Regioselective quinazoline C2 modifications through the azide-tetrazole tautomeric equilibrium.

2-Chloro-4-sulfonylquinazolines undergo functional group swap when treated with an azide nucleophile: 1) the azide replaces the sulfonyl group at the C4 position; 2) the intrinsic azide-tetrazole tautomeric equilibrium directs the nucleofugal sulfinate from the first step to replace chloride at the C2 position. This transformation is effective with quinazolines bearing electron-rich substituents. Therefore, the title transformations are demonstrated on the 6,7-dimethoxyquinazoline core, which is present in pharmaceutically active substances. The methodology application is showcased by transforming the obtained 4-azido-6,7-dimethoxy-2-sulfonylquinazolines into the α1-adrenoceptor blockers terazosin and prazosin by further C2-selective SNAr reaction and azide reduction.

5+1-Heterocyclization as preparative approach for carboxy-containing triazolo[1,5-c]quinazolines with anti-inflammatory activity.

Present article is devoted to the purposeful search of novel anti-inflammatory agents among carboxyl-containing partially hydrogenated [1,2,4]triazolo[1,5-с]quinazolines and products of their tandem cyclization. It has been shown that target compound's could be obtained via interaction between [2-(3-R-1H-1,2,4-triazol-5-yl)phenyl]amines and oxo-containing carboxylic acids and their esters of various structure. The structures of synthesized compounds were verified by appropriate methods, the features of NMR-spectra patterns were discussed as well. The low predicted toxicity of obtained compounds has been estimated using in silico methods. In vivo study on the model of acute aseptic inflammation (carrageenan test) have been revealed that synthesized compounds expose anti-inflammatory activity in the range of 0.94-52.66%. 4-(2-(Ethoxycarbonyl)-5,6-dihydro-[1,2,4]triazolo[1,5-c]quinazolin-5-yl)benzoic acid has been identified as most active compound. Additionally, the effects of some (2-R-5,6-dihydro[1,2,4]triazolo[1,5-c]quinazolin-5-yl)benzoic acids (compounds 3) on the levels of key inflammatory markers have been estimated. It has been shown that studied compounds decrease the level of neutrophils, COX-2, nitrotyrosine, IL-1b, C-reactive protein and increase level of eNOS. 4-(2-(Ethoxycarbonyl)-5,6-dihydro-[1,2,4]triazolo[1,5-c]quinazolin-5-yl)benzoic acid (3.2) has been identified as compound with most expressed anti-inflammatory activity and significant effect on the levels of marker of inflammatory processes. Molecular docking study towards СОХ-1 and СОХ-2 has been conducted to substantiate possible mechanism of obtained compounds anti-inflammatory activity. It has been found that fixation of 4-(2-(ethoxycarbonyl)-5,6-dihydro-[1,2,4]triazolo[1,5-c]quinazolin-5-yl)benzoic acid (3.2) molecule in active site of enzyme is outstandingly similar to the reference ligands. The essential value of carboxylic group for presence of anti-inflammatory activity has been estimated as result of SAR-analysis. It has been found that studied class of compounds is perspective for further structural modification aimed to the creation of novel anti-inflammatory agents.

Anti-babesial activity of a series of 6,7-dimethoxyquinazoline-2,4-diamines (DMQDAs).

Diminazene aceturate (DA), imidocarb dipropionate (ID), atovaquone (ATO), azithromycin (AZI), clindamycin, and quinine have been used to treat animal and human babesiosis for many years, despite their negative effects and rising indications of resistance. Thus, finding anti-babesial compounds that can either treat the infection or lower the dose of drugs given has been a primary objective. Quinazolines are one of the most important nitrogen heterocycles, with a wide range of pharmacological activities including analgesic, anti-inflammatory, sedative-hypnotic, anti-histaminic, anti-cancer, and anti-protozoan properties. The present study investigated the anti-babesial activities of twenty 6,7-dimethoxyquinazoline-2,4-diamines on Babesia spp. One candidate, 6,7-dimethoxy-N4-ethylisopropyl-N2-ethyl(pyridin-4-yl)quinazoline-2,4-diamine (SHG02), showed potent inhibition on Babesia gibsoni in vitro, as well as on B. microti and B. rodhaini in mice. Our findings indicate that the candidate compound SHG02 is promising for further development of anti-babesial drugs and provides a new structure to be explored for developing anti-Babesia therapeutics.

Synthesis and Biological Evaluation of 2-Substituted Quinazolin-4(3H)-Ones with Antiproliferative Activities.

Sixteen new 2-substituted quinazolines were synthesized using a straightforward methodology starting from 2-methoxybezoic acid or 3-methoxy-2-naphthoic acid. The anti-proliferative activity of the target compounds was evaluated against nine cancer cell lines. Additionally, all the compounds were screened for their potency and selectivity against a panel of 109 kinases and four bromodomains, using Differential Scanning Fluorimetry (DSF). Compound 17 bearing a 2-methoxyphenyl substitution along with a basic side chain displayed a remarkable profile against the majority of the tested cell lines.

Design, synthesis, and carbonic anhydrase inhibition activities of Schiff bases incorporating benzenesulfonamide scaffold: Molecular docking application.

In this study, The inhibitory actions of human carbonic anhydrase (CA, EC 4.2.1.1) (hCA) isoforms I, II, IX, and XII are being examined using recently synthesized substituted hydroxyl Schiff derivatives based on the quinazoline scaffold 4-22. Quinazolines 2, 3, 4, 5, 7, 10, 15, and 18 reduce the activity of hCA I isoform effectively to a Ki of 87.6-692.3 nM, which is nearly equivalent to or more potent than that of the standard drug AAZ (Ki, 250.0 nM). Similarly, quinazolines 2, 3, and 5 and quinazoline 14 effectively decrease the inhibitory activity of the hCA II isoform to a KI of 16.9-29.7 nM, comparable to that of AAZ (Ki, 12.0 nM). The hCA IX isoform activity is substantially diminished by quinazolines 2-12 and 14-21 (Ki, 8.9-88.3 nM against AAZ (Ki, 25.0 nM). Further, the activity of the hCA XII isoform is markedly inhibited by the quinazolines 3, 5, 7, 14, and 16 (Ki, 5.4-19.5 nM). Significant selectivity levels are demonstrated for inhibiting tumour-associated isoforms hCA IX over hCAI, for sulfonamide derivatives 6-15 (SI; 10.68-186.29), and 17-22 (SI; 12.52-57.65) compared to AAZ (SI; 10.0). Sulfonamide derivatives 4-22 (SI; 0.50-20.77) demonstrated a unique selectivity in the concurrent inhibition of hCA IX over hCA II compared to AAZ (SI; 0.48). Simultaneously, benzenesulfonamide derivative 14 revealed excellent selectivity for inhibiting hCA XII over hCA I (SI; 60.35), whereas compounds 5-8, 12-14, 16, and 18-22 demonstrated remarkable selectivity for hCA XII inhibitory activity over hCA II (SI; 2.09-7.27) compared to AAZ (SI; 43.86 and 2.10, respectively). Molecular docking studies additionally support 8 to hCA IX and XII binding, thus indicating its potential as a lead compound for inhibitor development.

Molecular modeling, dynamic simulation, and metabolic reactivity studies of quinazoline derivatives to investigate their anti-angiogenic potential by targeting wild EGFRwt and mutant EGFRT790M receptor tyrosine kinases.

Non-small cell lung cancer, head and neck cancer, glioblastoma, and various other cancer types often demonstrate persistent elevation in EGFR tyrosine kinase activity due to acquired mutations in its kinase domain. Any alteration in the EGFR is responsible for triggering the upregulation of tumor angiogenic pathways, such as the PI3k-AKT-mTOR pathway, MAPK-ERK pathway and PLC-Ƴ pathway, which are critically involved in promoting tumor angiogenesis in cancer cells. The emergence of frequently occurring EGFR kinase domain mutations (L858R/T790M/C797S) that confer resistance to approved therapeutic agents has presented a significant challenge for researchers aiming to develop effective and well-tolerated treatments against tumor angiogenesis. In this study, we directed our efforts towards the rational design and development of novel quinazoline derivatives with the potential to act as antagonists against both wild-type and mutant EGFR. Our approach encompasing the application of advanced drug design strategies, including structure-based virtual screening, molecular docking, molecular dynamics, metabolic reactivity and cardiotoxicity prediction studies led to the identification of two prominent lead compounds: QU648, for EGFRwt inhibition and QU351, for EGFRmt antagonism. The computed binding energies of selected leads and their molecular dynamics simulations exhibited enhanced conformational stability of QU648 and QU351 when compared to standard drugs Erlotinib and Afatinib. Notably, the lead compounds also demonstrated promising pharmacokinetic properties, metabolic reactivity, and cardiotoxicity profiles. Collectively, the outcomes of our study provide compelling evidence supporting the potential of QU648 and QU351 as prominent anti-angiogenic agents, effectively inhibiting EGFR activity across various cancer types harboring diverse EGFR mutations.Communicated by Ramaswamy H. Sarma.

Structure Activity Relationship and Molecular Docking of Some Quinazolines Bearing Sulfamerazine Moiety as New 3CLpro, cPLA2, sPLA2 Inhibitors.

The current work was conducted to synthesize several novel anti-inflammatory quinazolines having sulfamerazine moieties as new 3CLpro, cPLA2, and sPLA2 inhibitors. The thioureido derivative 3 was formed when compound 2 was treated with sulfamerazine. Also, compound 3 was reacted with NH2-NH2 in ethanol to produce the N-aminoquinazoline derivative. Additionally, derivative 4 was reacted with 4-hydroxy-3-methoxybenzaldehyde, ethyl chloroacetate, and/or diethyl oxalate to produce quinazoline derivatives 5, 6, and 12, respectively. The results of the pharmacological study indicated that the synthesized 4-6 and 12 derivatives showed good 3CLpro, cPLA2, and sPLA2 inhibitory activity. The IC50 values of the target compounds 4-6, and 12 against the SARS-CoV-2 main protease were 2.012, 3.68, 1.18, and 5.47 µM, respectively, whereas those of baicalein and ivermectin were 1.72 and 42.39 µM, respectively. The IC50 values of the target compounds 4-6, and 12 against sPLA2 were 2.84, 2.73, 1.016, and 4.45 µM, respectively, whereas those of baicalein and ivermectin were 0.89 and 109.6 µM, respectively. The IC50 values of the target compounds 4-6, and 12 against cPLA2 were 1.44, 2.08, 0.5, and 2.39 µM, respectively, whereas those of baicalein and ivermectin were 3.88 and 138.0 µM, respectively. Also, incubation of lung cells with LPS plus derivatives 4-6, and 12 caused a significant decrease in levels of sPLA2, cPLA2, IL-8, TNF-α, and NO. The inhibitory activity of the synthesized compounds was more pronounced compared to baicalein and ivermectin. In contrast to ivermectin and baicalein, bioinformatics investigations were carried out to establish the possible binding interactions between the newly synthesized compounds 2-6 and 12 and the active site of 3CLpro. Docking simulations were utilized to identify the binding affinity and binding mode of compounds 2-6 and 12 with the active sites of 3CLpro, sPLA2, and cPLA2 enzymes. Our findings demonstrated that all compounds had outstanding binding affinities, especially with the key amino acids of the target enzymes. These findings imply that compound 6 is a potential lead for the development of more effective SARS-CoV-2 Mpro inhibitors and anti-COVID-19 quinazoline derivative-based drugs. Compound 6 was shown to have more antiviral activity than baicalein and against 3CLpro. Furthermore, the IC50 value of ivermectin against the SARS-CoV-2 main protease was revealed to be 42.39 µM, indicating that it has low effectiveness.

Synthesis of Quinazolin-2,4,6-triamine Derivatives as Non-purine Xanthine Oxidase Inhibitors and Exploration of Their Toxicological Potential.

In this work, a new set of quinazolin-2,4,6-triamine derivatives were synthesized to explore their potential biological activity as xanthine oxidase (XO) inhibitors, superoxide scavengers and screening of their toxicological profile. Among all the synthesized compounds, B1 exhibited better inhibitory activity against bovine xanthine oxidase (bXO) than allopurinol (IC50 =1.56 µM and IC50 =6.99 µM, respectively). As superoxide scavengers, B1, B2 and B13 exhibited a better effect than allopurinol (97.3 %, 82.1 %, 87.4 % and 69.4 %, respectively). Regarding the toxicological profile, B1 was less cytotoxic than methotrexate on HCT-15 cancer cells. Apoptosis results obtained in cells of female and male mice, showed that B1 and B2 presented a similar behaviour to CrO3 (positive control) with respect to the average frequency to induce apoptosis; while B13 apoptosis induced effect was similar to DMSO and control group. Finally, B1, B2, B13 did not induce genotoxicity in a micronuclei murine model compared to CrO3 .

2-Substituted quinazolines: Partial agonistic and antagonistic ligands of the constitutive androstane receptor (CAR).

Following the discovery of 2-(3-methoxyphenyl)-3,4-dihydroquinazoline-4-one and 2-(3-methoxyphenyl)quinazoline-4-thione as potent, but non-specific activators of the human Constitutive Androstane Receptor (CAR, NR1I3), a series of quinazolinones substituted at the C2 phenyl ring was prepared to examine their ability to selectively modulate human CAR activity. Employing cellular and in vitro TR-FRET assays with wild-type CAR or its variant 3 (CAR3) ligand binding domains (LBD), several novel partial human CAR agonists and antagonists were identified. 2-(3-Methylphenyl) quinazolinone derivatives 7d and 8d acted as partial agonists with the recombinant CAR LBD, the former in nanomolar units (EC50 = 0.055 µM and 10.6 µM, respectively). Moreover, 7d did not activate PXR, and did not show any signs of cytotoxicity. On the other hand, 2-(4-bromophenyl)quinazoline-4-thione 7l possessed significant CAR antagonistic activity, although the compound displayed no agonistic or inverse agonistic activities. A compound possessing purely antagonistic effect was thus identified for the first time. These and related compounds may serve as a remedy in xenobiotic intoxication or, conversely, in suppression of undesirable hepatic CAR activation.

Synthesis of substituted 8H-benzo[h]pyrano[2,3-f]quinazolin-8-ones via photochemical 6π-electrocyclization of pyrimidines containing an allomaltol fragment.

For the first time, we elaborated a method for the synthesis of pyrimidines containing an allomaltol unit. The suggested approach is based on the reaction of 2-(1-(dimethylamino)-3-oxo-3-arylprop-1-en-2-yl)-3-hydroxy-6-methyl-4H-pyran-4-ones with cyanamide. The photochemical behavior of the obtained pyrimidines was investigated. It was shown that for the hydroxy derivatives the main pathway of phototransformation is a 6π-electrocyclization of the 1,3,5-hexatriene system and subsequent [1,9]-H sigmatropic shift leading to dihydrobenzo[h]pyrano[2,3-f]quinazolines. At the same time, for methylated analogues the photoreaction proceeds in two directions resulting in the formation of a mixture of the corresponding dihydrobenzo[h]pyrano[2,3-f]quinazolines and polyaromatic products. The obtained dihydro derivatives are stable compounds and do not undergo aromatization upon further UV irradiation. The structures of two of the dihydrobenzo[h]pyrano[2,3-f]quinazolines were confirmed by X-ray diffraction analysis. Based on the performed studies, a two-stage telescopic method for the synthesis of polyaromatic benzo[h]pyrano[2,3-f]quinazolines including the initial photocyclization of the starting pyrimidines and the final dehydration was proposed.

Biological Investigation of 2-Thioxo-benzo[g]quinazolines against Adenovirus Type 7 and Bacteriophage Phi X174: An In Vitro Study.

Mortality and morbidity caused by viruses are a global health problems. Therefore, there is always a need to create novel therapeutic agents and refine existing ones to maximize their efficacy. Our lab has produced benzoquinazolines derivatives that have proven effective activity as antiviral compounds against herpes simplex (HSV 1 and 2), coxsackievirus B4 (CVB4), and hepatitis viruses (HAV and HCV). This in vitro study was aimed at investigating the effectiveness of benzoquinazoline derivatives 1-16 against adenovirus type 7 and bacteriophage phiX174 using a plaque assay. The cytotoxicity against adenovirus type 7 was also performed in vitro, using a MTT assay. Most of the compounds exhibited antiviral activity against bacteriophage phiX174. However, compounds 1, 3, 9, and 11 showed statistically significant reductions of 60-70% against bacteriophage phiX174. By contrast, compounds 3, 5, 7, 12, 13, and 15 were ineffective against adenovirus type 7, and compounds 6 and 16 had remarkable efficacy (50%). Using the MOE-Site Finder Module, a docking study was carried out in order to create a prediction regarding the orientation of the lead compounds (1, 9, and 11). This was performed in order to investigate the activity of the lead compounds 1, 9, and 11 against the bacteriophage phiX174 by locating the ligand-target protein binding interaction active sites.

Benzo[g]quinazolines as antifungal against candidiasis: Screening, molecular docking, and QSAR investigations.

Candida albicans, an opportunistic pathogen, is the most common type of fungus and represents a substantial source of human invasive disease (nosocomial infection). This category of fungi are part of our microbiota, and given the appropriate environmental conditions, it has the potential to cause both superficial and systemic infections. There is a soaring resistance against the available anticandidal agents. The purpose of this research is to investigate the activity of certain previously synthesized benzo[g]quinazolines against C. albicans in vitro by using the cup-plate diffusion method. There was a marked difference in the effectiveness of the target compounds 1-6 against the sample of C. albicans that was tested. Benzo[g]quinazolines 1 (inhibition zone = 20 mm) and 2 (inhibition zone = 22 mm) had good effects in comparison to fluconazole (inhibition zone = 26 mm). A docking study was conducted between benzo[g]quinazolines 1-6 and Candida spp. CYP51 to establish the binding mode compared with fluconazole and VT-1161 (oteseconazole) as reference medicines, and it was determined that binding at the active site of Candida spp. CYP51 occurred in the same manner. Quantitative structure-activity relationship (QSAR) investigation was performed to further characterize the identified anticandidal agents and recognize the major regulatory components governing such activity. In future studies, the benzo[g]quinazoline scaffold could serve as a model for the design and development of novel derivatives with antifungal potential.

Antiviral activity of some benzo[g]quinazolines against coxsackievirus B4: biological screening and docking study.

BACKGROUND: Serotype coxsackievirus B (CVB) infection has been linked to viral myocarditis, dilated cardiomyopathy, meningitis, and pancreatitis in children and young adults. As of yet, no antiviral drug has been authorized for the treatment of coxsackievirus infection. Therefore, there is perpetual demand for new therapeutic agents and the improvement of existing ones. Benzo[g]quinazolines, the subject of several well-known heterocyclic systems, have risen to prominence and played a significant role in the development of antiviral agents, particularly those for anti-coxsackievirus B4 infection. METHODS: This study investigated the cytotoxicity of the target benzo[g]quinazolines (1-16) in the BGM cells line as well as their anti-coxsackievirus B4 activity. Determination of CVB4 titers using a plaque assay. RESULTS: Most of the target benzoquinazolines exhibited antiviral activity, however, compounds 1-3 appeared to be the most effective (reduction percentages of 66.7, 70, and 83.3%, respectively). The binding mechanisms and interactions of the three most active 1-3 with the constitutive amino acids in the active site of the multi-target of coxsackievirus B4 (3Clpro and RdRp) targets were also investigated using molecular docking. CONCLUSION: The anti coxsackievirus B4 activity has resulted, and the top three active benzoquinazolines (1-3) have bonded to and interacted with the constitutive amino acids in the active region of the multi-target coxsackievirus B4 (RdRp and 3Clpro). Further research is required in the lab. to determine the exact benzoquinazolines mechanism of action.

Recent Advances in the Transition-Metal-Free Synthesis of Quinazolines.

Quinazolines are a privileged class of nitrogen-containing heterocycles, widely present in a variety of natural products and synthetic chemicals with a broad spectrum of biological and medicinal activities. Owing to their pharmaceutical applications and promising biological value, a variety of synthetic methodologies have been reported for these scaffolds. From the perspective of green and sustainable chemistry, transition-metal-free synthesis provides an alternative method for accessing several biologically active heterocycles. In this review, we summarize the recent progress achieved in the transition-metal-free synthesis of quinazolines and we cover the literature from 2015 to 2022. This aspect is present alongside the advantages, limitations, mechanistic rationalization, and future perspectives associated with the synthetic methodologies.

5,6-Dihydrotetrazolo[1,5-c]quinazolines: Toxicity prediction, synthesis, antimicrobial activity, molecular docking, and perspectives.

Antimicrobial resistance is a never-ending challenge, which should be considered seriously, especially when using unprescribed "over-the-counter" drugs. The synthesis and investigation of novel biologically active substances is among the directions to overcome this problem. Hence, 18 novel 5,6-dihydrotetrazolo[1,5-c]quinazolines were synthesized, their identity, purity, and structure were elucidated by elemental analysis, IR, LC-MS, 1 Н, and 13 C NMR spectra. According to the computational estimation, 15 substances were found to be of toxicity Class V, two of Class IV, and only one of Class II. The in vitro serial dilution method of antimicrobial screening against Escherichia coli, Staphylococcus aureus, Klebsiella aerogenes, Pseudomonas aeruginosa, and Candida albicans determined b3, c1, c6, and c10 as the "lead-compounds" for further modifications to increase the level of activity. Substance b3 demonstrated antibacterial activity that can be related to the calculated high affinity toward all studied proteins: 50S ribosomal protein L19 (PDB ID: 6WQN), sterol 14-alpha demethylase (PDB ID: 5TZ1), and ras-related protein Rab-9A (PDB ID: 1WMS). The structure-activity and structure-target affinity relationships are discussed. The targets for further investigations and the anatomical therapeutic chemical codes of drug similarity are predicted.

3D,2D-QSAR study and docking of novel quinazolines as potential target drugs for osteosarcoma.

Background: Quinazolines are an important class of benzopyrimidine heterocyclic compounds with a promising antitumor activity that can be used for the design and development of osteosarcoma target compounds. Objective: To predict the compound activity of quinazoline compounds by constructing 2D- and 3D-QSAR models, and to design new compounds according to the main influencing factors of compound activity in the two models. Methods: First, heuristic method and GEP (gene expression programming) algorithm were used to construct linear and non-linear 2D-QSAR models. Then a 3D-QSAR model was constructed using CoMSIA method in SYBYL software package. Finally, new compounds were designed according to molecular descriptors of 2D-QSAR model and contour maps of 3D-QSAR model. Several compounds with optimal activity were used for docking experiments with osteosarcoma related targets (FGFR4). Results: The non-linear model constructed by GEP algorithm was more stable and predictive than the linear model constructed by heuristic method. A 3D-QSAR model with high Q2 (0.63) and R 2 (0.987) values and low error values (0.05) was obtained in this study. The success of the model fully passed the external validation formula, proving that the model is very stable and has strong predictive power. 200 quinazoline derivatives were designed according to molecular descriptors and contour maps, and docking experiments were carried out for the most active compounds. Compound 19g.10 has the best compound activity with good target binding capability. Conclusion: To sum up, the two novel QSAR models constructed were very reliable. The combination of descriptors in 2D-QSAR with COMSIA contour maps provides new design ideas for future compound design in osteosarcoma.

Evaluation of Some Benzo[g]Quinazoline Derivatives as Antiviral Agents against Human Rotavirus Wa Strain: Biological Screening and Docking Study.

Globally, rotavirus (RV) is the most common cause of acute gastroenteritis in infants and toddlers; however, there are currently no agents available that are tailored to treat rotavirus infection in particular. Improved and widespread immunization programs are being implemented worldwide to reduce rotavirus morbidity and mortality. Despite certain immunizations, there are no licensed antivirals that can attack rotavirus in hosts. Benzoquinazolines, chemical components synthesized in our laboratory, were developed as antiviral agents, and showed good activity against herpes simplex, coxsackievirus B4 and hepatitis A and C. In this research project, an in vitro investigation of the effectiveness of benzoquinazoline derivatives 1-16 against human rotavirus Wa strains was carried out. All compounds exhibited antiviral activity, however compounds 1-3, 9 and 16 showed the greatest activity (reduction percentages ranged from 50 to 66%). In-silico molecular docking of highly active compounds, which were selected after studying the biological activity of all investigated of benzo[g]quinazolines compounds, was implemented into the protein's putative binding site to establish an optimal orientation for binding. As a result, compounds 1, 3, 9, and 16 are promising anti-rotavirus Wa strains that lead with Outer Capsid protein VP4 inhibition.

3-Aryl-5-aminobiphenyl Substituted [1,2,4]triazolo[4,3-c]quinazolines: Synthesis and Photophysical Properties.

Amino-[1,1']-biphenyl-containing 3-aryl-[1,2,4]triazolo[4,3-c]quinazoline derivatives with fluorescent properties have been designed and synthesized. The type of annelation of the triazole ring to the pyrimidine one has been unambiguously confirmed by means of an X-ray diffraction (XRD) method; the molecules are non-planar, and the aryl substituents form the pincer-like conformation. The UV/Vis and photoluminescent properties of target compounds were investigated in two solvents of different polarities and in a solid state. The samples emit a broad range of wavelengths and display fluorescent quantum yields of up to 94% in toluene solutions. 5-(4'-Diphenylamino-[1,1']-biphenyl-4-yl)-3-(4-(trifluoromethyl)phenyl)-[1,2,4]triazolo[4,3-c]quinazoline exhibits the strongest emission in toluene and a solid state. Additionally, the solvatochromic properties were studied for the substituted [1,2,4]triazolo[4,3-c]quinazolines. Moreover, the changes in absorption and emission spectra have been demonstrated upon the addition of water to MeCN solutions, which confirms aggregate formation, and some samples were found to exhibit aggregation-induced emission enhancement. Further, the ability of triazoloquinazolines to detect trifluoroacetic acid has been analyzed; the presence of TFA induces changes in both absorption and emission spectra, and acidochromic behavvior was observed for some triazoloquinazoline compounds. Finally, electronic-structure calculations with the use of quantum-chemistry methods were performed for synthesized compounds.

Novel acetic acid derivatives containing quinazolin-4(3H)-one ring: Synthesis, in vitro, and in silico evaluation of potent aldose reductase inhibitors.

Aldose reductase (AR) is a crucial enzyme of the polyol pathway through which glucose is metabolized under conditions of hyperglycemia related to diabetes. A series of novel acetic acid derivatives containing quinazolin-4(3H)-one ring (1-22) was synthesized and tested for in vitro AR inhibitory effect. All the target compounds exhibited nanomolar activity against the target enzyme, and all compounds displayed higher activity as compared to the reference drug epalrestat. Among them, Compound 19, named 2-(4-[(2-[(4-methylpiperazin-1-yl)methyl]-4-oxoquinazolin-3(4H)-ylimino)methyl]phenoxy)acetic acid, displayed the strongest inhibitory effect with a KI value of 61.20 ± 10.18 nM. Additionally, these compounds were investigated for activity against L929, nontumoral fibroblast cells, and MCF-7, breast cancer cells using the MTT assay. Compounds 16 and 19 showed lower toxicity against the normal L929 cells. The synthesized compounds' (1-22) absorption, distribution, metabolism, and excretion properties were also evaluated. Molecular docking simulations were used to look into the possible binding mechanisms of these inhibitors against AR.

GlmU Inhibitors as Promising Antibacterial Agents: A Review.

Bacterial infections are a major cause of mortality and morbidity in humans throughout the world. Infections due to resistant bacterial strains such as methicillin-resistant Staphyloccocusaureus vancomycin, resistant Enterococci, Klebsiella pneumoniae, Staphylococcus aureus, and Mycobacterium are alarming. Hence the development of new antibacterial agents, which act via a novel mechanism of action, became a priority in antibacterial research. One such approach to overcome bacterial resistance is to target novel protein and develop antibacterial agents that act via different mechanisms of action. Bacterial GlmU is one such bifunctional enzyme that catalyzes the two consecutive reactions during the biosynthesis of uridine 5'-diphospho-Nacetylglucosamine, an essential precursor for the biosynthesis of bacterial cell wall peptidoglycan. This enzyme comprises two distinct active sites; acetyltransferase and uridyltransferase and both these active sites act independently during catalytic reactions. GlmU is considered an attractive target for the design and development of newer antibacterial agents due to its important role in bacterial cell wall synthesis and the absence of comparable enzymes in humans. Availability of three dimensions X-crystallographic structures of GlmU and their known catalytic mechanism from different bacterial strains have instigated research efforts for the development of novel antibacterial agents. Several GlmU inhibitors belonging to different chemical classes like 2- phenylbenzofuran derivative, quinazolines, aminoquinazolines, sulfonamides, arylsulfonamide, D-glucopyranoside 6-phosphates, terreic acid, iodoacetamide, N-ethyl maleimide, and Nethylmaleimide etc., have been reported in the literature. In the present review, we present an update on GlmU inhibitors and their associated antibacterial activities. This review may be useful for the design and development of novel GlmU inhibitors with potent antibacterial activity.