI◦ can replace H2O and OH at the preoxidized Cu surface. The results are compared with those obtained with 2-mercaptobenzothiazole, a similar azole derivative with corrosion inhibition properties.

Discovery of potent α‐glucosidase inhibitors through structure‐based virtual screening of an in‐house azole collection

Diabetes mellitus, a chronic disorder characterized by hyperglycemia, is considered a pandemic of modern times. α-Glucosidase inhibitors emerged as a promising class of antidiabetic drugs with better tolerability compared with its alternatives. Azoles, although widely preferred in drug design, have scarcely been investigated for their potential against α-glucosidase. In this study, we evaluated α-glucosidase inhibitory effects 20 azole derivatives selected out of an in-house collection via structure-based virtual screening (VS) with consensus scoring approach. Seven compounds were identified with better IC50 values than acarbose (IC50 =68.18±1.01µM), a well-known α-glucosidase inhibitor drug, which meant 35% success for our VS methodology. Compound 52, 54, 56, 59, and 81 proved highly potent with IC50 values in the range of 40-60µM. According to the enzyme kinetics study, four of them were competitive, 56 was non-competitive inhibitor. Structure-activity relationships, quantum mechanical, and docking analyses showed that azole rings at ionized state may be key to the potency observed for the active compounds and modifications to shift the balance between the neutral and ionized states further to the latter could yield more potent derivatives.

Heterocyclization of Cyanoacetamide Derivatives: Synthesis and Biological Activity of Novel Azoles and Azines

The intermolecular cyclization of N-benzyl-2-cyanoacetamide with carbon disulfide followed by intramolecular cyclization gave thioxothiazinone 3. This compound was used to synthesize a series of novel fused furopyrrole, pyridine, pyrimidine and other azine and azole derivatives. The Michael-type reaction of compound 3 with maleic anhydride followed by pyrrole and furan cyclizations and aromatization yielded polycyclic compound 7. The [3+3]-cycloaddition of benzylidene malononitrile and its derivative to compound 3 gave pyridothiazines 10–12. The ring opening in compound 3 under the action of urea or thiourea followed by pyrimidine cyclization and subsequent air oxidation resulted in the synthesis of oxa- and thiadiazolopyrimidinones 15 and 16, respectively. The reaction of compound 3 with H2O2 in a basic medium provided pyrimidine derivative 17. The oxidation of compound 3 with Br2 in an acid medium led to bromo derivative 19. The synthesized novel compounds were characterized by elemental analysis and IR and 1H and 13C NMR spectroscopy and tested antibacterial and anticancer activities.

A Facile C‐H Insertion Strategy using Combination of HFIP and Isocyanides: Metal‐Free Access to Azole Derivatives

AbstractAn efficient metal‐free approach has been devised towards the synthesis of azoles via C−H insertion protocol. Various isocyanides were examined as effective C1‐synthons. The HFIP plays crucial role as hydrogen source and promoter of the reaction in order to reveal the maximum efficacies to accomplish the transformation in high yields of the products with excellent functional group tolerance. The control experiment affirmed 83% of deuterium incorporation, when the reaction was performed using HFIP‐d2.