Design, synthesis, docking, and antiviral evaluation of some novel pyrimidinone-based α-aminophosphonates as potent H1N1 and HCoV-229E inhibitors.

Dialkyl/aryl aminophosphonates, 3a-g and 4a-e were synthesized using the LiClO4 catalyzed Kabachnic Fields-type reaction straightforwardly and efficiently. The synthesized phosphonates structures were characterized using elemental analyses, FT-IR, 1H NMR, 13C NMR, and MS spectroscopy. The new compounds were subjected to in-silico molecular docking simulations to evaluate their potential inhibition against Influenza A Neuraminidase and RNA-dependent RNA polymerase of human coronavirus 229E. Subsequently, the compounds were further tested in vitro using a cytopathic inhibition assay to assess their antiviral activity against both human Influenza (H1N1) and human coronavirus (HCoV-229E). Diphenyl ((2-(5-cyano-6-oxo-4-phenyl-1,6-dihydropyrimidin-2-yl) hydrazinyl) (furan-2-yl) methyl) phosphonate (3f) and diethyl ((2-(5-cyano-6-oxo-4-phenyl-1,6-dihydropyrimidin-2-yl) hydrazinyl) (1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl) methyl) phosphonate (4e) were demonstrated direct inhibition activity against Influenza A Neuraminidase and RNA-dependent RNA polymerase. This was supported by their highly favorable binding energies in-silico, with top-ranked values of -12.5 kcal/mol and -14.2 kcal/mol for compound (3f), and -13.5 kcal/mol and -9.89 kcal/mol for compound (4e). Moreover, they also displayed notable antiviral efficacy in vitro against both viruses. These compounds demonstrated significant antiviral activity, as evidenced by selectivity indices (SI) of 101.7 and 51.8, respectively against H1N1, and 24.5 and 5.1 against HCoV-229E, respectively.

Design, Synthesis, and Insecticidal Activity of Mesoionic Pyrido[1,2-a]pyrimidinone Containing Isoxazole/Isoxazoline Moiety as a Potential Insecticide.

Bean aphid (Aphis craccivora) resistance to commonly used insecticides has made controlling these pests increasingly difficult. In this study, we introduced isoxazole and isoxazoline, which possess insecticidal activity, into pyrido[1,2-a]pyrimidinone through a scaffold hopping strategy. We designed and synthesized a series of novel mesoionic compounds that exhibited a range of insecticidal activities against A. craccivora. The LC50 values of compounds E1 and E2 were 0.73 and 0.88 µg/mL, respectively, better than triflumezopyrim (LC50 = 2.43 µg/mL). Proteomics and molecular docking analyses showed that E1 might influence the A. craccivora nervous system by interacting with neuronal nicotinic acetylcholine receptors (nAChRs). This research offers a new approach to the advancement of novel mesoionic insecticides.

Synthesis of 4,4-Disubstituted 3,4-Dihydropyrimidin-2(1H)-ones and -thiones, the Corresponding Products of Biginelli Reaction Using Ketone, and Their Antiproliferative Effect on HL-60 Cells.

An efficient synthetic method for novel 4,4-disubstituted 3,4-dihydropyrimidin-2(1H)-ones 5 and -thiones 6 was developed. The cyclocondensation reaction of O-methylisourea hemisulfate salt 11 with 8 gives a tautomeric mixture of dihydropyrimidines 12 and 13 following acidic hydrolysis of the cyclized products to produce 5 in high yields. Thionation reaction of 5 at the 2-position smoothly proceeds to give 2-thioxo derivatives 6. These compounds 5 and 6, corresponding to the products of a Biginelli-type reaction using urea or thiourea, a ketone and a 1,3-dicarbonyl compound, have long been inaccessible and hitherto unavailable for medicinal chemistry. These methods are invaluable for the synthesis of 5 and 6, which have been inaccessible by conventional methods. Therefore, the synthetic methods established in this study will expand the molecular diversity of their related derivatives. These compounds were also assessed for their antiproliferative effect on a human promyelocytic leukemia cell line, HL-60. Treatment of 10 µM 6b and 6d showed high inhibitory activity similarly to 1 µM all-trans retinoic acid (ATRA), indicating that the 2-thioxo group and length of two alkyl substituents at the 4-position are strongly related to activity.

Deep eutectic solvent mediated synthesis of 3,4-dihydropyrimidin-2(1H)-ones and evaluation of biological activities targeting neurodegenerative disorders.

Substitution of hazardous and often harmful organic solvents with "green" and "sustainable" alternative reaction media is always desirous. Ionic liquids (IL) have emerged as valuable and versatile liquids that can replace most organic solvents in a variety of syntheses. However, recently new types of low melting mixtures termed as Deep Eutectic Solvents (DES) have been utilized in organic syntheses. DES are non-volatile in nature, have sufficient thermal stability, and also have the ability to be recycled and reused. Hence DES have been used as alternative reaction media to perform different organic reactions. The availability of green, inexpensive and easy to handle alternative solvents for organic synthesis is still scarce, hence our interest in DES mediated syntheses. Herein we have investigated Biginelli reaction in different DES for the synthesis of 3,4-dihydropyrimidin-2(1H)-ones. Monoamine oxidases and cholinesterases are important drug targets for the treatment of various neurological disorders such as Alzheimer's disease, Parkinson's disease, depression and anxiety. The compounds synthesized herein were evaluated for their inhibitory potential against these enzymes. Some of the compounds were found to be highly potent and selective inhibitors. Compounds 1 h and 1c were the most active monoamine oxidase A (MAO A) (IC50 = 0.31 ± 0.11 µM) and monoamine oxidase B (MAO B) (IC50 = 0.34 ± 0.04 µM) inhibitors respectively. All compounds were selective AChE inhibitors and did not inhibit BChE (<29% inhibition). Compound 1 k (IC50 = 0.13 ± 0.09 µM) was the most active AChE inhibitor.

Design, Synthesis, and Antiviral activity of 1,2,3,4-Tetrahydropyrimidine derivatives acting as novel entry inhibitors to target at "Phe43 cavity" of HIV-1 gp120.

The HIV-1 invasion is initiated with the interaction of viral glycoprotein gp120 and cellular receptor CD4. The binding mechanism reveals two major hotspots involved in gp120-CD4 interaction. The first one is a hydrophobic cavity (Phe43 cavity) on gp120 capped with phenyl ring of phe43CD4 and the second is the electrostatic interaction between positive charge of Arg59CD4 and negative charge of Asp368gp120. Targeting these hotspots, small molecules for entry inhibition and HIV-1 neutralization were designed and tested. In the process, pyrimidine derivatives were identified as potent molecules to intercept gp120-CD4 binding by targeting both the hotspots. Herein, the synthesis, characterization of 1,2,3,4-Tetrahydropyrimidine derivatives, and biological evaluation on 93IN101, a clade C virus are presented. The paper presents a novel set of entry inhibitors to target dual hotspots on gp120 to inhibit protein-protein interactions.

Next generation Glucose-1-phosphate thymidylyltransferase (RmlA) inhibitors: An extended SAR study to direct future design.

The monosaccharide l-Rhamnose is an important component of bacterial cell walls. The first step in the l-rhamnose biosynthetic pathway is catalysed by glucose-1-phosphate thymidylyltransferase (RmlA), which condenses glucose-1-phosphate (Glu-1-P) with deoxythymidine triphosphate (dTTP) to yield dTDP-d-glucose. In addition to the active site where catalysis of this reaction occurs, RmlA has an allosteric site that is important for its function. Building on previous reports, SAR studies have explored further the allosteric site, leading to the identification of very potent P. aeruginosa RmlA inhibitors. Modification at the C6-NH2 of the inhibitor's pyrimidinedione core structure was tolerated. X-ray crystallographic analysis of the complexes of P. aeruginosa RmlA with the novel analogues revealed that C6-aminoalkyl substituents can be used to position a modifiable amine just outside the allosteric pocket. This opens up the possibility of linking a siderophore to this class of inhibitor with the goal of enhancing bacterial cell wall permeability.

Design, synthesis and biological evaluation of novel pyrazolopyrimidone derivatives as potent PDE1 inhibitors.

Phosphodiesterase-1 (PDE1) is a promising drug target closely related to central and peripheral diseases. With the assistance of molecular docking and dynamics simulations, we designed and synthesized a novel series of pyrazolopyrimidone derivatives as effective and metabolically stable inhibitors against PDE1. Most compounds have good inhibitory activities against PDE1 at the concentration of 20 nM. Compound 2j with the IC50 of 21 nM against PDE1B, shows good metabolic stability in the rat liver microsomes (RLM) (t1/2 of 28.5 min), indicating that compound 2j can be used as a tool to explore the molecular recognition mechanism between inhibitors and the target protein PDE1.

Discovery of novel N-1 substituted pyrazolopyrimidinones as potent, selective PDE2 inhibitors.

A focused SAR study was conducted on a series of N1-substituted pyrazolopyrimidinone PDE2 inhibitors to reveal compounds with excellent potency and selectivity. The series was derived from previously identified internal leads and designed to enhance steric interactions with key amino acids in the PDE2 binding pocket. Compound 26 was identified as a lead compound with excellent PDE2 selectivity and good physicochemical properties.

Design, synthesis and biological evaluations of a series of Pyrido[1,2-a]pyrimidinone derivatives as novel selective FGFR inhibitors.

Aberrant signaling of fibroblast growth factor receptors (FGFRs) has been identified as a driver of tumorigenesis and the development of many solid tumors, making FGFRs a compelling target for anticancer therapy. Herein, we describe the design and synthesis of pyrido[1,2-a]pyrimidinone derivatives as potent FGFR inhibitors. Examination of structure-activity relationships and preliminary assessment identified 23d as a novel FGFR inhibitor that displayed excellent potency in vitro. Candidate 23d suppressed the phosphorylation of FGFR signaling pathways and induced cell cycle arrest and apoptosis at low nanomolar concentration. In the kinase inhibition profile, 23d showed excellent kinase selectivity for the FGFR family. Furthermore, 23d showed higher aqueous solubility than Erdafitinib. Moreover, 23d exhibited potent antitumor activity (tumor growth inhibition = 106.4%) in FGFR2-amplified SNU-16 gastric cancer xenograft model using a daily oral dose of 30 mg/kg. These results suggest that 23d is a promising candidate for further drug development.

Molecular Docking and Biophysical Studies for Antiproliferative Assessment of Synthetic Pyrazolo-Pyrimidinones Tethered with Hydrazide-Hydrazones.

Chemotherapy represents the most applied approach to cancer treatment. Owing to the frequent onset of chemoresistance and tumor relapses, there is an urgent need to discover novel and more effective anticancer drugs. In the search for therapeutic alternatives to treat the cancer disease, a series of hybrid pyrazolo[3,4-d]pyrimidin-4(5H)-ones tethered with hydrazide-hydrazones, 5a-h, was synthesized from condensation reaction of pyrazolopyrimidinone-hydrazide 4 with a series of arylaldehydes in ethanol, in acid catalysis. In vitro assessment of antiproliferative effects against MCF-7 breast cancer cells, unveiled that 5a, 5e, 5g, and 5h were the most effective compounds of the series and exerted their cytotoxic activity through apoptosis induction and G0/G1 phase cell-cycle arrest. To explore their mechanism at a molecular level, 5a, 5e, 5g, and 5h were evaluated for their binding interactions with two well-known anticancer targets, namely the epidermal growth factor receptor (EGFR) and the G-quadruplex DNA structures. Molecular docking simulations highlighted high binding affinity of 5a, 5e, 5g, and 5h towards EGFR. Circular dichroism (CD) experiments suggested 5a as a stabilizer agent of the G-quadruplex from the Kirsten ras (KRAS) oncogene promoter. In the light of these findings, we propose the pyrazolo-pyrimidinone scaffold bearing a hydrazide-hydrazone moiety as a lead skeleton for designing novel anticancer compounds.

Solvothermal Synthesis of Multiple Dihydropyrimidinones at a Time as Inhibitors of Eg5.

Solvothermal synthesis of multiple dihydropyrimidinones at a time has been developed in inexpensive and green bio-based solvent lactic acid without any additional catalysts or additives. By this method, thirty new dihydropyrimidinone derivatives were synthesized in two batches and characterized. All of the compounds were screened by Eg5 motor protein ATPase assay, and the positive compounds were tested against the Caco-2 cell line, HeLa cell line, L929 cell line and T24 cell line in vitro. Among them, compound C9 exhibited the best inhibitory activity against motor protein ATPase with an IC50 value of 30.25 µM and significant cytotoxic activity in the micromolar range against the cells above. The Lineweaver-Burk plot revealed that compound C9 was a mixed-type Eg5 inhibitor. A molecular modeling study using the Discovery Studio program was performed, where compound C9 exhibited good binding interaction with Eg5 motor protein ATPase, and this was consistent with the attained experimental results.

Controlling the selectivity of aminergic GPCR ligands from the extracellular vestibule.

In addition to the orthosteric binding pocket (OBP) of GPCRs, recent structural studies have revealed that there are several allosteric sites available for pharmacological intervention. The secondary binding pocket (SBP) of aminergic GPCRs is located in the extracellular vestibule of these receptors, and it has been suggested to be a potential selectivity pocket for bitopic ligands. Here, we applied a virtual screening protocol based on fragment docking to the SBP of the orthosteric ligand-receptor complex. This strategy was employed for a number of aminergic receptors. First, we designed dopamine D3 preferring bitopic compounds from a D2 selective orthosteric ligand. Next, we designed 5-HT2B selective bitopic compounds starting from the 5-HT1B preferring ergoline core of LSD. Comparing the serotonergic profiles of the new derivatives to that of LSD, we found that these derivatives became significantly biased towards the desired 5-HT2B receptor target. Finally, addressing the known limitations of H1 antihistamines, our protocol was successfully used to eliminate the well-known side effects related to the muscarinic M1 activity of amitriptyline while preserving H1 potency in some of the designed bitopic compounds. These applications highlight the usefulness of our new virtual screening protocol and offer a powerful strategy towards bitopic GPCR ligands with designed receptor profiles.

Recent Developments on the Synthesis and Biological Activities of Fused Pyrimidinone Derivatives.

Heterocyclic compounds constitute a unique class of organic compounds endowed with a wide range of synthetic and pharmaceutical applications. Pyrimidinones and their fused analogues have received focused attention in this regard, partly due to their mimicry of nucleobases which consequently forges their interesting medicinal properties. Over the years, the medicinal chemistry research community has experienced an upsurge in articles describing the exploration of these scaffolds to develop effective therapeutic agents. Several biological activities, including antimicrobial, antiviral, anticancer, antidiabetic, anti-inflammatory, anticonvulsive, and antihistaminic, have been well documented. This minireview presents a compendium of recent developments (2017-2020) focused on the synthesis and biological activities of fused pyrimidinones. The goal is to update medicinal chemists on the therapeutic relevance of fused pyrimidinones and the molecular architecture of clinic-worthy drug candidates. A brief account of the structure-activity relationships (SAR) revealed from different biological assays is also discussed.

Discovery of a Pyrimidinedione Derivative as a Potent and Orally Bioavailable Axl Inhibitor.

The receptor tyrosine kinase Axl plays important roles in promoting cancer progression, metastasis, and drug resistance and has been identified as a promising target for anticancer therapeutics. We used molecular modeling-assisted structural optimization starting with the low micromolar potency compound 9 to discover compound 13c, a highly potent and orally bioavailable Axl inhibitor. Selectivity profiling showed that 13c could inhibit the well-known oncogenic kinase Met with equal potency to its inhibition of Axl superfamily kinases. Compound 13c significantly inhibited cellular Axl and Met signaling, suppressed Axl- and Met-driven cell proliferation, and restrained Gas6/Axl-mediated cancer cell migration or invasion. Furthermore, 13c exhibited significant antitumor efficacy in Axl-driven and Met-driven tumor xenograft models, causing tumor stasis or regression at well-tolerated doses. All these favorable data make 13c a promising therapeutic candidate for cancer treatment.

Design, synthesis and pharmacological evaluation of tricyclic derivatives as selective RXFP4 agonists.

Relaxin family peptide receptors (RXFPs) are the potential therapeutic targets for neurological, cardiovascular, and metabolic indications. Among them, RXFP3 and RXFP4 (formerly known as GPR100 or GPCR142) are homologous class A G protein-coupled receptors with short N-terminal domain. Ligands of RXFP3 or RXFP4 are only limited to endogenous peptides and their analogues, and no natural product or synthetic agonists have been reported to date except for a scaffold of indole-containing derivatives as dual agonists of RXFP3 and RXFP4. In this study, a new scaffold of tricyclic derivatives represented by compound 7a was disclosed as a selective RXFP4 agonist after a high-throughput screening campaign against a diverse library of 52,000 synthetic and natural compounds. Two rounds of structural modification around this scaffold were performed focusing on three parts: 2-chlorophenyl group, 4-hydroxylphenyl group and its skeleton including cyclohexane-1,3-dione and 1,2,4-triazole group. Compound 14b with a new skeleton of 7,9-dihydro-4H-thiopyrano[3,4-d][1,2,4]triazolo[1,5-a]pyrimidin-8(5H)-one was thus obtained. The enantiomers of 7a and 14b were also resolved with their 9-(S)-conformer favoring RXFP4 agonism. Compared with 7a, compound 9-(S)-14b exhibited 2.3-fold higher efficacy and better selectivity for RXFP4 (selective ratio of RXFP4 vs. RXFP3 for 9-(S)-14b and 7a were 26.9 and 13.9, respectively).

Synthesis and in vitro study of antiproliferative benzyloxy dihydropyrimidinones.

In this study, we report on antiproliferative benzyloxy dihydropyrimidinones (DHPMs) produced by the Biginelli reaction of benzyloxy benzaldehyde, urea, and diverse 1,3-diones. The reaction was catalyzed by lanthanum triflate and completed within 1-1.5 h, with 74-97% yield. The antiproliferative assay was carried out for all synthesized dihydropyrimidinones against six human solid tumor cell lines. Six compounds showed good antiproliferative activity with GI50 values below 5 µM. Among all the synthesized compounds, the most potent derivative showed good antiproliferative activity against all cell lines with GI50 values in the range of 1.1-3.1 µM. These DHPMs comply with druglikeness. Furthermore, ADMET prediction and the effect of P-glycoprotein on the antiproliferative activity were also studied. Overall, our method allows eco-friendly access to benzyloxy DHPMs as potential anticancer drugs.

Design of pyrido[2,3-d]pyrimidin-7-one inhibitors of receptor interacting protein kinase-2 (RIPK2) and nucleotide-binding oligomerization domain (NOD) cell signaling.

Receptor interacting protein kinase-2 (RIPK2) is an enzyme involved in the transduction of pro-inflammatory nucleotide-binding oligomerization domain (NOD) cell signaling, a pathway implicated in numerous chronic inflammatory conditions. Herein, a pyrido[2,3-d]pyrimidin-7-one based class of RIPK2 kinase and NOD2 cell signaling inhibitors is described. For example, 33 (e.g. UH15-15) inhibited RIPK2 kinase (IC50 = 8 ± 4 nM) and displayed > 300-fold selectivity versus structurally related activin receptor-like kinase 2 (ALK2). This molecule blocked NOD2-dependent HEKBlue NF-κB activation (IC50 = 20 ± 5 nM) and CXCL8 production (at concentrations > 10 nM). Molecular docking suggests that engagement of Ser25 in the glycine-rich loop may provide increased selectivity versus ALK2 and optimal occupancy of the region between the gatekeeper and the αC-helix may contribute to potent NOD2 cell signaling inhibition. Finally, this compound also demonstrated favorable in vitro ADME and pharmacokinetic properties (e.g. Cmax = 5.7 µM, Tmax = 15 min, t1/2 = 3.4 h and Cl = 45 mL/min/kg following single 10 mg/kg intraperitoneal administration) further supporting the use of pyrido[2,3-d]pyrimidin-7-ones as a new structure class of RIPK2 kinase and NOD cell signaling inhibitors.

Antiproliferative effect, alteration of cancer cell cycle progression and potential MET kinase inhibition induced by 3,4-dihydropyrimidin-2(1H)-one C5 amide derivatives.

Cancer continues to be the second leading cause of death worldwide. Discovery of novel therapeutic agents has crucial importance for improvement of our medical management capabilities. Dysregulation of the MET receptor tyrosine kinase pathway plays an important role in cancer progression, making this receptor an attractive molecular target for anticancer drug discovery. In this study, twenty-seven 3,4-dihydropyrimidin-2(1H)-one C5 amide derivatives were synthesized and their cancer cell growth inhibitory activity was examined against MCF-7, HT-29 and MOLT-4 cells and also NIH/3T3 non-cancer cells by MTT assay. The antiproliferative effect of the most potent derivatives were tested against MET-dependent EBC-1 and MKN-45, lung and gastric cancer cell lines, respectively. MET kinase inhibition was measured by a Homogenous Time Resolved Fluorescence (HTRF) Assay. The influence of the test compounds on cell cycle was examined by RNase/PI flow cytometric assay. A number of compounds exhibited considerable antiproliferative effects against breast and colon cancer and leukemia cell lines, relatively sparing non-cancer cells. Some derivatives bearing benzothiazolyl carboxamide moiety at C5 position (15, 21, 23, 31, and 37) showed the highest activities with IC50 values as low as 10.9 µM. These compounds showed antiproliferative effects also against MET-amplified cells and dose-dependently inhibited MET kinase activity. They also induced G0/G1 cell cycle arrest at lower doses and apoptosis at higher doses. Molecular docking and dynamics simulation studies confirmed the interaction of compound 23 with the active site of the MET receptor. These findings demonstrate that 3,4-dihydropyrimidin-2(1H)-one analogues may represent promising targeted anticancer agents.

Design and synthesis of acrylate and acrylamide substituted pyrimidinediones as potential PPO herbicides.

PPO herbicides emerge to be widely use in the agricultural field and a focus of research to many scientists due to its environmentally-friendly properties. In lieu with this, this study presents acrylate and acrylamide substituted pyrimidinediones as PPO herbicide candidates. Most synthesized compounds exhibits herbicidal activities against both monocot and dicot weeds, especially, compound 5a which showed non-selective superior activity against the commercialized, Saflufenacil. Compound 5a was further tested for residual effect and showed promising results as shorter period is needed to cultivate the next crops. The synthesized acrylate and acrylamide substituted pyrimidinediones, especially, 5a could potentially be utilized in the development of commercial protoporphyrinogen oxidase inhibitors with further tests and studies.

Activated Carbon/MoO3: Efficient Catalyst for Green Synthesis of Chromeno[d]pyrimidinediones and Xanthenones.

BACKGROUND: Nanoscale metal oxide catalysts have been extensively employed in organic reactions because they have been found to influence the chemical and physical properties of bulk material. The chromene (benzopyran) nucleus constitutes the core structure in a major class of many biologically active compounds, and interest in their chemistry consequently continues because of their numerous biological activities. The xanthene (dibenzopyran) derivatives are classified as highly significant compounds which display a number of various bioactive properties. Pyrimidinones have also gained interest due to their remarkable biological utilization, such as antiviral, antibacterial, antihypertensive, antitumor, and calcium blockers effects. OBJECTIVE: The aim of this work presented herein was to prepare activated carbon/MoO3 nanocomposite and explore its role as a green and recyclable catalyst for the synthesis of chromeno[d]pyrimidinediones and xanthenones under ethanol-drop grinding at room temperature. METHODS: The activated carbon/MoO3 nanocomposite was prepared successfully via a simple route in which the carbonization of gums as new natural precursors was used for the synthesis of activated carbon. This nanocomposite was then effectively used in a reaction of 3,4-methylenedioxyphenol, aromatic aldehydes, and active methylene compounds, including 1,3-dimethylbarbituric acid and dimedone, to synthesize a series of chromeno[d]pyrimidinediones and xanthenones in high yields. The synthesized catalyst was characterized by Fourier transform infrared spectroscopy (FT-IR), Powder x-ray diffractometry (XRD), Scanning electron microscope (SEM), Raman spectroscopy, and also by TGA analysis. Confirmation of the structures of compounds 5(a-g) and 6(a-g) were also established with IR, 1H NMR, and 13C NMR spectroscopic data and also by elemental analyses. RESULTS: A number of 6,8-dimethyl-10-phenyl-6,10-dihydro-7H-[1,3]dioxolo[4´,5´:6,7]chromeno[2,3- d]pyrimidine-7,9(8H)-diones and 7,7-dimethyl-10-(4-methylphenyl)-6,7,8,10-tetrahydro-9H-[1,3]dioxolo[ 4,5-b]xanthen-9-ones were effectively synthesized using activated carbon/MoO3 nanocomposite (0.05 gr) as a catalyst under ethanol-drop grinding at room temperature. The desired products were obtained in high yields (93-97%) within short reaction times (15-20 min). CONCLUSION: This paper investigates the catalytic potential of the synthesized activated carbon/MoO3 nanocomposite for the preparation of chromeno[d]pyrimidinediones and xanthenones under the ethanol-drop grinding procedure. The mildness of the reaction conditions, high yields of products, short reaction times, experimental simplicity, and avoiding the use of harmful solvents or reagents makes this procedure preferable for the synthesis of these compounds.