Synthesis, anticancer activity and molecular docking of new quinolines, quinazolines and 1,2,4-triazoles with pyrido[2,3-d] pyrimidines.

Recently, heterocyclic compounds such as pyrido [2,3-d] pyrimidinones, 1,2,4-triazolopyrimidines, pyrimidoquinazolines, and quinoline derivatives have gained attention from researchers due to their pharmacological and biological activities. To synthesize new compounds, quinoline-2-thioxopyrido [2,3-d] pyrimidinone (1) and methylthioquinoline-pyrido [2,3-d] pyrimidinones (2) were used as starting materials. The new compounds synthesized were quinoline-pyrido [2,3-d] (DeGoey et al., 2013; Gouda et al., 2020; Dangolani et al., 2018) [1, 2,4]triazolopyrimidinones (5a-d), 2-methylsulfonyl-quinoline-pyrido [2,3-d]pyrimidinone (6), pyrido [2,3-d]pyrimidine derivatives, pyridopyrimido (Gouda et al., 2020; DeGoey et al., 2013) 2,12,1-b] quinazoline (9), pyrido [(Khajouei et al., 2021; Gouda et al., 2020) 3,23,2-e]bis (1,2,4-triazole)pyrimidine (12a,b) and pyridopyrimido-diquinazoline-dione (16) derivatives. These compounds were synthesized with high efficiency, producing yields ranging from 69% to 90%, under moderate conditions, through treating (2) or (10) with various reagents such as anthranilic acid, phosphorus oxychloride, hydrazine hydrate, formic acid, glacial acetic acid, arylamine (aniline, 4-chloroaniline, or 4-methoxyaniline), and sec-amine (piperazine or morpholine). The new structures of the synthesized compounds were verified using various spectroscopic procedures, such as IR, NMR, and mass spectra. Molecular docking studies were carried out to investigate and discuss how the prepared compounds bind to amino acids such as Estrogen Receptor alpha, EGFR, and NADPH oxidase protein. Also, the synthesized products were tested for their anticancer and antioxidant activities against the (MCF-7) breast carcinoma cell line and human normal Retina pigmented epithelium cells (RPE-1). The study on the structure-activity relationship (SAR) established a correlation between the chemical structure of the newly synthesized compounds and their anticancer activity. The findings suggest that compounds 5a-d, 9,12a-b, and 16 exhibited promising anticancer activity and antioxidant effects as measured by DPPH inhibition.

Discovery of new piperaquine hybrid analogs linked by triazolopyrimidine and pyrazolopyrimidine scaffolds with antiplasmodial and transmission blocking activities.

The World Health Organization (WHO) estimated that there were 247 million malaria cases in 2021 worldwide, representing an increase in 2 million cases compared to 2020. The urgent need for the development of new antimalarials is underscored by specific criteria, including the requirement of new modes of action that avoid cross-drug resistance, the ability to provide single-dose cures, and efficacy against both assexual and sexual blood stages. Motivated by the promising results obtained from our research group with [1,2,4]triazolo[1,5-a]pyrimidine and pyrazolo[1,5-a]pyrimidine derivatives, we selected these molecular scaffolds as the foundation for designing two new series of piperaquine analogs as potential antimalarial candidates. The initial series of hybrids was designed by substituting one quinolinic ring of piperaquine with the 1,2,4-triazolo[1,5-a]pyrimidine or pyrazolo[1,5-a]pyrimidine nucleus. To connect the heterocyclic systems, spacers with 3, 4, or 7 methylene carbons were introduced at the 4 position of the quinoline. In the second series, we used piperazine as a spacer to link the 1,2,4-triazolo[1,5-a]pyrimidine or pyrazolo[1,5-a]pyrimidine group to the quinoline core, effectively merging both pharmacophoric groups via a rigid spacer. Our research efforts yielded promising compounds characterized by low cytotoxicity and selectivity indices exceeding 1570. These compounds displayed potent in vitro inhibitory activity in the low nanomolar range against the erythrocytic form of the parasite, encompassing both susceptible and resistant strains. Notably, these compounds did not show cross-resistance with either chloroquine or established P. falciparum inhibitors. Even though they share a pyrazolo- or triazolo-pyrimidine core, enzymatic inhibition assays revealed that these compounds had minimal inhibitory effects on PfDHODH, indicating a distinct mode of action unrelated to targeting this enzyme. We further assessed the compounds' potential to interfere with gametocyte and ookinete infectivity using mature P. falciparum gametocytes cultured in vitro. Four compounds demonstrated significant gametocyte inhibition ranging from 58 % to 86 %, suggesting potential transmission blocking activity. Finally, we evaluated the druggability of these new compounds using in silico methods, and the results indicated that these analogs had favorable physicochemical and ADME (absorption, distribution, metabolism, and excretion) properties. In summary, our research has successfully identified and characterized new piperaquine analogs based on [1,2,4]triazolo[1,5-a]pyrimidine and pyrazolo[1,5-a]pyrimidine scaffolds and has demonstrated their potential as promising candidates for the development of antimalarial drugs with distinct mechanisms of action, considerable selectivity, and P. falciparum transmission blocking activity.

Insight into the Inhibitory Mechanism of Embryonic Ectoderm Development Subunit by Triazolopyrimidine Derivatives as Inhibitors through Molecular Dynamics Simulation.

Inhibition of the Embryonic Ectoderm Development (EED) subunit in Polycomb Repressive Complex 2 (PRC2) can inhibit tumor growth. In this paper, we selected six experimentally designed EED competitive Inhibitors of the triazolopyrimidine derivatives class. We investigated the difference in the binding mode of the natural substrate to the Inhibitors and the effects of differences in the parent nuclei, heads, and tails of the Inhibitors on the inhibitory capacity. The results showed that the binding free energy of this class of Inhibitors was close to or lower compared to the natural substrate, providing an energetic basis for competitive inhibition. For the Inhibitors, the presence of a strong negatively charged group at the 6-position of the parent nucleus or the 8'-position of the head would make the hydrogen atom on the head imino group prone to flip, resulting in the vertical movement of the parent nucleus, which significantly decreased the inhibitory ability. When the 6-position of the parent nucleus was a nonpolar group, the parent nucleus would move horizontally, slightly decreasing the inhibitory ability. When the 8'-position of the head was methylene, it formed an intramolecular hydrophobic interaction with the benzene ring on the tail, resulting in a significant increase in inhibition ability.

Three Component One-Pot Synthesis and Antiproliferative Activity of New [1,2,4]Triazolo[4,3-a]pyrimidines.

A series of new [1,2,4]triazolo[4,3-a]pyrimidine derivatives was prepared using a one-pot three-component synthesis from 5-amino-1-phenyl-1H-1,2,4-triazoles, aromatic aldehydes and ethyl acetoacetate. The compound structures were confirmed by IR, 1H-NMR, 13C-NMR, HRMS and X-ray analyses. The biological activity of these compounds as antitumor agents was evaluated. Their antitumor activities against cancer cell lines (MDA-MB-231 and MCF-7) were tested by the MTT in vitro method. Among them, compounds 4c and 4j displayed the best antitumor activity with IC50 values of 17.83 µM and 19.73 µM against MDA-MB-231 and MCF-7 cell lines, respectively, compared to the Cisplatin reference.

Design, synthesis and in vitro/in vivo anticancer activity of tranylcypromine-based triazolopyrimidine analogs as novel LSD1 inhibitors.

Histone lysine specific demethylase 1 (LSD1) is responsible for the demethylation of mono-/dimethylated lysine residue on histone proteins. LSD1 plays an extensive and essential role in the pathogenesis and progression of many human diseases such as cancers, and thus is becoming an attractive therapeutic target for cancer treatment. Tranylcypromine (TCP) is an important chemical template for developing irreversible LSD1 inhibitors, representing a major chemotype of clinical candidates. Here we report a novel pool of TCP derivatives with triazolopyrimidine as a privileged heterocylic motif. Starting from ticagrelor, a clinically available antiplatelet agent, as a hit compound, our medicinal efforts have led to the identification of compound 9j with nanomolar inhibitory potency against LSD1 as well as broad-spectrum antiproliferative activities against tumor cells. Enzyme studies show that compound 9j is selective over MAO-A/B enzymes, and also cellular active to elevate the expression of H3K4me2 by inhibiting LSD1 in cells. Furthermore, in a H1650 xenograft mouse model, oral administration of compound 9j at low 10 and 20 mg/kg dosages could enable a significant reduction in tumor size and a remarkable extension of survival. The current work is expected to provide an additional strategy to achieve new TCP-based LSD1 inhibitors.

Triazolopyrimidine derivatives: An updated review on recent advances in synthesis, biological activities and drug delivery aspects.

Molecules containing triazolopyrimidine core showed diverse biological activities, including anti-Alzheimer, antidiabetes, anticancer, antimicrobial, antituberculosis, antiviral, antimalarial, anti-inflammatory, anti-parkinsonism activities, and treatment of glaucoma. Triazolopyrimidines have around 8 isomeric structures including the most stable 1,2,4-triazolo[1,5-a] pyrimidine ones. Triazolopyrimidines were obtained by using various chemical reactions, among them a) 1,2,4-triazole nucleus annulation to pyrimidine, b) pyrimidines annulation to 1,2,4-triazole structure, c) 1,2,4-triazolo[l,5-a] pyrimidines rearrangement, and d) pyrimido-tetrazine rearrangement. This review discusses synthetic methods, recent pharmacological actions and drug delivery perspectives of triazolopyrimidines.

Ticagrelor.

Ticagrelor is one of the most recent antiplatelet agents used to inhibit platelet aggregation via blocking the ADP receptors of the subtype P2Y12. It belongs to the non-thienopyridine class. The drug was first discovered by Astra Zeneca and approved for use in 2011 by the FDA. Ticagrelor is usually used for the prevention and treatment of thromboembolism in adult patients with acute coronary syndrome. This chapter include an overview on the physical properties, chemical properties, mode of action, pharmacokinetics and common uses of ticagrelor. In addition, the reported methods of ticagrelor assay will be discussed briefly in order to help analysts to find the most convenient method for its estimation in routine analysis. The methods of synthesis used for the preparation of ticagrelor will also be covered in this chapter. Moreover, the analytical and characterization techniques used to characterize ticagrelor row material are summarized herein.

Factors Affecting the Stability of Platinum(II) Complexes with 1,2,4-Triazolo[1,5-a]pyrimidine Derivatives and Tetrahydrothiophene-1-Oxide or Diphenyl Sulfoxide.

The platinum(II) complexes of general formula [PtCl2(dstp)(S-donor)] were dstp 5,7-dimethyl-1,2,4-triazolo[1,5-a]-pyrimidine (dmtp), 5,7-ditertbutyl-1,2,4-triazolo[1,5-a]pyrimidine (dbtp), 5-methyl-7-isobutyl-1,2,4-triazolo[1,5-a]pyrimidine (ibmtp) or 5,7-diphenyl-1,2,4-triazolo[1,5-a]pyrimidine (dptp), whereas S-tetrahydrothio-phene-1-oxide (TMSO) or diphenyl sulfoxide (DPSO) were synthesized in a one-pot reaction. Here, we present experimental data (1H, 13C, 15N, 195Pt NMR, IR, X-ray) combined with density functional theory (DFT) computations to support and characterize structure-spectra relationships and determine the geometry of dichloride platinum(II) complexes with selected triazolopyrimidines and sulfoxides. Based on the experimental and theoretical data, factors affecting the stability of platinum(II) complexes have been determined.

Computational Analysis Reveals Monomethylated Triazolopyrimidine as a Novel Inhibitor of SARS-CoV-2 RNA-Dependent RNA Polymerase (RdRp).

The human population is still facing appalling conditions due to several outbreaks of Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) virus. The absence of specific drugs, appropriate vaccines for mutants, and knowledge of potential therapeutic agents makes this situation more difficult. Several 1, 2, 4-triazolo [1, 5-a] pyrimidine (TP)-derivative compounds were comprehensively studied for antiviral activities against RNA polymerase of HIV, HCV, and influenza viruses, and showed immense pharmacological interest. Therefore, TP-derivative compounds can be repurposed against the RNA-dependent RNA polymerase (RdRp) protein of SARS-CoV-2. In this study, a meta-analysis was performed to ensure the genomic variability and stability of the SARS-CoV-2 RdRp protein. The molecular docking of natural and synthetic TP compounds to RdRp and molecular dynamic (MD) simulations were performed to analyse the dynamic behaviour of TP compounds at the active site of the RdRp protein. TP compounds were also docked against other non-structural proteins (NSP1, NSP2, NSP3, NSP5, NSP8, NSP13, and NSP15) of SARS-CoV-2. Furthermore, the inhibition potential of TP compounds was compared with Remdesivir and Favipiravir drugs as a positive control. Additionally, TP compounds were analysed for inhibitory activity against SARS-CoV RdRp protein. This study demonstrates that TP analogues (monomethylated triazolopyrimidine and essramycin) represent potential lead molecules for designing an effective inhibitor to control viral replication. Furthermore, in vitro and in vivo studies will strengthen the use of these inhibitors as suitable drug candidates against SARS-CoV-2.

Design, synthesis, biological assessment, and in-Silico studies of 1,2,4-triazolo[1,5-a]pyrimidine derivatives as tubulin polymerization inhibitors.

A series of 1,2,4-triazolo[1,5-a]pyrimidine derivatives have been designed and synthesized as combretastatin CA-4 analogs. They were screened for anticancer and tubulin polymerization inhibition activities. The trimethoxyphenyl 1,2,4-triazolo[1,5-a]pyrimidine derivative 4c showed significant antiproliferative activity in which it exhibited IC50 = 0.53 µM against HCT-116 cancer cell line. It was further tested as a tubulin polymerization inhibitor showing an IC50 = 3.84 µM if compared to combretastatin IC50 = 1.10 µM. Further mechanism studies revealed that compound 4c could obviously inhibit the proliferation of HCT-116 cancer cells by inducing apoptosis and arresting the cell cycle at the G2/M phase. Furthermore, docking studies showed that compound 4c illustrated good fitting to the colchicine binding site of tubulin. Thus, it is considered an anticancer lead compound worthy of further development as a tubulin polymerization inhibitor.

Zinc 1,2,4-triazolo[1,5-a]pyrimidine Complexes: Synthesis, Structural Characterization and their Effect Against Chagas Disease.

BACKGROUND: The World Health Organization catalogues illnesses such as Chagas disease as neglected diseases, due to the low investment in new drugs to fight them. The search for novel and non-side effects anti-parasitic compounds is one of the urgent needs of the Third World. The use of triazolopyrimidines and their metal complexes have demonstrated hopeful results in this field. OBJECTIVE: This work studies the antiparasitic efficacy against Trypanosoma cruzi strains of a series of zinc triazolopyrimidine complexes. METHODS: A series of Zn complexes has been synthesized by the reaction between the triazolopyrimidine derivatives 7-amino-1,2,4-triazolo[1,5-a]pyrimidine (7atp) and 5,7-dimethyl-1,2,4-triazolo[1,5- a]pyrimidine (dmtp) with Zn(SO4) · 7H2O, ZnCl2, and Zn(NO3)2 · 6H2O salts. The complexes have been analyzed by spectroscopic and thermal assays and X-ray diffraction methods have been used to dilucidate the crystalline structure of one of them. The antiparasitic efficacy was tested in vitro against Trypanosoma cruzi to compare the trypanocidal effect of different ligands and counteranions to fight Chagas disease. RESULTS: The efficacy of these compounds against Trypanosoma cruzi has also been tested to compare the influence of different ligands and counteranions on the trypanocidal effect against Chagas disease. CONCLUSION: Antiproliferative tests corroborate the synergistic trypanocidal effect of the triazolopyrimidine coordination complexes.

Synthesis, anticancer activity and molecular docking of new triazolo[4,5-d]pyrimidines based thienopyrimidine system and their derived N-glycosides and thioglycosides.

A series of new substituted triazolo[4,5-d]pyrimidine derivatives linked to thienopyrimidine ring system were prepared as a hybrid heterocyclic systems, as possible nucleobases analogs, starting from the key carboxamide derivative 2 and its azide precursor via heterocyclization reactions and their structures were characterized. Glycosylation of the prepared triazolopyrimidine derivatives was performed and afforded, regioselctively, the corresponding thienopyrimidine-triazolopyrimidine hybrid N1-glycosides and their thioglycoside analogues in good yields. The synthesized glycosyl heterocycles were studied for their cytotoxic activity against HepG-2 and MCF-7 human cancer cells and significant results were obtained. Compounds 7a, 8 b, 9 b, 9a and 7 b demonstrated promising activities comparable to the activity of the doxorubicin for (HepG-2) cell line. Furthermore, a number of the afforded triazolopyrimidine glycosides were found potent against cancer cells (MCF-7). Furthermore, docking simulation the promising thienopyrimidine analogues 7-13 was done against EGFR kinase to provide a binding model that could serve in discovery of further anticancer agents.

Optimisation of 2-(N-phenyl carboxamide) triazolopyrimidine antimalarials with moderate to slow acting erythrocytic stage activity.

Malaria is a devastating parasitic disease caused by parasites from the genus Plasmodium. Therapeutic resistance has been reported against all clinically available antimalarials, threatening our ability to control the disease and therefore there is an ongoing need for the development of novel antimalarials. Towards this goal, we identified the 2-(N-phenyl carboxamide) triazolopyrimidine class from a high throughput screen of the Janssen Jumpstarter library against the asexual stages of the P. falciparum parasite. Here we describe the structure activity relationship of the identified class and the optimisation of asexual stage activity while maintaining selectivity against the human HepG2 cell line. The most potent analogues from this study were shown to exhibit equipotent activity against P. falciparum multidrug resistant strains and P. knowlesi asexual parasites. Asexual stage phenotyping studies determined the triazolopyrimidine class arrests parasites at the trophozoite stage, but it is likely these parasites are still metabolically active until the second asexual cycle, and thus have a moderate to slow onset of action. Non-NADPH dependent degradation of the central carboxamide and low aqueous solubility was observed in in vitro ADME profiling. A significant challenge remains to correct these liabilities for further advancement of the 2-(N-phenyl carboxamide) triazolopyrimidine scaffold as a potential moderate to slow acting partner in a curative or prophylactic antimalarial treatment.

Design, Synthesis and Biological Evaluation of Novel Pyrazolo[1,2,4]triazolopyrimidine Derivatives as Potential Anticancer Agents.

Three novel pyrazolo-[4,3-e][1,2,4]triazolopyrimidine derivatives (1, 2, and 3) were designed, synthesized, and evaluated for their in vitro biological activity. All three compounds exhibited different levels of cytotoxicity against cervical and breast cancer cell lines. However, compound 1 showed the best antiproliferative activity against all tested tumor cell lines, including HCC1937 and HeLa cells, which express high levels of wild-type epidermal growth factor receptor (EGFR). Western blot analyses demonstrated that compound 1 inhibited the activation of EGFR, protein kinase B (Akt), and extracellular signal-regulated kinase (Erk)1/2 in breast and cervical cancer cells at concentrations of 7 and 11 µM, respectively. The results from docking experiments with EGFR suggested the binding of compound 1 at the ATP binding site of EGFR. Furthermore, the crystal structure of compound 3 (7-(4-bromophenyl)-9-(pyridin-4-yl)-7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine) was determined by single crystal X-ray analysis. Our work represents a promising starting point for the development of a new series of compounds targeting EGFR.

Comparative study between the anti-P. falciparum activity of triazolopyrimidine, pyrazolopyrimidine and quinoline derivatives and the identification of new PfDHODH inhibitors.

In this work, we designed and synthesized 35 new triazolopyrimidine, pyrazolopyrimidine and quinoline derivatives as P. falciparum inhibitors (3D7 strain). Thirty compounds exhibited anti-P. falciparum activity, with IC50 values ranging from 0.030 to 9.1 µM. The [1,2,4]triazolo[1,5-a]pyrimidine derivatives were more potent than the pyrazolo[1,5-a]pyrimidine and quinoline analogues. Compounds 20, 21, 23 and 24 were the most potent inhibitors, with IC50 values in the range of 0.030-0.086 µM and were equipotent to chloroquine. In addition, the compounds were selective, showing no cytotoxic activity against the human hepatoma cell line HepG2. All [1,2,4]triazolo[1,5-a]pyrimidine derivatives inhibited PfDHODH activity in the low micromolar to low nanomolar range (IC50 values of 0.08-1.3 µM) and did not show significant inhibition against the HsDHODH homologue (0-30% at 50 µM). Molecular docking studies indicated the binding mode of [1,2,4]triazolo[1,5-a]pyrimidine derivatives to PfDHODH, and the highest interaction affinities for the PfDHODH enzyme were in agreement with the in vitro experimental evaluation. Thus, the most active compounds against P. falciparum parasites 20 (R = CF3, R1 = F; IC50 = 0.086 µM), 21 (R = CF3; R1 = CH3; IC50 = 0.032 µM), 23, (R = CF3, R1 = CF3; IC50 = 0.030 µM) and 24 (R = CF3, 2-naphthyl; IC50 = 0.050 µM) and the most active inhibitor against PfDHODH 19 (R = CF3, R1 = Cl; IC50 = 0.08 µM - PfDHODH) stood out as new lead compounds for antimalarial drug discovery. Their potent in vitro activity against P. falciparum and the selective inhibition of the PfDHODH enzyme strongly suggest that this is the mechanism of action underlying this series of new [1,2,4]triazolo[1,5-a]pyrimidine derivatives.

Synthesis and Antimicrobial Activity of Novel 1, 2, 4-Triazolopyrimidofuroquinazolinones from Natural Furochromones (Visnagenone and Khellinone).

BACKGROUND: Previous and recent scientific research has shown that triazolopyrimidine and furochromones have a wide range of pharmacological activities for the treatment of numerous diseases, including anticancer, antiviral, anti-depressant, anti-microbial, anti-inflammatory, and analgesic activities. OBJECTIVE: Preparation of new drugs derived from a natural furochromones as (1-hydrazinyl or methylthio),-furopyrimidoquinazolinone, 1, 2, 4-triazolopyrimidofuroquinazolin-5-one, and quinazoline- pyrimidofuro- quinazoline-8, 10-dione and the study of their biological activity as antimicrobial agents. METHODS: A series of novel N'-furopyrimidoquinazoline-hydrazide; 1, 2, 4-triazolopyrimidofuroquinazolin- 5-one; furopyrimidoquinazolin-3-one and quinazoline-pyrimidofuroquinazoline-8, 10- dione derivatives were synthesized from substituted (methylthio)-furopyrimidoquinazolinone (3ab) and 1-hydrazinyl-furopyrimido- quinazolinone (4a-b) as the starting material. RESULTS: All compounds were synthesized in good yields (71-95%) in a gradually efficient system under mild condition and some of the procedures were used such as microwave oven. The new compounds have been confirmed by means of different spectroscopic methods such as IR, 1D and 2D -NMR techniques and mass spectrum. The in vitro antimicrobial activities were evaluated for the prepared compounds using many types of bacteria (Gram-positive and Gram-negative) and fungi. CONCLUSION: 1, 2, 4-triazolopyrimidofuroquinazolin-5-one derivatives (10a-f, 8a-b, 7a-b and 6a-d) showed the most efficient antimicrobial activities compared with the cefotaxime sodium and nystatin as standard drugs.

Design and synthesis of new pyranoquinolinone heteroannulated to triazolopyrimidine of potential apoptotic antiproliferative activity.

Pyrano[3,2-c]quinoline derivatives have been synthesized and utilized to obtain various new hetero-annulated triazolopyrimidine, containing quinoline, pyran, 1,2,4-triazine and pyrimidine in good yields. Newly synthesized compounds have been characterized by spectral data and elemental analysis. Most of the synthesized compounds showed moderate to weak antiproliferative activity on most cancer cell lines, especially leukemia and breast cancer cell lines. The open chain formimidic acid ethyl ester is slightly more potent than hetero-annulated systems. The most active compounds were further investigated for caspase activation, Bax activation and Bcl-2 down regulation compared to doxorubicin as a standard, and indeed exhibited mainly cell cycle arrest at the Pre-G1 and G2/M phases. The transcription effects of 5a and 5b on the p53 were assessed and compared with the reference doxorubicin. The results revealed an increase of 12-19 in p53 level compared to the test cells and that p53 protein level of 5a and 5b was significantly inductive (991, and 639 pg/mL, respectively) in relation to doxorubicin (1263 pg/mL).

Targeted potent antimicrobial benzochromene-based analogues: Synthesis, computational studies, and inhibitory effect against 14α-Demethylase and DNA Gyrase.

7H-Benzo[7,8]chromeno[2,3-d]pyrimidin-9(8H)-amine (6a,b) have been synthesized via hydrazinolysis of the imidates (5a,b). Polysubstituted chromenotriazolopyrimidine (7a-j), (12a,b) and Schiff base (8a,b) derivatives have also been prepared. The new heterocyclic derivatives were affirmed by spectral data. The target compounds have been screened for antibacterial and antifungal activity. Compounds 6a,b and 7a-c, g,h displayed the most favorable antimicrobial activities in resemblance to the reference antimicrobial agents by IZ range over 24 mm. In addition, MIC, MBC and MFC were also tested and screen for most active compound 6a by 6.25 µg/mL showing bactericidal effect. SAR study revealed that the antimicrobial vitality of the target compounds was safely influenced by the lipophilicity substituents and the calculated log P value. The potent compounds were subjected into in vitro enzyme screening (14α-Demethylase and DNA Gyrase) against both interesting targets and showed good inhibitory profile. Molecular modeling analyses were introduced and discussed focusing on the docking of active compounds into two essential targets, and their ADMET properties were studied.

Potential for Treatment of Neurodegenerative Diseases with Natural Products or Synthetic Compounds that Stabilize Microtubules.

No effective therapeutics to treat neurodegenerative diseases exist, despite significant attempts to find drugs that can reduce or rescue the debilitating symptoms of tauopathies such as Alzheimer's disease, Parkinson's disease, frontotemporal dementia, amyotrophic lateral sclerosis, or Pick's disease. A number of in vitro and in vivo models exist for studying neurodegenerative diseases, including cell models employing induced-pluripotent stem cells, cerebral organoids, and animal models of disease. Recent research has focused on microtubulestabilizing agents, either natural products or synthetic compounds that can prevent the axonal destruction caused by tau protein pathologies. Although promising results have come from animal model studies using brainpenetrant natural product microtubule-stabilizing agents, such as paclitaxel analogs that can access the brain, epothilones B and D, and other synthetic compounds such as davunetide or the triazolopyrimidines, early clinical trials in humans have been disappointing. This review aims to summarize the research that has been carried out in this area and discuss the potential for the future development of an effective microtubule stabilizing drug to treat neurodegenerative disease.

Structure-based design and optimization of pyrimidine- and 1,2,4-triazolo[4,3-a]pyrimidine-based matrix metalloproteinase-10/13 inhibitors via Dimroth rearrangement towards targeted polypharmacology.

Recently, interest in matrix metalloproteinases (MMPs) -10 and -13 has been revitalized with the growing knowledge on their relevance within the MMPs network and significance of their inhibition for treatment of various diseases like arthritis, cancer, atherosclerosis and Alzheimer. Within this approach, dual MMP-10/13 inhibition was disclosed as new approach for targeted polypharmacology. While several efficient MMP-13 inhibitors are known, very few potent and selective MMP-10 inhibitors were reported. This study describes the design, synthesis and optimization of novel MMP-10/13 inhibitors with enhanced MMP-10 potency and selectivity towards polypharmacology. Starting with a lead fused pyrimidine-based MMP-13 inhibitor with weak MMP-10 inhibition, a structure-based design of pyrimidine and fused pyrimidine scaffolds was rationalized to enhance activity against MMP-10 in parallel with MMP-13. Firstly, a series of 6-methyl pyrimidin-4-one hydrazones 6-10 was synthesized via conventional and ultrasonic-assisted methods, then evaluated for MMP-10/13 inhibition. The most active derivative 9 exhibited acceptable dual potency with 7-fold selectivity for MMP-10 (IC50 = 53 nM) over MMP-13. Such hydrazones were then cyclized to the corresponding isomeric 1,2,4-triazolo[4,3-a]pyrimidines 12-19. Their MMP-10/13 inhibition assay revealed, in most cases, superior dual activities with general MMP-10 selectivity compared to the corresponding precursors 6-10. In addition, a clear structure activity relationship trend was deduced within the identified regioisomers, where the 5-oxo-1,2,4-triazolo[4,3-a]pyrimidine derivatives 15 and 16 were far more active against MMP-10/13 than their regioisomers 12 and 13. Remarkably, the p-bromophenyl derivative 16 exhibited the highest MMP-10 inhibition (IC50 = 24 nM), whereas the p-methoxy derivative 18 was the most potent MMP-13 inhibitor (IC50 = 294 nM). Moreover, 16 exhibited 19-fold selectivity for MMP-10 over MMP-13, 10-fold over MMP-9, and 29-fold over MMP-7. Docking studies were performed to provide reasonable explanation for structure-activity relationships and isoform selectivity. 16 and 18 were then evaluated for their anticancer activities against three human cancers to assess their therapeutic potential at cellular level via MTT assay. Both compounds exhibited superior anticancer activities compared to quercetin. Their in silico ligand efficiency metrics, physicochemical properties and ADME parameters were drug-like. Guided by such findings that point to 16 as the most promising compound in this study, further structure optimization was carried out via photoirradiation-mediated Dimroth rearrangement of the inactive triazolopyrimidine 13 to its potent regioisomer 16.