Synthesis of Novel Triazine-Based Chalcones and 8,9-dihydro-7H-pyrimido[4,5-b][1,4]diazepines as Potential Leads in the Search of Anticancer, Antibacterial and Antifungal Agents.

This study presents the synthesis of four series of novel hybrid chalcones (20,21)a-g and (23,24)a-g and six series of 1,3,5-triazine-based pyrimido[4,5-b][1,4]diazepines (28-33)a-g and the evaluation of their anticancer, antibacterial, antifungal, and cytotoxic properties. Chalcones 20b,d, 21a,b,d, 23a,d-g, 24a-g and the pyrimido[4,5-b][1,4]diazepines 29e,g, 30g, 31a,b,e-g, 33a,b,e-g exhibited outstanding anticancer activity against a panel of 60 cancer cell lines with GI50 values between 0.01 and 100 µM and LC50 values in the range of 4.09 µM to >100 µM, several of such derivatives showing higher activity than the standard drug 5-fluorouracil (5-FU). On the other hand, among the synthesized compounds, the best antibacterial properties against N. gonorrhoeae, S. aureus (ATCC 43300), and M. tuberculosis were exhibited by the pyrimido[4,5-b][1,4]diazepines (MICs: 0.25-62.5 µg/mL). The antifungal activity studies showed that triazinylamino-chalcone 29e and triazinyloxy-chalcone 31g were the most active compounds against T. rubrum and T. mentagrophytes and A. fumigatus, respectively (MICs = 62.5 µg/mL). Hemolytic activity studies and in silico toxicity analysis demonstrated that most of the compounds are safe.

1,3-Disubstituted-1,2,4-triazin-6-ones with potent activity against androgen receptor-dependent prostate cancer cells.

Synthesis and biological evaluation of a small, focused library of 1,3-disubstituted-1,2,4-triazin-6-ones for in vitro inhibitory activity against androgen-receptor-dependent (22Rv1) and androgen-receptor independent (PC3) castration-resistant prostate cancer (CRPC) cells led to highly active compounds with in vitro IC50 values against 22Rv1 cells of <200 nM, and with apparent selectivity for this cell type over PC3 cells. From metabolic/PK evaluations of these compounds, a 3-benzyl-1-(2,4-dichlorobenzyl) derivative had superior properties and showed considerably stronger activity, by nearly an order of magnitude, against AR-dependent LNCaP and C4-2B cells compared to AR-independent DU145 cells. This lead compound decreased AR expression in a dose and time dependent manner and displayed promising therapeutic effects in a 22Rv1 CRPC xenograft mouse model. Computational target prediction and subsequent docking studies suggested three potential known prostate cancer targets: p38a MAPK, TGF-ß1, and HGFR/c-Met, with the latter case of c-Met appearing stronger, owing to close structural similarity of the lead compound to known pyridazin-3-one derivatives with potent c-Met inhibitory activity. RNA-seq analysis showed dramatic reduction of AR signalling pathway and/or target genes by the lead compound, subsequently confirmed by quantitative PCR analysis. The lead compound was highly inhibitory against HGF, the c-Met ligand, which fitted well with the computational target prediction and docking studies. These results suggest that this compound could be a promising starting point for the development of an effective therapy for the treatment of CRPC.

Cystoisospora spp. infection at a dog breeding facility in the Madrid region: Infection rate and clinical management based on toltrazuril metaphylaxis.

Canine coccidiosis caused by Cystoisospora canis and Cystoisospora ohioensis-complex is common in kennels. While often underestimated, coccidiosis may cause severe clinical signs in puppies and sometimes even lead to death, so preventative measures are important. This study examines Cystoisospora spp. infection at a Labrador retriever breeding facility in Madrid, Spain. To identify environmental factors associated with infection, dams were examined throughout a reproductive cycle (from oestrus to 60 days postpartum) and their puppies during their first 60 days of life. Also assessed was the efficacy of combined treatment with emodepside (0.9 mg/ml) and toltrazuril (18 mg/ml) at a dose of 0.5 ml/kg of weight, equivalent to 0.45 mg/kg and 9 mg/kg, respectively, in puppies on day 35 of life. Oocyst shedding was detected in 4.6-18.6% of 45 dams examined and in 2.2-9.1% of their litters (315 puppies). In both cases, peak opg elimination was recorded on day 30 postpartum/of life. The species of Cystoisospora detected were C. canis (91.3%) and C. ohioensis-complex (8.7%). While in both dams and puppies opg counts were higher in autumn when rainfall was at its highest, correlation between opg and rainfall emerged as significant only in puppies (p = 0.031). The treatment of 35 day-old puppies with toltrazuril was 100% effective in controlling this infection in the kennel. Our findings therefore suggest the need for a strict hygiene regime and the use of toltrazuril as blanket treatment to reduce Cystoisospora transmission in dog breeding facilities.

Discovery of a Macrocyclic Influenza Cap-Dependent Endonuclease Inhibitor.

Influenza viruses (IFVs) have caused several pandemics and have claimed numerous lives since their first record in the early 20th century. While the outbreak of COVID-19 seemed to expel influenza from the sight of people for a short period of time, it is not surprising that it will recirculate around the globe after the coronavirus has mutated into a less fatal variant. Baloxavir marboxil (1), the prodrug of baloxavir (2) and a cap-dependent endonuclease (CEN) inhibitor, were approved by the FDA for the first treatment in almost 20 years. Despite their high antiviral potency, drug-resistant variants have been observed in clinical trials. Herein, we report a novel CEN inhibitor 8 with a delicately designed macrocyclic scaffold that exhibits a significantly smaller shift of inhibitory activity toward baloxavir-resistant variants.

Tri-substituted 1,3,5-triazine-based analogs as effective HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs): A systematic review.

Non-nucleoside reverse transcriptase inhibitors (NNRTIs) have significantly impacted the HIV-1 wild-type due to their high specificity and superior potency. As well as different combinations of NNRTIs have been used on clinically approved combining highly active antiretroviral therapy (HAART) to resist the growth of HIV-1 and decrease the mortality rate of HIV/AIDS. Although the feeble strength against the drug-resistant mutant strains and the long-term damaging effects have been reducing the effectiveness of HAART, it could be a crucial challenge to develop novel Anti-HIV leads with a vital mode of action and the least side effects. The extensive chemical reactivity and the diverse chemotherapeutic applications of the 1,3,5-triazine have provided a wide scope of research in medicinal chemistry via a structural modification. In this review, we focused on the Anti-HIV profile of the tri-substituted s-triazine derivatives with structure-based features and also discussed the active mode of action to evaluate the significant findings. The tri-substituted 1,3,5-triazine derivatives have been found more promising to inhibit the growth of the drug-sensitive and drug-resistant variants of HIV-1, especially HIV-1 wild-type, HIV-1 K103N/Y181C, and HIV-1 Tyr181Cys. It has been observed that these derivatives have interacted with the enzyme protein residues via a significant π $\pi $ - π $\pi $ interaction and hydrogen bonding to resist the proliferation of the viral genomes. Further, the SAR and the active binding modes are critically described and highlight the role of structural variations with functional groups along with the binding affinity of targeted enzymes, which may be beneficial for rational drug discovery to develop highly dynamic Anti-HIV agents.

Metaphylactic strategies using toltrazuril against coccidiosis in goat kids.

Goat coccidiosis compromises animal welfare, reduces productivity and may cause mortality and delayed growth rates in goat kids around the weaning period worldwide. This field study was conducted to evaluate the efficacy of metaphylactic treatments with two doses of toltrazuril (20 or 40 mg/kg body weight - BW, p. o.), at different timing, in kids naturally infected with Eimeria spp. A total of 97 healthy goat kids (Majorera milk aptitude breed) were divided into five groups, depending on the age of treatment (2 or 7 weeks). One group remained untreated as a negative control until the end of the study. Faecal oocyst shedding, faecal consistency, and body weight of the animals were monitored at day 0 and at weekly intervals. Counts of oocysts per gram of faeces (OPG) were determined by a modified McMaster technique. Morphometric identification of Eimeria species was carried out on individual faecal samples from each experimental group after oocyst sporulation. Goat kids treated at two weeks of age maintained OPG values close to zero during the 5 weeks post-treatment and, overall, had lower faecal oocyst counts than untreated control animals. No significant differences were observed between the two doses of toltrazuril used in two-week-old treated animals. By contrast, when treatment was carried out at seven weeks of age, the dose of 40 mg/kg BW of toltrazuril reduced oocyst levels for longer and to a greater extent than the 20 mg/kg dose. Irrespectively of the treatment and dose, toltrazuril delayed the appearance of pathogenic Eimeria species, i. e. Eimeria ninakohlyakimovae and Eimeria arloingi. As a whole, Eimeria christenseni, with a rather moderate pathogenicity, was highly predominant throughout the study period, including the untreated control group, which was probably the reason why clinical signs of coccidiosis were barely observed throughout the experiment. Under these circumstances, the positive effect of toltrazuril on body weight condition observed in some treated groups was difficult to correlate to the timing and doses. Metaphylactic treatments with 20 mg/kg BW toltrazuril given at two weeks of age are sufficient to control oocyst excretion in goat kids; whereas if administered later in 7-week-old animals, thereby coinciding with the frequently observed peak of oocyst elimination in goat kids under field conditions, a higher dose might be advisable to prevent environmental contamination with infectious oocysts.

Ponazuril: Clinical efficacy, ultrastructure, and histopathology studies of in vivo anticoccidial action against Eimeria tenella.

Ponazuril, a novel antiprotozoal drug in the class of triazine, has shown a promising application on apicomplexan infections in poultry and livestock. However, the effect and mechanism of action of ponazuril against Eimeria tenella (E. tenella) are unclear. The efficacy against E. tenella was initially studied by administering different doses of ponazuril in drinking water. The treated stage and site of ponazuril on E. tenella were observed through ultrastructural and histopathological analyses. Chicks were orally treated with a dose of 15 mg/kg body weight of ponazuril at different endogenous stages of E. tenella post-infection. According to the clinical study, the values of anticoccidial indices (ACI) were 157.0, 162.3, 196.9, 194.5, and 190.9, respectively, when the ponazuril was administered in drinking water at doses of 5, 10, 20, 40, and 50 mg/L for two consecutive days after infection. Among them, the 20 mg/L ponazuril group showed the best anticoccidial effect, which was superior to that of the toltrazuril treatment group, with an ACI value of 191.7. Histological analysis indicated that ponazuril effectively relieved cecal lesions, and decreased the number of merozoites. Transmission electron micrographs (TEM) observed that merozoites became irregular in shape, and some apparent protrusions of the outer membrane were presented especially the second-generation merozoites. Additionally, abnormalities in the development of WFBI and WFBII in the macrogametocyte were observed, which may affect the formation of the ovule wall. Moreover, merozoites in the treated group showed uneven and marginalized chromatin and mitochondrial swelling. These results suggested ponazuril is a potential anticoccidial drug, providing information on the mechanism of anticoccidial effects.

Structural Studies of Inhibitors with Clinically Relevant Influenza Endonuclease Variants.

Vital to the treatment of influenza is the use of antivirals such as Oseltamivir (Tamiflu) and Zanamivir (Relenza); however, antiviral resistance is becoming an increasing problem for these therapeutics. The RNA-dependent RNA polymerase acidic N-terminal (PAN) endonuclease, a critical component of influenza viral replication machinery, is an antiviral target that was recently validated with the approval of Baloxavir Marboxil (BXM). Despite its clinical success, BXM has demonstrated susceptibility to resistance mutations, specifically the I38T, E23K, and A36 V mutants of PAN. To better understand the effects of these mutations on BXM resistance and improve the design of more robust therapeutics, this study examines key differences in protein-inhibitor interactions with two inhibitors and the I38T, E23K, and A36 V mutants. Differences in inhibitor binding were evaluated by measuring changes in binding to PAN using two biophysical methods. The binding mode of two distinct inhibitors was determined crystallographically with both wild-type and mutant forms of PAN. Collectively, these studies give some insight into the mechanism of antiviral resistance of these mutants.

Synthetic and pharmacological developments in the hybrid s-triazine moiety: A review.

This article summarizes the most recent advancements in the synthetic and pharmacological approaches along with the structure activity relationship towards the s-triazine and its derivatives. Much attention has been given to s-triazine core due to its facile synthesis, interesting pharmacology, high reactivity, and binding characteristics towards various enzymes. An array of biological applications has been demonstrated by s-triazines including antimalarial, anti-HIV, anti-viral, antimicrobial, anti-tuberculosis to name a few. In the present investigation s-triazine based molecular structures have been assembled in respect to their synthesis and medicinal properties. Further, the competence of s-triazine has been correlated and compared with the other heterocyclic moieties to substantiates-triazine a privileged scaffold. From the literature it is revealed that nucleophilic substitution at 2, 4, and 6 positions is significant for various biological applications. This article would help in assisting the chemists in designing novel molecular entities with high medicinal value.

Synthesis and evaluation of novel pleuromutilin derivatives targeting the 50S ribosomal subunit for antibacterial ability.

Multidrug-resistant bacteria, particularly methicillin-resistant Staphylococcus aureus, have become a major global public health concern. Therefore, developing new antibiotics that do not possess cross-resistance for the currently available antibiotics is critical. Herein, we synthesized a novel class of pleuromutilin derivatives containing substituted triazine with improved antibacterial activity. Among these derivatives, 6d, which contains 4-dimethylamino-1,3,5-triazine in the side chain of pleuromutilin, exhibited highly promising antimicrobial activity and mitigated antibiotic resistance. The high antibacterial potency of 6d was further supported by docking model analysis and green fluorescent protein inhibition assay. Additionally, cytotoxicity and acute oral toxicity evaluation and in vivo mouse systemic infection experiments revealed that 6d possessed tolerable toxicity and promising therapeutic efficacy.

Hybrid PABA-glutamic acid conjugated 1,3,5-triazine derivatives: Design, synthesis, and antimalarial activity screening targeting Plasmodium falciparum dihydro folate reductase enzyme.

Despite the successful reduction in the malaria health burden in recent years, it continues to remain a significant global health problem mainly because of the emerging resistance to first-line treatments. Also because of the disruption in malaria prevention services during the COVID-19 pandemic, there was an increase in malaria cases in 2021 compared to 2020. Hence, the present study outlined the in silico study, synthesis, and antimalarial evaluation of 1,3,5-triazine hybrids conjugated with PABA-glutamic acid. Docking study revealed higher binding energy compared to the originally bound ligand WR99210, predominant hydrogen bond interaction, and involvement of key amino acid residues, like Arg122, Ser120, and Arg59. Fourteen compounds were synthesized using traditional and microwave synthesis. The in vitro antimalarial evaluation against chloroquine-sensitive 3D7 and resistant Dd2 strain of Plasmodium falciparum showed a high to moderate activity range. Compounds C1 and B4 showed high efficacy against both strains and a further study revealed that compound C1 is non-cytotoxic against the HEK293 cell line with no acute oral toxicity. In vivo, study was performed for the most potent antimalarial compound C1 to optimize the research work and found to be effectively suppressing parasitemia of Plasmodium berghei strain in the Swiss albino mice model.

Battling colorectal cancer via s-triazine-based MMP-10/13 inhibitors armed with electrophilic warheads for concomitant ferroptosis induction; the first-in-class dual-acting agents.

There is an increasing interest in halting CRC by combining ferroptosis with other forms of tumor cell death. However, ferroptosis induction is seldom studied in tandem with inhibiting MMPs. A combination that is expected to enhance the therapeutic outcome based on mechanistic ferroptosis studies highlighting the interplay with MMPs, especially MMP-13 associated with CRC metastasis and poor prognosis. Herein, we report new hybrid triazines capable of simultaneous MMP-10/13 inhibition and ferroptosis induction bridging the gap between their anticancer potentials. The MMP-10/13 inhibitory component of the scaffold was based on the non-hydroxamate model inhibitors. s-Triazine was rationalized as the core inspired by altretamine, an FDA-approved ferroptosis inducer. The ferroptosis pharmacophores were then installed as Michael acceptors via triazole-based spacers. The electrophilic reactivity was tuned by incorporating cyano and/or substituted phenyl groups influencing their electronic and steric properties and enriching the SAR study. Initial screening revealed the outstanding cytotoxicity profiles of the nitrophenyl-tethered chalcone 5e and the cyanoacrylohydrazides bearing p-fluorophenyl 9b and p-bromophenyl 9d appendages. 9b and 9d surpassed NNGH against MMP-10 and -13, especially 9d (IC50 = 0.16 µM). Ferroptosis studies proved that 9d depleted GSH in HCT-116 cells by a relative fold decrement of 0.81 with modest direct GPX4 inhibition, thus inducing lipid peroxidation, the hallmark of ferroptosis, by 1.32 relative fold increment. Docking presumed that 9d could bind to the MMP-10 S1' pocket and active site His221, extend through the MMP-13 hydrophobic pocket, and interact covalently with the GPX4 catalytic selenocysteine. 9d complexed with ferrous oxide nanoparticles was 7.5 folds more cytotoxic than its free precursor against HCT-116 cells. The complex-induced intracellular iron overload, depleted GSH with a relative fold decrement of 0.12, consequently triggering lipid peroxidation and ferroptosis by a 3.94 relative fold increment. Collectively, 9d could be a lead for tuning MMPs selectivity and ferroptosis induction potential to maximize the benefit of such a combination.

Diphenyl-substituted triazine derivatives: synthesis, α-glucosidase inhibitory activity, kinetics and in silico studies.

Background: Diabetes mellitus (DM) is a chronic disorder, considered to be a major global health challenge in the 21st century. α-Glucosidase enzyme is a well-known drug target to treat Type II DM. Methods: A new library of biphenyl-substituted triazines was synthesized and confirmed by various spectroscopic techniques. Results: All compounds showed potent α-glucosidase inhibitory activity, with IC50 values ranging from 35.35 ± 0.34 to 564.41 ± 0.91 µM, as the standard acarbose, IC50 value of 750.7 ± 0.13 µM. Our in silico study has predicted key interactions with the enzyme's active site. Drug-likeness and absorption, distribution, metabolism, excretion and toxicity were also studied. Conclusion: This study has identified a range of potential hits against the α-glucosidase enzyme that may serve as antidiabetic agents after further investigations.

Design, synthesis and biological evaluation of 2,4,6- trisubstituted triazine derivatives as new nonpeptide small-molecule SIRT5 inhibitors.

Human sirtuin 5 (SIRT5) participates in a variety of metabolic disorder-associated diseases, including cancer. Inhibition of SIRT5 has been confirmed to provide a new strategy for treatment of related diseases. Previously, we discovered a pyrimidine skeleton inhibitor XIV, which showed low micromolar inhibitory activity against SIRT5. Herein, we utilized the scaffold-hopping strategy to design and synthesize a series of 2,4,6- trisubstituted triazine derivatives. The SAR analysis led to the discovery of several new SIRT5 inhibitors with low micromolar inhibition levels. The most potent compounds 10 (IC50 = 5.38 µM), and 14 (IC50 = 4.07 µM) were further confirmed to be the substrate-competitive SIRT5 inhibitors through enzyme kinetic assays, which is consistent with the molecular docking analyses. Fluorescence-based thermal shift assays proved that these compounds may stabilize SIRT5 by binding withprotein.. In addition, compounds 10 and 14 were also revealed to have moderate selectivity to SIRT5 over SIRT1-3. This study will aid further efforts to develop highly potent and selective SIRT5 inhibitors for the treatment of cancer and other related diseases.

New insights into the antimicrobial action and protective therapeutic effect of tirapazamine towards Escherichia coli-infected mice.

OBJECTIVES: Escherichia coli is an important pathogen responsible for numerous cases of diarrhoea worldwide. The bioreductive agent tirapazamine (TPZ), which was clinically used to treat various types of cancers, has obvious antibacterial activity against E. coli strains. In the present study, we aimed to evaluate the protective therapeutic effects of TPZ in E. coli-infected mice and provide insights into its antimicrobial action mechanism. METHODS: The MIC and MBC tests, drug sensitivity test, crystal violet assay and proteomic analysis were used to detect the in vitro antibacterial activity of TPZ. The clinical symptoms of infected mice, tissue bacteria load, histopathological features and gut microbiota changes were regarded as indicators to evaluation the efficacy of TPZ in vivo. RESULTS: Interestingly, TPZ-induced the reversal of drug resistance in E. coli by regulating the expression of resistance-related genes, which may have an auxiliary role in the clinical treatment of drug-resistant bacterial infections. More importantly, the proteomics analysis showed that TPZ upregulated 53 proteins and downregulated 47 proteins in E. coli. Among these, the bacterial defence response-related proteins colicin M and colicin B, SOS response-related proteins RecA, UvrABC system protein A, and Holliday junction ATP-dependent DNA helicase RuvB were all significantly upregulated. The quorum sensing-related protein glutamate decarboxylase, ABC transporter-related protein glycerol-3-phosphate transporter polar-binding protein, and ABC transporter polar-binding protein YtfQ were significantly downregulated. The oxidoreductase activity-related proteins pyridine nucleotide-disulfide oxidoreductase, glutaredoxin 2 (Grx2), NAD(+)-dependent aldehyde reductase, and acetaldehyde dehydrogenase, which participate in the elimination of harmful oxygen free radicals in the oxidation-reduction process pathway, were also significantly downregulated. Moreover, TPZ improved the survival rate of infected mice; significantly reduced the bacteria load in the liver, spleen, and colon; and alleviated E. coli-associated pathological damages. The gut microbiota also changed in TPZ-treated mice, and these genera were considerably differentiated: Candidatus Arthromitus, Eubacterium coprostanoligenes group, Prevotellaceae UCG-001, Actinospica, and Bifidobacterium. CONCLUSIONS: TPZ may represent an effective and promising lead molecule for the development of antimicrobial agents for the treatment of E. coli infections.

Pyrazolo[4,3-e]tetrazolo[1,5-b][1,2,4]triazine Sulfonamides as an Important Scaffold for Anticancer Drug Discovery-In Vitro and In Silico Evaluation.

Pyrazolo[4,3-e]tetrazolo[1,5-b][1,2,4]triazine sulfonamides (MM-compounds) are a relatively new class of heterocyclic compounds that exhibit a wide variety of biological actions, including anticancer properties. Here, we used caspase enzyme activity assays, flow cytometry analysis of propidium iodide (PI)-stained cells, and a DNA laddering assay to investigate the mechanisms of cell death triggered by the MM-compounds (MM134, -6, -7, and -9). Due to inconsistent results in caspase activity assays, we have performed a bromodeoxyuridine (BrdU) incorporation assay, colony formation assay, and gene expression profiling. The compounds' cytotoxic and pro-oxidative properties were also assessed. Additionally, computational studies were performed to demonstrate the potential of the scaffold for future drug discovery endeavors. MM-compounds exhibited strong micromolar (0.06-0.35 µM) anti-proliferative and pro-oxidative activity in two cancer cell lines (BxPC-3 and PC-3). Activation of caspase 3/7 was observed following a 24-h treatment of BxPC-3 cells with IC50 concentrations of MM134, -6, and -9 compounds. However, no DNA fragmentation characteristics for apoptosis were observed in the flow cytometry and DNA laddering analysis. Gene expression data indicated up-regulation of BCL10, GADD45A, RIPK2, TNF, TNFRSF10B, and TNFRSF1A (TNF-R1) following treatment of cells with the MM134 compound. Moreover, in silico studies indicated AKT2 kinase as the primary target of compounds. MM-compounds exhibit strong cytotoxic activity with pro-oxidative, pro-apoptotic, and possibly pro-necroptotic properties that could be employed for further drug discovery approaches.

Novel fused imidazotriazines acting as promising top. II inhibitors and apoptotic inducers with greater selectivity against head and neck tumors: Design, synthesis, and biological assessments.

Although the great effectiveness of doxorubicin (Dox) in the treatment of many types of tumors, it showed limited effectiveness against the head and neck squamous cell carcinoma (HNSCC) subtype which is attributed to its reported multiple drug resistance (MDR). In the current study, we considered the essential pharmacophoric features of Dox as an effective Top. II inhibitor and sought to develop a novel set of imidazo[1,2-a] [1,3,5]triazin-2-amines (2a-2p) as a suggested anticancer option that could intercalate the DNA base pairs. We evaluated the % inhibition of the newly synthesized compounds on thirteen cancer cell lines and the analysis of structure-activity relationships revealed that the human head and neck cancer cell line (HNO97) was the most sensitive to their growth inhibition effect. Then, the IC50 values were recorded against the most sensitive cancer cell lines (HNO97, MDA-MB-231, and HEPG2), and compared to the normal cell line OEC (human oral epithelial cells). Compounds 2f and 2g showed very strong activities against HNO97 with IC50 values of (4 ± 1 and 3 ± 1.5 µg/mL), respectively, compared to that of Dox (9 ± 1.6 µg/mL). Next, a quantitative determination of human DNA Top. II concentrations in the most sensitive cell line (HNO97) were recorded for the most active anticancer derivatives. Again, compound 2f showed a superior Top. II inhibition with 87.86% compared to that of Dox (86.44%), while compound 2g achieved an inhibition of 81.37% which was close to the effect of Dox. To further investigate their effects on cell cycle progression and apoptosis induction in HNO97 cells, both 2f and 2g were selected for analysis. Both candidates arrested cell cycle progression at both the S and G2-M phases, as well as increased the early and late apoptosis phase ratios. Besides, both 2f and 2g were subjected to protein expression analysis of apoptosis-related genes (p53, BAX, IL-6, and BCL2). Moreover, the antioxidant effect of 2f and 2g was evaluated by measuring GSH, MDA, and NO markers in HNO97 cells. Furthermore, molecular docking for the newly designed tricyclic derivatives against both the Top. II and DNA double helix was carried out.

Discovery of novel 1,3,5-triazine derivatives as an antidiabetic agent in Wistar rats via inhibition of DPP-4.

Aim: To develop imeglimin-inspired novel 1,3,5-triazine derivatives as antidiabetic agents. Materials & methods: These derivatives were synthesized and tested against DPP enzymes. Compound 8c was tested for in vivo antidiabetic activity in streptozotocin-induced diabetes in Wistar rats by estimating various biochemical parameters. Docking experiments were also performed. Results: Compound 8c was identified as a selective and potent DPP-4 inhibitor. It was proficiently docked into the catalytic triad of Ser 630, Asp 710 and His740 in S1 and S2 pockets of DPP-4. In experimental animals, it also showed dose-dependent improvement in blood glucose, blood insulin, bodyweight, lipid profile and kidney and liver antioxidant profiles. Conclusion: This study demonstrated the discovery of imeglimin-inspired novel 1,3,5-triazines as a potent antidiabetic agent.

Type 2 diabetes mellitus is a complicated heterogeneous and polygenic metabolic disease. Therefore, in search of a potent antidiabetic drug, the authors have synthesized 13 novel 1,3,5-triazine-morpholino-pyrazole derivatives, compounds 8(a­m), and they were subsequently tested for in vitro inhibitory activity against a panel of DPP enzymes (DPP-4, DPP-8 and DPP-9) where they are found active toward DPP-4 while inactive toward DPP-8 and DPP-9. Compound 8c was observed to be the most potent DPP-4 inhibitor and showed excellent interaction with DPP-4 in docking analysis. Furthermore, in high-fat, low-dose streptozotocin-induced diabetes in rats, compound 8c significantly reduced blood glucose, cholesterol, triglyceride, low-density lipoprotein, very low-density lipoprotein and reactive species levels and increased high-density lipoprotein levels, possibly by the potent inhibition of DPP-4. It also showed intense antioxidant activity. The potent DPP-4 inhibition, antidiabetic and antioxidant activity render compound 8c a probable lead for antidiabetic drug discovery.

Membrane-active substituted triazines as antibacterial agents against Staphylococcus aureus with potential for low drug resistance and broad activity.

A library of new naphthalimide-triazine analogues was synthesized as broad-spectrum antibacterial agents to overcome drug resistance. Bioactivity assay reveals that derivative 8e, with benzylamine in its structure, exhibits strong antibacterial properties against multi-drug resistance Staphylococcus aureus at a concentration of 1.56 µg/ml. It was also found to be better than chloromycin and amoxicillin. The active compound 8e efficiently inhibits the development of drug resistance within 11 passages. In addition, compound 8e inhibits the formation of biofilms in S. aureus and acts rapidly in bactericidal efficacy. Furthermore, mechanistic studies reveal that compound 8e effectively destroys the cytoplasmic membrane of bacteria, leading to leakage of intercellular protein content and loss in metabolic activity. Compound 8e binds to HSA readily with a binding constant of 1.32 × 105 M-1, indicating that the compound could be delivered to the target site effectively. Compound 8e can also form a supramolecular complex with DNA to obstruct DNA replications. These results suggest that analogue 8e could be further developed as a potential antibacterial agent. Furthermore, the cytotoxicity of all the synthesized compounds was evaluated against 60 human cancer cell lines to test their potential for anticancer agents.