Petroselinum crispum L., essential oil as promising source of bioactive compounds, antioxidant, antimicrobial activities: In vitro and in silico predictions.

This exploratory study aims to identify the volatile compounds in PC-Eo (Petroselinum crispum L. essential oil) and evaluate its antioxidant and antimicrobial properties in vitro. Molecular docking, drug-likeness prediction, and pharmacokinetics (absorption, distribution, metabolism, excretion, and toxicity-ADMET) were among the in silico simulations that were used to explain the biological properties observed in vitro. For PC-Eo's chemical screening, gas chromatography-mass spectrophotometry (GC-MS) was employed. The antioxidant activity of PC-Eo was evaluated using five in vitro complementary techniques, including 2,2-diphenyl-1-picrylhydrazyl (DPPH), 2,2'-azinobis(3-ethylbenzothiazoline-6-sulfonate) (ABTS) radical scavenging activity, ß-Carotene bleaching test (BCBT), reducing power (RP), and phosphomolybdenum assay (TAC). GC-MS analysis revealed that the primary components of PC-Eo are apiol (49.05 %), Myristicin (21.01 %), and 1-allyl-2,3,4,5-tetramethoxybenzene (13.14 %). The results of the in vitro antioxidant assays indicate that PC-Eo exhibits a superior antioxidant profile. The in vitro antimicrobial activity of PC-Eo was assessed against five strains, including 2 g-positive bacteria, 2 g-negative bacteria, and one fungal strain (Candida albicans). The disc-diffusion assay revealed significant antibacterial and antifungal activities against all strains, with zones of inhibition exceeding 15 mm. The microdilution test highlighted the lowest MIC and MBC values with gram-positive bacteria, ranging from 0.25 to 0.5 % v/v for MIC and 0.5-1.0 % v/v for MBC. For the fungal strain, MIC was recorded at 1.25 % and MFC at 2.5 % v/v. PC-Eo demonstrates bactericidal and fungicidal activity based on the MBC/MIC and MFC/MIC ratios. According to the ADMET study, the primary PC-Eo compounds have advantageous pharmacokinetic characteristics. These findings provide empirical support for the traditional uses of this plant and indicate its possible use as a natural remedy.

Metamagnetism and canted antiferromagnetic ordering in two monomeric CoII complexes with 1-(2-pyrimidyl)piperazine. Hirshfeld surface analysis and theoretical studies.

Here we present the magnetic properties of two cobalt complexes formulated as: [Co(SCN)2(L)2] (1) and (H2L)2[Co(SCN)4]·H2O (2) (L = 1-(2-pyrimidyl)piperazine). The two compounds contain isolated tetrahedral CoII complexes with important intermolecular interactions that lead to the presence of a canted antiferromagnetic order below 11.5 and 10.0 K, with coercive fields at 2 K of 38 and 68 mT, respectively. Theoretical calculations have been used to explain this behaviour. Hirshfeld surface analysis shows the presence of strong intermolecular interactions in both compounds. The crystal geometries were used for geometry optimization using the DFT method. From the topological properties, electrostatic potential maps and molecular orbital analysis, information about the noncovalent interaction and chemical reactivity was obtained.

Investigation of the in vitro biological activities of polyethylene glycol-based thermally stable polyurethane elastomers.

The intense urge to replace conventional polymers with ecofriendly monomers is a step towards green products. The novelty of this study is the extraction of starch from the biowaste of wheat bran (WB) and banana peel (BP) for use as a monomer in the form of chain extenders. For the synthesis of polyurethane (PU) elastomers, polyethylene glycol (PEG) bearing an average molecular weight Mn = 1000 g mol-1 was used as a macrodiol, which was reacted with isophorone diisocyanate (IPDI) to develop NCO-terminated prepolymer chains. These prepolymer chains were terminated with chain extenders. Two series of linear PU elastomers were prepared by varying the concentration of chain extenders (0.5-2.5 mol%), inducing a variation of 40 to 70 wt% in the hard segment (HS). Fourier-transform infrared (FTIR) spectroscopy confirmed the formation of urethane linkages. Thermal gravimetric analysis (TGA) showed a thermal stability of up to 250 °C. Dynamic mechanical analysis (DMA) revealed a storage modulus (E') of up to 140 MPa. Furthermore, the hemolytic activities of up to 8.97 ± 0.1% were recorded. The inhibition of biofilm formation was investigated against E. coli and S. aureus (%), which was supported by phase contrast microscopy.

Catalytic Mechanism of Nonglycosidic C-N Bond Formation by the Pseudoglycosyltransferase Enzyme VldE.

The pseudoglycosyltransferase (PsGT) enzyme VldE is a homologue of the retaining glycosyltransferase (GT) trehalose 6-phosphate synthase (OtsA) that catalyzes a coupling reaction between two pseudo-sugar units, GDP-valienol and validamine 7-phosphate, to give a product with α,α-N-pseudo-glycosidic linkage. Despite its biological importance and unique catalytic function, the molecular bases for its substrate specificity and reaction mechanism are still obscure. Here, we report a comparative mechanistic study of VldE and OtsA using various engineered chimeric proteins and point mutants of the enzymes, X-ray crystallography, docking studies, and kinetic isotope effects. We found that the distinct substrate specificities between VldE and OtsA are most likely due to topological differences within the hot spot amino acid regions of their N-terminal domains. We also found that the Asp158 and His182 residues, which are in the active site, play a significant role in the PsGT function of VldE. They do not seem to be directly involved in the catalysis but may be important for substrate recognition or contribute to the overall architecture of the active site pocket. Moreover, results of the kinetic isotope effect experiments suggest that VldE catalyzes a C-N bond formation between GDP-valienol and validamine 7-phosphate via an SNi-like mechanism. The study provides new insights into the substrate specificity and catalytic mechanism of a member of the growing family of PsGT enzymes, which may be used as a basis for developing new PsGTs from GTs.

Fabrication and In Vitro Biological Assay of Thermo-Mechanically Tuned Chitosan Reinforced Polyurethane Composites.

The progressive trend of utilizing bioactive materials constitutes diverse materials exhibiting biocompatibility. The innovative aspect of this research is the tuning of the thermo-mechanical behavior of polyurethane (PU) composites with improved biocompatibility for vibrant applications. Polycaprolactone (CAPA) Mn = 2000 g-mol-1 was used as a macrodiol, along with toluene diisocyanate (TDI) and hexamethylene diisocyanate (HMDI), to develop prepolymer chains, which were terminated with 1,4 butane diol (BD). The matrix was reinforced with various concentrations of chitosan (1-5 wt %). Two series of PU composites (PUT/PUH) based on aromatic and aliphatic diisocyanate were prepared by varying the hard segment (HS) ratio from 5 to 30 (wt %). The Fourier-transformed infrared (FTIR) spectroscopy showed the absence of an NCO peak at 1730 cm-1 in order to confirm polymer chain termination. Thermal gravimetric analysis (TGA) showed optimum weight loss up to 500 °C. Dynamic mechanical analysis (DMA) showed the complex modulus (E*) ≥ 200 MPa. The scanning electron microscope (SEM) proved the ordered structure and uniform distribution of chain extender in PU. The hemolytic activities were recorded up to 15.8 ± 1.5% for the PUH series. The optimum values for the inhibition of biofilm formation were recorded as 46.3 ± 1.8% against E. coli and S. aureus (%), which was supported by phase contrast microscopy.

Priestia megaterium Metabolism: Isolation, Identification of Naringenin Analogues and Genes Elevated Associated with Nanoparticle Intervention.

The impact of gold nanoparticles (AuNPs) on the biosynthetic manipulation of Priestia megaterium metabolism where an existing gene cluster is enhanced to produce and enrich bioactive secondary metabolites has been studied previously. In this research, we aimed to isolate and elucidate the structure of metabolites of compounds 1 and 2 which have been analyzed previously in P. megaterium crude extract. This was achieved through a PREP-ODS C18 column with an HPLC-UV/visible detector. Then, the compounds were subjected to nuclear magnetic resonance (NMR), electrospray ionization mass spectrometry (ESI-MS), and Fourier-transform infrared spectroscopy (FT-IR) techniques. Furthermore, bioinformatics and transcriptome analysis were used to examine the gene expression for which the secondary metabolites produced in the presence of AuNPs showed significant enhancement in transcriptomic responses. The metabolites of compounds 1 and 2 were identified as daidzein and genistein, respectively. The real-time polymerase chain reaction (RT-PCR) technique was used to assess the expression of three genes (csoR, CHS, and yjiB) from a panel of selected genes known to be involved in the biosynthesis of the identified secondary metabolites. The expression levels of two genes (csoR and yijB) increased in response to AuNP intervention, whereas CHS was unaffected.

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.

Draft genome sequence of potato crop bacterial isolates and nanoparticles-intervention for the induction of secondary metabolites biosynthesis.

Introduction: Insights about the effects of gold nanoparticles (AuNPs) on the biosynthetic manipulation of unknown microbe secondary metabolites could be a promising technique for prospective research on nano-biotechnology. Aim: In this research, we aimed to isolate a fresh, non-domesticated unknown bacterium strain from a common scab of potato crop located in Saudi Arabia and study the metabolic profile. Methodology: This was achieved through genomic DNA (gDNA) sequencing using Oxford Nanopore Technology. The genomic data were subjected to several bioinformatics tools, including canu-1.9 software, Prokka, DFAST, Geneious Prime, and AntiSMASH. We exposed the culture of the bacterial isolate with different concentrations of AuNPs and investigated the effects of AuNPs on secondary metabolites biosynthesis using several analytical techniques. Furthermore, Tandem-mass spectrometric (MS/MS) technique was optimized for the characterization of several significant sub-classes. Results: The genomic draft sequence assembly, alignment, and annotation have verified the bacterial isolate as Priestia megaterium. This bacterium has secondary metabolites related to different biosynthetic gene clusters. AuNPs intervention showed an increase in the production of compounds with the molecular weights of 254 and 270 Da in a direct-dependent manner with the increase of the AuNPs concentrations. Conclusion: The increase in the yields of compound 1 and 2 concomitantly with the increase in the concentration of the added AuNPs provide evidences about the effects of nanoparticles on the biosynthesis of the secondary metabolites. It contributes to the discovery of genes involved in different biosynthetic gene clusters (BGCs) and prediction of the structures of the natural products.

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.

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.

Piperazine ring toxicity in three novel anti-breast cancer drugs: an in silico and in vitro metabolic bioactivation approach using olaparib as a case study.

The metabolic activation of small-molecule drugs into electrophilic reactive metabolites is widely recognized as an indicator of idiosyncratic adverse drug reactions (IADRs). Three novel anti-breast cancer drugs containing piperazine rings, ribociclib (Kisqali®, RCB), abemaciclib (Verzenio®, ABC), and olaparib (Lynparza®, OLP), were selected to study the effect of different chemical environment on the piperazine ring activation using in silico and in vitro metabolic experiments. ABC and RCB were previously studied and we noticed the piperazine ring in ABC could be strongly bioactivated generating more reactive intermediates than piperazine ring in RCB. OLP was further used as a case study to show the power of in silico software to predict the piperazine ring activation that was approved using in vitro experiments. Initially, predictions of susceptible sites in the metabolism and reactivity pathways were performed using the StarDrop P450 model and XenoSite reactivity tool, respectively. Later, in vitro OLP metabolites were characterized based on rat liver microsomes (RLMs) using KCN (trapping agent) using LC-MS/MS. The main goal of the current study was to answer the question of whether the presence of a piperazine ring in the chemical structure should be always considered a structural alert. Piperazine ring in RBC and ABC was bioactivated through a metabolic sequence that involves the hydroxylation of α-carbon to the tertiary nitrogen atoms of the piperazine ring. In the case of OLP, no cyano adduct was formed due to the presence of two carbonyl groups attached to the two nitrogen atoms of the piperazine ring (neutral amide groups). From the results, piperazine ring in certain cases should not be considered as a structural alert as in the case of OLP due to the presence of two electron withdrawing group that stops the proposed toxicity. Also blocking the bioactive center (α-carbon) using steric hindrances such as methyl group, also the isosteric replacement of α-carbon hydrogen with fluoro atom can aid in reducing the toxic side effects of ABC and RCB. These experiments were done in vitro through incubation with RLMs in the presence of KCN. Also, the results are supported by data generated from in silico software. In the future, drug discovery studies using this concept could be undertaken, allowing for the development of new drugs with reasonable safety profiles. Overall, in vitro RLMs incubations and in silico experiments were able to predict successfully that the piperazine ring should not always be considered a structural alert.

Significant pharmacological activities of benzoquinazolines scaffold.

Benzoquinazolines, the essential constituents of numerous well-known heterocyclic systems, have occupied a prominent position and played a significant part in the synthesis of various pharmaceutical compounds. The wide range of pharmacological effects attributed to benzoquinazolines has been the subject of extensive study. These include their roles as anticancer, antimicrobial, anti-monoamine oxidase, anticonvulsant, antiviral, antinociceptive, antioxidant, antineoplastic, antituberculosis, antiplatelet, and antiphlogistic agents. This work provides an attempt at a literature review of the pharmacological activities of benzoquinazoline derivatives, including an up-to-date account of recent research findings, and suggests avenues for future exploration in the pursuit of more potent and specific analogues for a wide range of biological targets using this platform.

Reactivity of 4,5-Dichlorophthalic Anhydride towards Thiosemicarbazide and Amines: Synthesis, Spectroscopic Analysis, and DFT Study.

The cyclic anhydrides are broadly employed in several fields, such as the chemical, plastic, agrochemical, and pharmaceutical industries. This study describes the chemical reactivity of 4,5-dichlorophthalic anhydride towards several nucleophiles, including thiosemicarbazide and different amines, to produce the carboxylic acid derivatives resulting from anhydride's opening, namely, phthalimide and dicarboxylic acid (1-12) products. Their chemical structures are confirmed by NMR, IR and MS spectra analyses. Density-functional theory (DFT) studies are performed using (DFT/B3LYP) with the 6-311G(d, p) basis sets to recognize different chemical and physical features of the target compounds.

Investigation of 4-Hydrazinobenzoic Acid Derivatives for Their Antioxidant Activity: In Vitro Screening and DFT Study.

Hydrazinobenzoic acid derivatives with isothiocyanate, benzylidene, and acid anhydride core units (1-13) were previously synthesized and fully characterized. Targets 1-13 were investigated for their antioxidant activities using different in vitro assays such as 1,1-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging, 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonate) (ABTS), ferric reducing antioxidant power (FRAP), and reducing power capability. All derivatives showed antioxidant properties in relation to the standard butylated hydroxylanisole (BHA). Superior antioxidant activities was observed for compounds 3 and 5-9 at a concentration of 20 µg/mL (70-72%) when tested by the DPPH method in comparison to BHA (92%), and compounds 1-10 showed the highest free radical quenching activity (80-85%) when examined by ABTS at 20 µg/mL in relation to BHA (85%). Density function theory (DFT) studies were carried out using the B3LYP/6-311G(d,p) level of theory. Several antioxidant descriptors were calculated for targets 1-13 compared with BHA. Targets 1-13 were proposed to exhibit their antioxidant activities via the following three proposed antioxidant mechanisms: single electron transfer (SET), hydrogen atom transfer (HAT), and sequential proton loss electron transfer (SPLET). The highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) energies and electron levels for 1-13 were also determined.

Genetic Insights into the Middle East Respiratory Syndrome Coronavirus Infection among Saudi People.

BACKGROUND: The Middle East respiratory syndrome coronavirus (MERS-CoV) was isolated for the first time in Saudi Arabia from a patient suffering from atypical pneumonia. The Saudi Genome database was built by King Abdulaziz Medical City via the next-generation sequencing of 7000 candidates. METHOD: A large list of point mutations were reported in the region of the dipeptidyl peptidase 4 (DPP4) gene. The DPP4 amino acid residues correlated to MERS-CoV entry and the site of activity of DPP4 inhibitors was investigated. We retrieved the SNPs (Single-Nucleotide Polymorphism) with a variation frequency of >0.05. RESULTS: SNP 2:162,890,175 and SNP 2:162,891,848 in the intronic region were located within 50 bp of amino acid residues responsible for MERS-CoV entry, amino acids 259-296 and 205-258, respectively. The variation frequency of SNP 2:162,890,175 was 2321 out of 2379 screened individuals. Moreover, mutation of SNP 2:162,891,848, which is located near amino acid residues E205 and E206 (crucial for the activity of DPP4 inhibitors), occurred in 76 out of 2379 screened individuals. CONCLUSIONS: Our study shows high variation frequency in the DPP4 region reported in the Saudi Genome database. The identified SNPs are of high significance for MERS-CoV infection in better understanding disease pathogenesis.

In silico study and biological screening of benzoquinazolines as potential antimicrobial agents against methicillin-resistant Staphylococcus aureus, carbapenem-resistant Klebsiella pneumoniae, and fluconazole-resistant Candida albicans.

Globally, antibiotic-resistant pathogens have become a serious threat to public health. The use of drugs having structures different from those applied in the clinical treatments of bacterial infections is a well-known potential solution to the antibiotic resistance crisis. Benzo-[g]-quinazolines were identified by our research group as a new class of antimicrobial agents. Herein, to follow-up the research on such compounds, three benzo-[g]-quinazolines (1-3) were studied, as in vitro antibacterial candidates against methicillin-resistant Staphylococcus aureus (MRSA), carbapenem-resistant Klebsiella pneumoniae, and fluconazole-resistant Candida albicans, as well. The minimum inhibitory concentration (MIC) assay for benzoquinazolines was carried out via the calorimetric broth microdilution method using the XTT assay in comparison with vancomycin, ciprofloxacin, and ketoconazole as reference drugs. The target compounds 1-3 revealed high variation in their activity against the examined resistant microbial strains. Benzoquinazoline 3 exhibited a more potent effect against the resistant strains compared with the reference drugs. A docking study was performed to identify the interactions between the benzoquinazolines 1-3 and ligand proteins (OXA-48 carbapenemase, ß-lactamase, and sterol 14-alpha demethylase (CYP51)) at the active sites. Benzoquinazolines 1-3 showed very weak cytotoxicity against human lung fibroblast normal cells (WI-38). The targets showed promising antimicrobial effects against the three resistant strains. These findings may inform future inhibitor discoveries targeting penicillin-binding proteins.

An overview of triazoloquinazolines: Pharmacological significance and recent developments.

Nitrogen heterocyclic rings have participated to constitute most of the drugs and several pharmacologically related compounds. The existence of such hetero atoms/groups in heterocyclic systems privileged specificities in their biological objectives. Particularly, quinazoline and triazole are biologically imperative platforms known to be linked with various pharmacological activities. Some of the prominent pharmacological responses ascribed to these systems are analgesic, antiinflammatory, anticonvulsant, hypnotic, antihistaminic, antihypertensive, anticancer, antimicrobial, antitubercular, antiviral and antimalarial activities. This diversity in the pharmacological outputs for both triazole and quinazoline systems has encouraged the medicinal chemistry researchers to create several chemical routes aiming at the incorporation of two rings in one molecule named triazoloquinazoline system. This system has shown multiple potential activities against numerous targets. Correlation the specific structural features of triazoloquinazoline system with its pharmacological purposes has successively been achieved by performing several pharmacological examinations and structure-activity relationship studies. The development of triazoloquinazoline derivatives and the understanding of their pharmacological targets offer opportunities for novel therapeutics. This review mainly emphases on the medicinal chemistry aspects of triazoloquinazolines including synthesis, reactivity, biological activity and structure activity relationship studies (SARs). Moreover, this review collates literature reported by researchers on triazoquinazolines and provides detailed attention on their analogs pharmacological activities in the perspective of drug development and discovery.

Antiproliferative and Antiangiogenic Properties of New VEGFR-2-targeting 2-thioxobenzo[g]quinazoline Derivatives (In Vitro).

A series of 3-ethyl(methyl)-2-thioxo-2,3-dihydrobenzo[g]quinazolines (1-17) were synthesized, characterized, and evaluated in vitro for their antiangiogenesis VEGFR-2-targeting, antiproliferative, and antiapoptotic activities against breast MCF-7 and liver HepG2 cells. Flow cytometry was used to determine cancer-cell cycle distributions, and apoptosis was detected using annexin-V-FITC (V) and propidium iodide (PI) dyes. Fluorescence microscopy, in combination with Hoechst staining was used to detect DNA fragmentation. Most of the tested benzo[g]quinazolines demonstrated promising activity (IC50 = 8.8 ± 0.5-10.9 ± 0.9 µM) and (IC50 = 26.0 ± 2.5-40.4 ± 4.1 µM) against MCF-7 and HepG2, respectively. Doxorubicin was used as a reference drug. Compounds 13-15 showed the highest activity against both cancer cell lines. Differential effects were detected by cell-cycle analysis, indicating similarities in the actions of 13 and 14 against both MCF7 and HepG2, involving the targeting of G1 and S phases, respectively. Compound 15 showed similar indices against both cells, indicating that its cytotoxicity toward the examined cancer cells could be unselective. Interestingly, 14 and 15 showed the highest apoptosis (30.76% and 25.30%, respectively) against MCF-7. The DNA fragmentation results agreed well with the apoptosis detected by flow cytometry. In terms of antiangiogenesis activity, as derived from VEGFR-2 inhibition, 13 and 15 were comparable to sorafenib and effected 1.5- and 1.4-fold inhibition relative to the standard sorafenib. A docking study was conducted to investigate the interaction between the synthesized benzo[g]quinazolines and the ATP-binding site within the catalytic domain of VEGFR-2.

Exploiting the 4-hydrazinobenzoic acid moiety for the development of anticancer agents: Synthesis and biological profile.

Thirteen 4-hydrazinobenzoic acid derivatives were elaborated and characterized by spectral analyses (NMR and MS). Evaluation of their in vitro cytotoxic activity showed that some of the targets demonstrated potent inhibitory effects against HCT-116 and MCF-7 cancer cells. The IC50 values ranged between 21.3 ± 4.1 and 28.3 ± 5.1 µM, respectively, whereas those of doxorubicin (reference drug) ranged between 22.6 ± 3.9 and 19.7 ± 3.1 µM, respectively. The active targets 6, 7 and 9 exhibited very weak cytotoxicity on normal cells (RPE-1) and showed higher IC50 values against HCT-116 and MCF-7 cells in comparison to doxorubicin. Furthermore, compounds 7, 9 and 10 inhibited the proliferation of MCF-7 by the induction of apoptosis. The bioassay results in the regression plots generated in 3D QSAR models were in agreement and correlated with the anticancer results of the target molecules. The 4-hydazinobenzoic acid derivatives can be used as cornerstones for further structural modifications as future anticancer agents.