Search

Novel (E)-3-(dimethylamino)-1-(quinolin-3-yl)prop-2-en-1-one and (E)-3-(dimethylamino)-1-(quinolin-3-yl)but-2-en-1-one (2) were synthesized in excellent yields by reacting 3-acetylquinoline with DMF-DMA and DMA-DMA respectively. Subsequently, 2 were used as the precursors for the synthesis of 3-(pyrazolo[1,5-a]pyrimidin-7-yl)quinolines and 3-(5-methylpyrazolo[1,5-a]pyrimidin-7-yl)quinolines (4). All the synthesized compounds were subjected to structure elucidation and evaluated for their antiparasitic potential with special reference to their anti-malarial properties. The in-vitro studies of the synthesized compounds revealed moderate anti-malarial efficacy for compounds 4b, 4c, 4d, 4k, 4l and 4m. Compounds 4g and 4i showed highest activity displaying IC50 values of 2.10 and 2.77 μ M, respectively, for the chloroquine-sensitive strain of P. falciparum, and 4.26 and 2.87 μ M, respectively, for the chloroquine-resistant strain. The in-vitro cytotoxicity of the compounds showed CC50 as >500 µM and thus, found to be safe. Molecular docking of the novel series of ligand 4a–4n against the target protein P. falciparum PfLDH enzyme target (PDB ID 1LDG) revealed good binding energies ranging from –8.06 to –11.02 kcal/mol with low inhibition constants summed up as 1.04, 473.55, 352.51, 290.9, 437.86, 1.23, 41.18, 26.81, 162.76, 300.38, 70.2, 29.84, 4.14, 8.4 µM, respectively. The lower the inhibition constant (µM), the greater is the binding affinity and lower the medication required to inhibit the activity of the target receptor. (E)-3-(dimethylamino)-1-(quinolin-3-yl)but-2-en-1-one with 3-aminopyrazole under ultrasonic irradiation in aqueous medium yielded novel 3-(pyrazolo[1,5-a]pyrimidin-7-yl)quinolines and 3-(5-methylpyrazolo[1,5-a]pyrimidin-7-yl)quinolines. Antimalarial studies against Pf3D7 strain resulted in moderate activity with compound 4g showing highest activity. Molecular docking analysis of the compounds reveals the potentiality of the series to serve as antimalarial agents against CQ-sensitive (Pf3D7) and multi-drug-resistant (PfK1). [ABSTRACT FROM AUTHOR]

The pyrazolopyrimidine moiety in the title molecule, C13H12N4S, is planar with the methylsulfanyl substituent lying essentially in the same plane. The benzyl group is rotated well out of this plane by 73.64 (6)°, giving the molecule an approximate L shape. In the crystal, C—H...π(ring) interactions and C—H...S hydrogen bonds form tubes extending along the a axis. Furthermore, there are π–π interactions between parallel phenyl rings with centroid-to-centroid distances of 3.8418 (12) Å. A Hirshfeld surface analysis of the crystal structure indicates that the most important contributions to the crystal packing are from H...H (47.0%), H...N/N...H (17.6%) and H...C/C...H (17.0%) interactions. The volume of the crystal voids and the percentage of free space were calculated to be 76.45 Å3 and 6.39%, showing that there is no large cavity in the crystal packing. Evaluation of the electrostatic, dispersion and total energy frameworks indicate that the cohesion of the crystal structure is dominated by the dispersion energy contributions.

Two libraries of quinoline‐based hybrids 1‐(7‐chloroquinolin‐4‐yl)‐1H‐pyrazolo[3,4–d]pyrimidin‐4‐amine and 7‐chloro‐N‐phenylquinolin‐4‐amine were synthesized and evaluated for their α‐glucosidase inhibitory and antioxidant properties. Compounds with 4‐methylpiperidine and para‐trifluoromethoxy groups, respectively, showed the most promising α‐glucosidase inhibition activity with IC50=46.70 and 40.84 μM, compared to the reference inhibitor, acarbose (IC50=51.73 μM). Structure‐activity relationship analysis suggested that the cyclic secondary amine pendants and para‐phenyl substituents account for the variable enzyme inhibition. Antioxidant profiling further revealed that compounds with an N‐methylpiperazine and N‐ethylpiperazine ring, respectively, have good DPPH scavenging abilities with IC50=0.18, 0.58 and 0.93 mM, as compared to ascorbic acid (IC50=0.05 mM), while the best DPPH scavenger is NO2‐substituted compound (IC50=0.08 mM). Also, compound with N‐(2‐hydroxyethyl)piperazine moiety emerged as the best NO radical scavenger with IC50=0.28 mM. Molecular docking studies showed that the present compounds are orthosteric inhibitors with their quinoline, pyrimidine, and 4‐amino units as crucial pharmacophores furnishing α‐glucosidase binding at the catalytic site. Taken together, these compounds exhibit dual potentials; i. e., potent α‐glucosidase inhibitors and excellent free radical scavengers. Hence, they may serve as structural templates in the search for agents to manage Type 2 diabetes mellitus. Finally, in preliminary assays investigating the anti‐tubercular potential of these compounds, two pyrazolopyrimidine series compounds and a 7‐chloro‐N‐phenylquinolin‐4‐amine hybrid showed sub‐10 μM whole‐cell activities against Mycobacterium tuberculosis. [ABSTRACT FROM AUTHOR]

Two compound derived from fused Pyrazolo-Triazolo-Pyrimidine (C1 and C2), have inhibitory action against corrosion of Zinc in 1 M HNO3 examined experimentally by electrochemical tests and theoretically by density functional theory (DFT). The findings demonstrate that zinc corrodes in acidic conditions with greater corrosion resistance than C1 and C2. Concentration and corrosion inhibition directly relate to one another. The two Pyrazolopyrimidine-derived compounds had optimum inhibition efficiency of 92.06 and 79.36% for C1 and C2, respectively, at 700 ppm. In accordance to the polarization curves, the antagonists feature a mixed but primarily anodic inhibitor and a Langmuir process. DFT computations validated the compounds apparent antagonistic response. SEM also show the development of a barrier on the zinc surface. In conclusion, these two antagonists, C1 and C2, are successful in avoiding zinc dissolution in HNO3. [ABSTRACT FROM AUTHOR]

Abstract Two libraries of quinoline‐based hybrids 1‐(7‐chloroquinolin‐4‐yl)‐1H‐pyrazolo[3,4–d]pyrimidin‐4‐amine and 7‐chloro‐N‐phenylquinolin‐4‐amine were synthesized and evaluated for their α‐glucosidase inhibitory and antioxidant properties. Compounds with 4‐methylpiperidine and para‐trifluoromethoxy groups, respectively, showed the most promising α‐glucosidase inhibition activity with IC50=46.70 and 40.84 μM, compared to the reference inhibitor, acarbose (IC50=51.73 μM). Structure‐activity relationship analysis suggested that the cyclic secondary amine pendants and para‐phenyl substituents account for the variable enzyme inhibition. Antioxidant profiling further revealed that compounds with an N‐methylpiperazine and N‐ethylpiperazine ring, respectively, have good DPPH scavenging abilities with IC50=0.18, 0.58 and 0.93 mM, as compared to ascorbic acid (IC50=0.05 mM), while the best DPPH scavenger is NO2‐substituted compound (IC50=0.08 mM). Also, compound with N‐(2‐hydroxyethyl)piperazine moiety emerged as the best NO radical scavenger with IC50=0.28 mM. Molecular docking studies showed that the present compounds are orthosteric inhibitors with their quinoline, pyrimidine, and 4‐amino units as crucial pharmacophores furnishing α‐glucosidase binding at the catalytic site. Taken together, these compounds exhibit dual potentials; i. e., potent α‐glucosidase inhibitors and excellent free radical scavengers. Hence, they may serve as structural templates in the search for agents to manage Type 2 diabetes mellitus. Finally, in preliminary assays investigating the anti‐tubercular potential of these compounds, two pyrazolopyrimidine series compounds and a 7‐chloro‐N‐phenylquinolin‐4‐amine hybrid showed sub‐10 μM whole‐cell activities against Mycobacterium tuberculosis.

Protein kinase casein kinase 2 (CK2/CSNK2) is a pleiotropic kinase involved in many cellular processes and, accordingly, has been identified as a potential target for therapeutic intervention for multiple indications. Significant research effort has been invested into identifying CK2 inhibitors as potential drug candidates and potent and selective CK2 chemical probes to interrogate CK2 function. Here, we review the small molecule inhibitors reported for CK2 and discuss various orthosteric, allosteric, and bivalent inhibitors of CK2. We focus on the pyrazolo[1,5-a]pyrimidines and naphthyridines, two chemotypes that have been extensively explored for chemical probe development. We highlight the uptake and demonstrated utility of the pyrazolo[1,5-a]pyrimidine chemical probe SGC-CK2-1 by the scientific community in cellular studies. Finally, we propose criteria for an ideal in vivo chemical probe for investigating CK2 function in a living organism. While no compound currently meets these metrics, we discuss ongoing and future directions in the development of in vivo chemical probes for CK2. [ABSTRACT FROM AUTHOR]

The increased burden of cancer disease globally arouses the urgent need for the development of novel chemical agent with improved efficacy and potency which can provide selective therapeutic outcome to an individual cancer patient. In this connection the in-silico designing of novel scaffolds are greatly helpful evading the need for synthesizing and evaluating the series of large number compounds. We have constructed novel pyrazolopyrimidines with reference to existing fused pyrimidine standards like central aromatic heterocycles, spacers, hydrophobic heads and tails. We examined for the nature and biochemical targets, ADMET evaluations using various online tools and molecular docking analysis through Schrodinger suite studied binding affinities with reference to standards as well as co-crystals. We designed pyrazolopyrimidines 7a-j and 12a-j along with molecular docking studies revealed that few were potential candidates compared to standard scores against various target kinases. The hydroxyl moiety in 7b & 7d, hydroxyl in 7e with 4-bromo showed more bonding affinity towards targets and remaining compounds produced mild to moderate affinities against various targets. GLU339, GLU51, LEU83, SER345, ASP404, ASN391, and ASP348 are major residues for H-bonding interactions, PHE80, LEU83, GLN275 influenced hydrophobic bonding and ASP404 for nitro group, GLU339 for hydroxyl group, LYS89 for methoxy groups are key residues in binding affinity. We also identified the key residues of target proteins involved in the interaction with ligands at the active pocket. We believe that these results could benefit the future development of anticancer scaffold containing pyrazolopyrimidine motifs in the core structure.

The reaction of enaminonitrile 2 with hydrazine hydrate yielded 5‐amino pyrazole derivative 4. Compound 4 reacted with ethyl acetoacetate, enaminone 8, chalcone 12, enaminonitrile 2, arylidene malononitrile 18, 3‐(3,5‐dimethyl‐1H‐pyrazol‐1‐yl)‐3‐oxopropanenitrile 21 and phenacyl bromide to give the corresponding pyrazolopyrimidine derivatives 7, 11, 14, 17, 20, 23, and imidazopyrazole 25, respectively. The newly synthesized compounds were characterized by spectral and elemental analyses. The antimicrobial activities of the new compounds were tested against S. aureus, E. coli, and C. albicans. It was found that compound 23 exhibited the highest antimicrobial activity against the tested microorganisms. All tested compounds did not have antifungal activity against A. niger as a fungal strain. Utilizing drug‐likeness (ADME) and molecular docking the effectiveness of compound 23 towards G+ve and G‐ve bacteria has been studied. Accordingly, compound 23 is expected to have a high chance of oral bioavailability due to its compliance with Lipinski′s rule of five. In addition, it plays a critical role in the inhibition of bacterial S. Ribosome, dihydropteroate synthase, transpeptidase, and gyrase B. subunit proteins. [ABSTRACT FROM AUTHOR]

Cyclin-dependent kinase inhibition is considered a promising target for cancer treatment for its crucial role in cell cycle regulation. Pyrazolo pyrimidine derivatives were well established for their antitumor activity via CDK2 inhibition. In this research, new series of pyrazolopyrimidine derivatives (4–15) was designed and synthesised as novel CDK2 inhibitors. The anti-proliferative activities against MCF-7, HCT-116, and HepG-2 were used to evaluate their anticancer activity as novel CDK2 inhibitors. Most of the compounds showed superior cytotoxic activity against MCF-7 and HCT-116 compared to Sorafenib. Only compounds 8, 14, and 15 showed potent activity against HepG-2. The CDK2/cyclin A2 enzyme inhibitory activity was tested for all synthesised compounds. Compound 15 showed the most significant inhibitory activity with IC50 0.061 ± 0.003 µM. It exerted remarkable alteration in Pre G1 and S phase cell cycle progression and caused apoptosis in HCT cells. In addition, the normal cell line cytotoxicity for compound 15 was assigned revealing low cytotoxic results in normal cells rather than cancer cells. Molecular docking was achieved on the designed compounds and confirmed the two essential hydrogen binding with Leu83 in CDK2 active site. In silico ADMET studies and drug-likeness showed proper pharmacokinetic properties which helped in structure requirements prediction for the observed antitumor activity.

The increased burden of cancer disease globally arouses the urgent need for the development of novel chemical agent with improved efficacy and potency which can provide selective therapeutic outcome to an individual cancer patient. In this connection the in-silico designing of novel scaffolds are greatly helpful evading the need for synthesizing and evaluating the series of large number compounds. We have constructed novel pyrazolopyrimidines with reference to existing fused pyrimidine standards like central aromatic heterocycles, spacers, hydrophobic heads and tails. We examined for the nature and biochemical targets, ADMET evaluations using various online tools and molecular docking analysis through Schrodinger suite studied binding affinities with reference to standards as well as co-crystals. We designed pyrazolopyrimidines 7a-j and 12a-j along with molecular docking studies revealed that few were potential candidates compared to standard scores against various target kinases. The hydroxyl moiety in 7b & 7d, hydroxyl in 7e with 4-bromo showed more bonding affinity towards targets and remaining compounds produced mild to moderate affinities against various targets. GLU339, GLU51, LEU83, SER345, ASP404, ASN391, and ASP348 are major residues for H-bonding interactions, PHE80, LEU83, GLN275 influenced hydrophobic bonding and ASP404 for nitro group, GLU339 for hydroxyl group, LYS89 for methoxy groups are key residues in binding affinity. We also identified the key residues of target proteins involved in the interaction with ligands at the active pocket. We believe that these results could benefit the future development of anticancer scaffold containing pyrazolopyrimidine motifs in the core structure. [ABSTRACT FROM AUTHOR]

The translocator protein (TSPO) is an interesting biological target for molecular imaging and therapy because the overexpression of TSPO is associated with microglial activation caused by neuronal damage or neuroinflammation, and these activated microglia are involved in various central nervous system (CNS) diseases. The TSPO is a target for neuroprotective treatment, which is used with the aim of reducing microglial cell activation. The novel N,N-disubstituted pyrazolopyrimidine acetamides scaffold (GMA 7–17), which bears a fluorine atom and is directly linked to the phenyl moiety, was synthesized, and each of the novel ligands was characterized in vitro. All of the newly synthesized ligands displayed picomolar to nanomolar affinity for the TSPO. Particularly, an in vitro affinity study led to the discovery of 2-(5,7-diethyl-2-(4-fluorophenyl)pyrazolo [1,5-a]pyrimidin-3-yl)-N-ethyl-N-phenylacetamide GMA 15 (Ki = 60 pM), a novel TSPO ligand that exhibits a 61-fold enhancement in affinity compared to the reference standard DPA-714 (Ki = 3.66 nM). Molecular dynamic (MD) studies of the highest affinity binder, GMA 15, were carried out to check its time-dependent stability with the receptor compared to DPA-714 and PK11195. The hydrogen bond plot also indicated that GMA 15 formed higher hydrogen bonds compared to DPA-714 and PK11195. We anticipate that further optimization to enhance the potency in a cellular assay needs to be followed, but our strategy of identifying potential TSPO binding novel scaffolds may open up a new avenue to develop novel TSPO ligands suited for potential molecular imaging and a wide range of therapeutic applications. [ABSTRACT FROM AUTHOR]

N-heterocyclic compounds are a natural and rich source of pharmacologically active molecules displaying anti-cancer properties through various antiproliferative mechanisms. Some of these N-heterocyclic compounds are already being utilized or evaluated in clinical settings for cancer treatment, highlighting their potential significance in discovering new anticancer agents. This study aims to gather information from articles published between 2019 and 2021 on the recent advancements in N-heterocyclic derivatives such as indazole, triazolopyrimidine, pyrazolopyrimidine, quinoxaline, benzimidazole, benzodiazepine, indole, and quinoline as promising anticancer agents, including their structure-activity relationships and mechanisms of action. [ABSTRACT FROM AUTHOR]

In the title molecule, C7H6N4O3, the bicyclic ring system is planar with the carboxymethyl group inclined by 81.05 (5)° to this plane. In the crystal, corrugated layers parallel to (010) are generated by N—H...O, O—H...N and C—H...O hydrogen-bonding interactions. The layers are associated through C—H...π(ring) interactions. A Hirshfeld surface analysis indicates that the most important contributions to the crystal packing are from H...O/O...H (34.8%), H...N/N...H (19.3%) and H...H (18.1%) interactions. The volume of the crystal voids and the percentage of free space were calculated to be 176.30 Å3 and 10.94%, showing that there is no large cavity in the crystal packing. Computational methods revealed O—H...N, N—H...O and C—H...O hydrogen-bonding energies of 76.3, 55.2, 32.8 and 19.1 kJ mol−1, respectively. Evaluations of the electrostatic, dispersion and total energy frameworks indicate that the stabilization is dominated via dispersion energy contributions. Moreover, the optimized molecular structure, using density functional theory (DFT) at the B3LYP/6–311G(d,p) level, was compared with the experimentally determined one. The HOMO–LUMO energy gap was determined and the molecular electrostatic potential (MEP) surface was calculated at the B3LYP/6–31G level to predict sites for electrophilic and nucleophilic attacks.

Pyrazolo[3,4- d ]pyrimidines represent one potent class of well tolerated and highly active rhinovirus (RV) inhibitors that act as capsid binders. The lead compound OBR-5-340 inhibits a broad-spectrum of RVs. Aiming to improve lead activity, we evaluated the impact of structural modifications in the 3-phenyl ring of OBR-5-340 on its potency and spectrum of anti-RV activity vitro. Our results demonstrate the crucial role of substitution at position 4 for strong, broad-spectrum anti-RV activity. The 4-methyl (RCB23137) and 4-chloro (RCB23138) derivatives outperformed OBR-5-340 in terms of potency and anti-RV activity spectrum. Based on these findings, the compounds were selected for computational binding studies. Molecular dynamic simulations with six RVs differing in OBR-5-340, RCB23137, and RCB23138 sensitivity proved the impact of dynamic features of two VP1 loops enveloping these inhibitors on antiviral potency. [Display omitted] • Rhinoviruses (RVs) differ in their sensitivity to the capsid-binding pyrazolo[3,4- d ]pyrimidine OBR-5-340. • Substitutions at position 4 in the 3-phenly ring of OBR-5-340 facilitated stronger, broad-spectrum anti-RV activity. • The 4-methyl and 4-chloro derivatives outperformed OBR-5-340 in terms of potency and anti-RV spectrum. • Dynamic features of VP1-compound complexes determine the binding affinity of considered compounds. [ABSTRACT FROM AUTHOR]

Cyclin-dependent kinase inhibition is considered a promising target for cancer treatment for its crucial role in cell cycle regulation. Pyrazolo pyrimidine derivatives were well established for their antitumor activity via CDK2 inhibition. In this research, new series of pyrazolopyrimidine derivatives (4-15) was designed and synthesised as novel CDK2 inhibitors. The anti-proliferative activities against MCF-7, HCT-116, and HepG-2 were used to evaluate their anticancer activity as novel CDK2 inhibitors. Most of the compounds showed superior cytotoxic activity against MCF-7 and HCT-116 compared to Sorafenib. Only compounds 8, 14, and 15 showed potent activity against HepG-2. The CDK2/cyclin A2 enzyme inhibitory activity was tested for all synthesised compounds. Compound 15 showed the most significant inhibitory activity with IC50 0.061 ±0.003 µM. It exerted remarkable alteration in Pre G1 and S phase cell cycle progression and caused apoptosis in HCT cells. In addition, the normal cell line cytotoxicity for compound 15 was assigned revealing low cytotoxic results in normal cells rather than cancer cells. Molecular docking was achieved on the designed compounds and confirmed the two essential hydrogen binding with Leu83 in CDK2 active site. In silico ADMET studies and drug-likeness showed proper pharmacokinetic properties which helped in structure requirements prediction for the observed antitumor activity. [ABSTRACT FROM AUTHOR]

The asymmetric unit of the title compound, C10H12N4O2S, contains two molecules differing slightly in the orientations of the methyl groups. In the crystal, a sandwich-type structure extending parallel to the ab plane is formed by weak C--H· · ·O and C--H· · ·N hydrogen bonds together with slipped π-stacking interactions. A Hirshfeld surface analysis of the crystal structure indicates that the most important contributions to the crystal packing are from H· · ·H (43.5%), H· · ·O/O· · ·H (17.9%) and H· · ·N/N· · ·H (17.4%) interactions. The molecular structure optimized by density functional theory (DFT) at the B3LYP/6-311 G(d,p) level is compared with the experimentally determined structure in the solid state. Further calculations include the HOMO-LUMO energies and molecular electrostatic potential (MEP) surfaces. [ABSTRACT FROM AUTHOR]

Lymphatic filariasis and onchocerciasis are common filarial diseases caused by filarial worms, which co-habit symbiotically with the Wolbachia organism. One good treatment method seeks Wolbachia as a drug target. Here, a computer-aided molecular docking screening and 3-D QSAR modeling were conducted on a series of Fifty-two (52) pyrazolopyrimidine derivatives against four Wolbachia receptors, including a pharmacokinetics study and Molecular Dynamic (MD) investigation, to find a more potent anti-filarial drug. The DFT approach (B3LYP with 6-31G** option) was used for the structural optimization. Five ligand-protein interaction pairs with the highest binding affinities were identified in the order; 23_7ESX (-10.2 kcal/mol) > 14_6EEZ (− 9.0) > 29_3F4R (− 8.0) > 26_6W9O (− 7.7) ≈ doxycycline_7ESX (− 7.7), with good pharmacological interaction profiles. The built 3-D QSAR model satisfied the requirement of a good model with R2 = 0.9425, Q2LOO = 0.5019, SDEC = 0.1446, and F test = 98.282. The selected molecules (14, 23, 26, and 29) perfectly obeyed Lipinski's RO5 for oral bio-availability, and showed excellent ADMET properties, except 14 with positive AMES toxicity. The result of the MD simulation showed the great stability associated with the binding of 23 onto 7ESX's binding pocket with an estimated binding free energy (MM/GBSA) of − 60.6552 kcal/mol. Therefore, 23 could be recommended as a potential anti-filarial drug molecule, and/or template for the design of more prominent inhibitors. [ABSTRACT FROM AUTHOR]

In the title molecule, C7H6N4O3, the bicyclic ring system is planar with the carboxymethyl group inclined by 81.05 (5)⋅ to this plane. In the crystal, corrugated layers parallel to (010) are generated by N--H⋅ ⋅ ⋅O, O--H⋅ ⋅ ⋅N and C--H⋅ ⋅ ⋅O hydrogen-bonding interactions. The layers are associated through C--H⋅ ⋅ ⋅⋅(ring) interactions. A Hirshfeld surface analysis indicates that the most important contributions to the crystal packing are from H⋅ ⋅ ⋅O/O⋅ ⋅ ⋅H (34.8%), H⋅ ⋅ ⋅N/N⋅ ⋅ ⋅H (19.3%) and H⋅ ⋅ ⋅H (18.1%) interactions. The volume of the crystal voids and the percentage of free space were calculated to be 176.30 A ° 3 and 10.94%, showing that there is no large cavity in the crystal packing. Computational methods revealed O--H⋅ ⋅ ⋅N, N--H⋅ ⋅ ⋅O and C--H⋅ ⋅ ⋅O hydrogen-bonding energies of 76.3, 55.2, 32.8 and 19.1 kJ mol1, respectively. Evaluations of the electrostatic, dispersion and total energy frameworks indicate that the stabilization is dominated via dispersion energy contributions. Moreover, the optimized molecular structure, using density functional theory (DFT) at the B3LYP/6-311G(d, p) level, was compared with the experimentally determined one. The HOMO-LUMO energy gap was determined and the molecular electrostatic potential (MEP) surface was calculated at the B3LYP/6-31G level to predict sites for electrophilic and nucleophilic attacks. [ABSTRACT FROM AUTHOR]

The translocator protein (TSPO) is an interesting biological target for molecular imaging and therapy because the overexpression of TSPO is associated with microglial activation caused by neuronal damage or neuroinflammation, and these activated microglia are involved in various central nervous system (CNS) diseases. The TSPO is a target for neuroprotective treatment, which is used with the aim of reducing microglial cell activation. The novel N,N-disubstituted pyrazolopyrimidine acetamides scaffold (GMA 7–17), which bears a fluorine atom and is directly linked to the phenyl moiety, was synthesized, and each of the novel ligands was characterized in vitro. All of the newly synthesized ligands displayed picomolar to nanomolar affinity for the TSPO. Particularly, an in vitro affinity study led to the discovery of 2-(5,7-diethyl-2-(4-fluorophenyl)pyrazolo [1,5-a]pyrimidin-3-yl)-N-ethyl-N-phenylacetamide GMA 15 (Ki = 60 pM), a novel TSPO ligand that exhibits a 61-fold enhancement in affinity compared to the reference standard DPA-714 (Ki = 3.66 nM). Molecular dynamic (MD) studies of the highest affinity binder, GMA 15, were carried out to check its time-dependent stability with the receptor compared to DPA-714 and PK11195. The hydrogen bond plot also indicated that GMA 15 formed higher hydrogen bonds compared to DPA-714 and PK11195. We anticipate that further optimization to enhance the potency in a cellular assay needs to be followed, but our strategy of identifying potential TSPO binding novel scaffolds may open up a new avenue to develop novel TSPO ligands suited for potential molecular imaging and a wide range of therapeutic applications.

Direct inhibitors of glycogen synthase kinase 3β (GSK3β) have been investigated and reported for the past 20 years. In the search for novel scaffold inhibitors, 3000 compounds were selected through structure-based virtual screening (SBVS), and then high-throughput enzyme screening was performed. Among the active hit compounds, pyrazolo [1,5-a]pyrimidin-7-amine derivatives showed strong inhibitory potencies on the GSK3β enzyme and markedly activated Wnt signaling. The result of the molecular dynamics (MD) simulation, enhanced by the upper-wall restraint, was used as an advanced structural query for the SBVS. In this study, strong inhibitors designed to inhibit the GSK3β enzyme were discovered through SBVS. Our study provides structural insights into the binding mode of the inhibitors for further lead optimization. [ABSTRACT FROM AUTHOR]

The current work presents an objective overview of the impact of one important heterocyclic structure, the pyrazole ring, in the development of anti-proliferative drugs. A set of 1551 pyrazole derivatives were extracted from the National Cancer Institute (NCI) database, together with their growth inhibition effects (GI%) on the NCI's panel of 60 cancer cell lines. The structures of these derivatives were analyzed based on the compounds' averages of GI% values across NCI-60 cell lines and the averages of the values for the outlier cells. The distribution and the architecture of the Bemis–Murcko skeletons were analyzed, highlighting the impact of certain scaffold structures on the anti-proliferative effect's potency and selectivity. The drug-likeness, chemical reactivity and promiscuity risks of the compounds were predicted using AMDETlab. The pyrazole ring proved to be a versatile scaffold for the design of anticancer drugs if properly substituted and if connected with other cyclic structures. The 1,3-diphenyl-pyrazole emerged as a useful scaffold for potent and targeted anticancer candidates. [ABSTRACT FROM AUTHOR]

Pyrazole-phenylmethanimines (Shiff bases), Py–N=CH–Ph, form molecular crystals whose supramolecular and self-assembly properties can be tuned according to the substitution made on the aromatic and pyrazole rings. In pursuit of the first pyrazole-pyridinemethanimine member, Py–N=CH–Pyr, by following the well-known synthetic scheme for these Shiff bases, two hitherto unknown crystalline derivatives of dipyrazolo-1,5-diazocine and dipyrazolopyrimidine were obtained instead, this depending on the use or not of acetic acid as the catalyst. 1,5-diazocine crystallizes in a single P-1 triclinic packing system (Z = 2, Z′ = 1), while dipyrazolopyrimidine exhibits isostructural dimorphic behavior by adopting two (pale pink and yellow) alike P21/c monoclinic systems (both Z = 4, Z′ = 1) as a function of the solvent used. Crystal structures were resolved by means of X-ray diffraction technique and their intramolecular, intermolecular, and supramolecular assemblies analyzed with the assistance of decorated Hirshfeld surfaces and the topology study of electron density using the quantum-theory of atoms in molecules (QTAIM). Although both dipyrazolopyrimidine polymorphs are stabilized by the same type of noncovalent motifs, the pale pink crystal has a slightly more compact structure, with more efficient inter- and intramolecular interactions. [ABSTRACT FROM AUTHOR]

4,6‐Disubstituted pyrazolo[3,4‐d]pyrimidine derivatives were explored as irreversible Bruton's tyrosine kinase (BTK) inhibitors. The structure–activity relationship was established with over 20 derivatives synthesized to determine initial hit compounds, based on activities against BTK enzyme and TMD8 cells. It turned out that introducing 1‐acrylamido‐4‐aminopiperdine (1b) at the C4 position of pyrazolopyrimidine as in 5e, and 3‐acrylamido‐aniline (1j) as 4‐position substituent, such as in 9d, 10d, and 10e, delivered potent in vitro enzyme activities as well as TMD8 cell‐based cytotoxicities. Considering kinase selectivity profiles, 5e was selected for in vivo efficacy studies with a murine xenograft model using TMD8 cells, where 5e exhibited moderate tumor growth inhibition activities. Further optimization of 5e and 9d may lead to clinically useful compounds to overcome B‐cell‐mediated hematologic cancers. [ABSTRACT FROM AUTHOR]

VEGF plays a crucial role in cancer development, angiogenesis and progression, principally liver and breast cancer. It is vital to uncover novel chemical candidates of VEGFR inhibitors to develop more potent anti-breast and anti-liver cancer agents than the currently available candidates, sorafenib and regorafenib, that face resistance obstacles and severe side effects. Herein, nine pyrazolopyrimidine derivatives were designed, synthesized as sorafenib and regorafenib analogues and screened for their in vitro cytotoxic and growth inhibition activities against four human cancer cell lines, namely breast cancer (Michigan Cancer Foundation-7 (MCF-7), hepatocellular carcinoma (HCC) type (HepG2), lung carcinoma (A-549) and human colorectal carcinoma-116 (HCT-116)). Among the tested compounds, compounds 1, 2a, 4b and 7 showed the uppermost cytotoxic activities against all aforementioned cell lines with IC50 estimates varying from 6 to 50 µM, among which compound 7 showed the best inhibitory activity on all tested compounds. Stunningly, compound 7 showed the best significant inhibition of the VEGFR-2 protein expression level (72.3%) as compared to the control and even higher than that produced with sorafenib and regorafenib (70.4% and 55.6%, respectively). Modeling studies provided evidence for the possible interactions of the synthesized compounds with the key residues of the ATP binding sites on the hinge region and the "DFG out" motif of VEGFR-2 kinase. Collectively, our present study suggests that pyrazolopyrimidine derivatives are a novel class of anti-cancer drug candidates to inhibit VEGF-VEGFR function. Aspiring to promote constrained aqueous solubility, hence poor oral bioavailability of the developed lead molecule, 7 and 2a-charged D-α-tocopherol polyethylene glycol 1000 succinate (TPGS) surface-coated niosomes were successfully constructed, adopting a thin film hydration technique striving to overcome these pitfalls. A 23 full factorial design was involved in order to investigate the influence of formulation variables: type of surfactant, either Span 60 or Span 40; surfactant:cholesterol ratio (8:2 or 5:5) along with the amount of TPGS (25 mg or 50 mg) on the characteristics of the nanosystem. F2 and S2 were picked as the optimum formula for compounds 2a and 7 with desirability values of 0.907 and 0.903, respectively. In addition, a distinguished improvement was observed in the compound's oral bioavailability and cytotoxic activity after being included in the nano-TPGS-coated niosomal system relative to the unformulated compound. The nano-TPGS-coated niosomal system increased the hepatocellular inhibitory activity four times fold of compound 7a (1.6 µM) and two-fold of 2a (3 µM) relative to the unformulated compounds (6 µM and 6.2 µM, respectively). [ABSTRACT FROM AUTHOR]

Twenty-five novel phenylpyrazole-pyrimidinamine and phenylpyrazole-pyrimidinone compounds were designed and synthesized based on the low-energy conformation of fipronil using scaffold hopping strategy. Their structures were confirmed by ¹H NMR, 13C NMR and HRMS. The insecticidal activity study indicated that compounds A5, B1, B4 and B5 showed 40%-73% mortality to Plutella xylostella at 500 mg/L. However, the insecticidal activities were still weaker than that of fipronil. The differences in physicochemical properties and binding mode with insectival γ-aminobutyric acid (GABA) receptor between these compounds and fipronil may be the major factor which reduced the insecticidal activities. [ABSTRACT FROM AUTHOR]

[Display omitted] • Novel pyrazolopyrimidines were designed as multitarget-directed drug candidates. • GI % against fifteen human cancer cell lines was recorded. • Cytotoxicity against HNO97, MDA-MB-468, FaDu, and HeLa were measured. • Compound 6l decreased EGFR protein concentration by a 6.10-fold change, compared to imatinib. • Compounds 6a and 6l exhibited IC 50 values of 17.89 and 19.39 μM, respectively, against TOPO II. • DNA fragmentation images described the great potential of 6a and 6l in inducing DNA degradation. • Protein expression analysis for caspases 3, 7, 8, and 9, Bax, p53, MMP2, MMP9, and BCL-2 was conducted. • Cell cycle analysis and molecular docking were performed. Herein, we envisioned the design and synthesis of novel pyrazolopyrimidines (confirmed by elemental analysis, 1H and 13C NMR, and mass spectra) as multitarget-directed drug candidates acting as EGFR/TOPO II inhibitors, DNA intercalators, and apoptosis inducers. The target diphenyl-tethered pyrazolopyrimidines were synthesized starting from the reaction of phenyl hydrazine and ethoxymethylenemalononitrile to give aminopyrazole-carbonitrile 2. The latter hydrolysis with NaOH and subsequent reaction with 4-chlorobenzaldhyde afforded the corresponding pyrazolo[3,4- d ]pyrimidin-4-ol 4. Chlorination of 4 with POCl 3 and sequential reaction with different amines afforded the target compounds in good yields (up to 73 %). The growth inhibition % of the new derivatives (6a-m) was investigated against different cancer and normal cells and the IC 50 values of the most promising candidates were estimated for HNO97, MDA-MB-468, FaDu, and HeLa cancer cells. The frontier derivatives (6a , 6i , 6k , 6l , and 6m) were pursued for their EGFR inhibitory activity. Compound 6l decreased EGFR protein concentration by a 6.10-fold change, compared to imatinib as a reference standard. On the other side, compounds (6a , 6i , 6k , 6l , and 6m) underwent topoisomerase II (TOPO II) inhibitory assay. In particular, compounds 6a and 6l exhibited IC 50 s of 17.89 and 19.39 μM, respectively, surpassing etoposide with IC 50 of 20.82 μM. Besides, the DNA fragmentation images described the great potential of both candidates 6a and 6l in inducing DNA degradation at lower concentrations compared to etoposide and doxorubicin. Moreover, compound 6l , with the most promising EGFR/TOPO II inhibition and DNA intercalation, was selected for further investigation for its apoptosis induction ability by measuring caspases 3, 7, 8, and 9, Bax, p53, MMP2, MMP9, and BCL-2 proteins. Additionally, molecular docking was used to explain the SAR results based on the differences in the molecular features of the investigated congeners and the target receptors' topology. [ABSTRACT FROM AUTHOR]

Inhibiting translation presents a tantalizing strategy to tackle the most virulent human malaria parasite. Xie et al. disclose a compound that binds selectively to Plasmodium falciparum tyrosine aminoacyl-tRNA synthetase, preventing the incorporation of tyrosine into nascent proteins and paving the way for a new generation of safe, effective antimalarials. [ABSTRACT FROM AUTHOR]

In the title molecule, C19H16N4O, the planar pyrazolopyrimidine moiety is inclined to the attached phenyl rings by 35.42 (4) and 54.51 (6)°. In the crystal, adjacent molecules are linked into chains parallel to [110] and [1\overline{1}0] by C—H...O and C—H...N hydrogen bonds. Additional C—H...π(ring) interactions lead to the formation of the final three-dimensional network structure. The Hirshfeld surface analysis of the title compound suggests that the most significant contributions to the crystal packing are from H...H (48.2%), C...H/H...C (23.9%) and N...H/H...N (17.4%) contacts.

Pyrazolone and its derivatives are an important class of heterocyclic compounds that are found in many drugs. They represent an interesting model for combinatorial and medicinal chemistry due to their simple preparation and their therapeutic and biological properties. Research on medicinal chemistry has drug-like pyrazolone candidates with various medicinal properties, including anti-inflammatory, antioxidant and antitumor activities, etc. Here, we summarize strategies to synthesize 3-amino-1-substituted-1H-pyrazol-5(4H)-ones and show that this class of compounds can be used as a kay intermediate for the discovery of new drugs and can be readily prepared owing to recent advances in synthetic medicinal chemistry. [ABSTRACT FROM AUTHOR]

In cancer disease, which is one of the problems of today's human societies, the expression of some tyrosine kinase receptors that are effective in the growth and proliferation of cancerous cells rises. Therefore, it is essential to develop and propose new drugs to target the receptors. Performing modeling calculations such as QSAR and docking makes the drug discovery process more efficient. Thus, backpropagation artificial neural network was used for multidimensional quantitative structure–activity relationship (QSAR) to identify essential features of pyrazolopyrimidine moiety, responsible for anticancer activity. The statistical parameters of the model show that multi-QSAR has sufficient validity and accuracy. According to the QSAR modeling, among 26 compounds, the interaction of eight candidates with EGFR, FGFR4, PDGFRA, and VEGFR2 was analyzed by docking modeling. The results showed that 1u compound binds to proteins in a more appropriate area (except FGFR4) with acceptable energy. The results of docking for VEGFR2 binding showed that 1u binds to the active site and binding site of receptor, and it was in the interaction with ten residues in the sites. Although the binding site of 1u molecule in the FGFR4 was not suitable, the binding free energy was excellent (− 9.22 kcal mol−1), which was less than those two anticancer drugs of gefitinib and regorafenib. Furthermore, the values of binding free energy were − 8.69, − 9.64, and − 9.19 kcal mol−1 for EGFR, PDGFRA, and VEGFR2, respectively. Therefore, this study introduces 1u as an anticancer agent that can inhibit the tyrosine kinase receptors. [ABSTRACT FROM AUTHOR]

Direct inhibitors of glycogen synthase kinase 3β (GSK3β) have been investigated and reported for the past 20 years. In the search for novel scaffold inhibitors, 3000 compounds were selected through structure-based virtual screening (SBVS), and then high-throughput enzyme screening was performed. Among the active hit compounds, pyrazolo [1,5-a]pyrimidin-7-amine derivatives showed strong inhibitory potencies on the GSK3β enzyme and markedly activated Wnt signaling. The result of the molecular dynamics (MD) simulation, enhanced by the upper-wall restraint, was used as an advanced structural query for the SBVS. In this study, strong inhibitors designed to inhibit the GSK3β enzyme were discovered through SBVS. Our study provides structural insights into the binding mode of the inhibitors for further lead optimization.

The current work presents an objective overview of the impact of one important heterocyclic structure, the pyrazole ring, in the development of anti-proliferative drugs. A set of 1551 pyrazole derivatives were extracted from the National Cancer Institute (NCI) database, together with their growth inhibition effects (GI%) on the NCI’s panel of 60 cancer cell lines. The structures of these derivatives were analyzed based on the compounds’ averages of GI% values across NCI-60 cell lines and the averages of the values for the outlier cells. The distribution and the architecture of the Bemis–Murcko skeletons were analyzed, highlighting the impact of certain scaffold structures on the anti-proliferative effect’s potency and selectivity. The drug-likeness, chemical reactivity and promiscuity risks of the compounds were predicted using AMDETlab. The pyrazole ring proved to be a versatile scaffold for the design of anticancer drugs if properly substituted and if connected with other cyclic structures. The 1,3-diphenyl-pyrazole emerged as a useful scaffold for potent and targeted anticancer candidates.

Pyrazole-phenylmethanimines (Shiff bases), Py–N=CH–Ph, form molecular crystals whose supramolecular and self-assembly properties can be tuned according to the substitution made on the aromatic and pyrazole rings. In pursuit of the first pyrazole-pyridinemethanimine member, Py–N=CH–Pyr, by following the well-known synthetic scheme for these Shiff bases, two hitherto unknown crystalline derivatives of dipyrazolo-1,5-diazocine and dipyrazolopyrimidine were obtained instead, this depending on the use or not of acetic acid as the catalyst. 1,5-diazocine crystallizes in a single P-1 triclinic packing system (Z = 2, Z′ = 1), while dipyrazolopyrimidine exhibits isostructural dimorphic behavior by adopting two (pale pink and yellow) alike P21/c monoclinic systems (both Z = 4, Z′ = 1) as a function of the solvent used. Crystal structures were resolved by means of X-ray diffraction technique and their intramolecular, intermolecular, and supramolecular assemblies analyzed with the assistance of decorated Hirshfeld surfaces and the topology study of electron density using the quantum-theory of atoms in molecules (QTAIM). Although both dipyrazolopyrimidine polymorphs are stabilized by the same type of noncovalent motifs, the pale pink crystal has a slightly more compact structure, with more efficient inter- and intramolecular interactions.

Copper-based oxide glass-ceramic was successfully synthesized through the single-step melt annealing technique. Synthesized glass-ceramics was characterized using X-ray diffraction (XRD) and scanning electron microscopy (SEM) supported with energy dispersive X-ray (EDX) and mapping. Pyrazolo[1,5- a]pyrimidines 5a-f were synthesized via the reaction of 5-amino-1H-pyrazole-4-carboxamide (1) with enaminones 2a-f in the presence of synthesized oxide glass-ceramic catalyst powder under solvent-free condition. The molecular docking study demonstrated that the COVID-19 main protease (MPro) inhibitor. [ABSTRACT FROM AUTHOR]

VEGF plays a crucial role in cancer development, angiogenesis and progression, principally liver and breast cancer. It is vital to uncover novel chemical candidates of VEGFR inhibitors to develop more potent anti-breast and anti-liver cancer agents than the currently available candidates, sorafenib and regorafenib, that face resistance obstacles and severe side effects. Herein, nine pyrazolopyrimidine derivatives were designed, synthesized as sorafenib and regorafenib analogues and screened for their in vitro cytotoxic and growth inhibition activities against four human cancer cell lines, namely breast cancer (Michigan Cancer Foundation-7 (MCF-7), hepatocellular carcinoma (HCC) type (HepG2), lung carcinoma (A-549) and human colorectal carcinoma-116 (HCT-116)). Among the tested compounds, compounds 1, 2a, 4b and 7 showed the uppermost cytotoxic activities against all aforementioned cell lines with IC50 estimates varying from 6 to 50 µM, among which compound 7 showed the best inhibitory activity on all tested compounds. Stunningly, compound 7 showed the best significant inhibition of the VEGFR-2 protein expression level (72.3%) as compared to the control and even higher than that produced with sorafenib and regorafenib (70.4% and 55.6%, respectively). Modeling studies provided evidence for the possible interactions of the synthesized compounds with the key residues of the ATP binding sites on the hinge region and the “DFG out” motif of VEGFR-2 kinase. Collectively, our present study suggests that pyrazolopyrimidine derivatives are a novel class of anti-cancer drug candidates to inhibit VEGF-VEGFR function. Aspiring to promote constrained aqueous solubility, hence poor oral bioavailability of the developed lead molecule, 7 and 2a-charged D-α-tocopherol polyethylene glycol 1000 succinate (TPGS) surface-coated niosomes were successfully constructed, adopting a thin film hydration technique striving to overcome these pitfalls. A 23 full factorial design was involved in order to investigate the influence of formulation variables: type of surfactant, either Span 60 or Span 40; surfactant:cholesterol ratio (8:2 or 5:5) along with the amount of TPGS (25 mg or 50 mg) on the characteristics of the nanosystem. F2 and S2 were picked as the optimum formula for compounds 2a and 7 with desirability values of 0.907 and 0.903, respectively. In addition, a distinguished improvement was observed in the compound’s oral bioavailability and cytotoxic activity after being included in the nano-TPGS-coated niosomal system relative to the unformulated compound. The nano-TPGS-coated niosomal system increased the hepatocellular inhibitory activity four times fold of compound 7a (1.6 µM) and two-fold of 2a (3 µM) relative to the unformulated compounds (6 µM and 6.2 µM, respectively).

Abstract Background Chalcones are intent in the daily diet as a favorable chemotherapeutic compound; on the other hand thiophene moiety is present in a large number of bioactive molecules having diverse biological efficiency. Results Our current goal is the synthesis of (E)-1-(pyridin-3-yl)-3-(thiophen-2-yl) prop-2-en-1-one 3 that’s used as a starting compound to synthesize the novel pyrimidine-2-thiol, pyrazole, pyran derivatives. Chalcones 3 was prepared by condensation of 3-acetylpyridine with thiophene 2-carboxaldehyde which reacted with thiourea to obtain pyrimidinthiol derivative 4. Compound 4 was allowed to react with hydrazine hydrate to afford 2-hydrazinylpyrimidine derivative 5. Compound 5 was used as a key intermediate for a facile synthesis of the targets 6 and 7. In contrast, pyranone 8 was obtained by transformation of compound 5. Using as a precursor for the synthesis of new pyrazolo pyrimidine derivatives 9–10. The major incentive behind the preparation of these compounds was the immense biological activities associated to these heterocyclic derivatives. Conclusions The newly synthesized compounds (1–4) showed potent anti-inflammatory activities both in vitro and in vivo. They also exhibited promising antioxidant vitalities against α, α-diphenyl-β-picrylhydrazyl scavenging activity and lipid peroxidation. In conclusion, compound 1 showed a hopefully anti-inflammatory and antioxidant activities.

Abstract Background Described a series of main target compounds pyrimido[5,4-e][1,2,4]triazines is obtained via condensation of 6-hydrazinyluracil with different aromatic aldehydes to give the hydrazones followed by nitrosation with HNO2 then intramolecular cyclization. On the other hand, pyrazolopyrimidines can be obtained by the reaction of hydrazones with dimethylformamide-dimethylacetal (DMF-DMA), DMF-DMA in the presence of DMF or by refluxing the hydrazinyluracil with DMF-DMA in the presence of DMF directly. The newly synthesized compounds are evaluated in vitro for their anticancer activity against human lung carcinoma (A549). Results A newly substituted compounds of benzaldehyde-pyrimidin-4-yl)hydrazones (5a–f), pyrimido[5,4-e][1,2,4]triazines 6a–e, arylethylidenehydrazinylpyrimidine 7a,b and pyrazolopyrimidines 9,11 are screened for cytotoxic activity against human lung carcinoma (A549) cell line. They exhibited a good yield. Compound 6b shows the highest effect with IC50 value 3.6 μM, followed by compounds 9, 5a, 8, 5e, 6e, 5b, 5f, 7a, 5c, 6c, 7b, 6a, 11, 5d and 6d. Conclusion A simple and efficient route is used for the synthesis of pyrimido[5,4-e][1,2,4]triazines and pyrazolopyrimidines. The synthesized compounds are screened for antitumor activity.

Cancer is caused by the uncontrolled development of abnormal cells, a severe and life-threatening health problem globally. It is a collection of various diseases kept referring to as perhaps the deadliest after cardiovascular disease in terms of lives lost. Despite large and innovative effective innovations to cancer issues, there are still gaps in cancer treatment; it is predicted to be the leading cause of death in the new millennium. Today, pharmaceutical manufacturing costs billions of dollars to discover effective, safe, and reliable cancer drugs in particular pyrazole derivatives. Pyrazole is a heterocyclic heterogeneous ring containing five adjacent atoms of nitrogen C3H3N2H. Interestingly, these scaffolds are present in the pharmacokinetics of various therapeutic classes, such as pyrazole pyrimidines, Known as adenine biotic, which is essential for all aspects of cell survival. Pyrazolo[1,5-a] pyrimidine have been investigated for their inhibitory potential against a diverse array of protein kinase enzymes and with their part as an anticancer drug. This study primarily addresses the artificial and anticancer activity of various pyrazole scaffolds, in particular pyrazole pyrimidine scaffolds. [ABSTRACT FROM AUTHOR]

A novel one-pot four-component reaction of an aldehyde, malononitrile, hydrazine and 4,4-dimethyl-3-oxopentanenitrile is described. As regio- and chemoselective products, 7-amino-2-(tert-butyl)-5-aryl-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carbonitriles are formed during the course of the reaction. [ABSTRACT FROM AUTHOR]

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 Pf DHODH, 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. [Display omitted] • • Triazolo- and pyrazolopyrimidine derivatives actives against P. falciparum strains. • • The componds has no cross-resistance with drug-resistant P. falciparum. • • The ability to interfere with gametocyte and ookinete infectivity was also evaluated. • • Four compounds demonstrated potential to block the transmission of such parasites. [ABSTRACT FROM AUTHOR]

Rhinoviruses (RVs) cause the common cold. Attempts at discovering small molecule inhibitors have mainly concentrated on compounds supplanting the medium chain fatty acids residing in the sixty icosahedral symmetry-related hydrophobic pockets of the viral capsid of the Rhinovirus-A and -B species. High-affinity binding to these pockets stabilizes the capsid against structural changes necessary for the release of the ss(+) RNA genome into the cytosol of the host cell. However, single-point mutations may abolish this binding. RV-B5 is one of several RVs that are naturally resistant against the well-established antiviral agent pleconaril. However, RV-B5 is strongly inhibited by the pyrazolopyrimidine OBR-5-340. Here, we report on isolation and characterization of RV-B5 mutants escaping OBR-5-340 inhibition and show that substitution of amino acid residues not only within the binding pocket but also remote from the binding pocket hamper inhibition. Molecular dynamics network analysis revealed that strong inhibition occurs when an ensemble of several sequence stretches of the capsid proteins enveloping OBR-5-340 move together with OBR-5-340. Mutations abrogating this dynamic, regardless of whether being localized within the binding pocket or distant from it result in escape from inhibition. Pyrazolo [3,4- d ]pyrimidine derivatives overcoming OBR-5-340 escape of various RV-B5 mutants were identified. Our work contributes to the understanding of the properties of capsid-binding inhibitors necessary for potent and broad-spectrum inhibition of RVs. [Display omitted] • Capsid-binding inhibitors of rhinoviruses (RVs) differ in molecular binding mechanism and resistance profiles. • The pyrazolo [3,4- d ]pyrimidine OBR-5-340 strongly inhibits the pleconaril-resistant RV-B5. • Some RV-B5 mutants escaping OBR-5-340 inhibition have amino acid substitutions distant from the binding pocket. • Their substitutions reduce the motion of several sequence stretches of the capsid proteins crucial for inhibitor binding. • Pyrazolo [3,4-d]pyrimidine derivatives inhibiting OBR-5-340 escape mutants of RV-B5 were identified. [ABSTRACT FROM AUTHOR]

A number of pyrrolo[2,3-c]pyridines, pyrrolo[3,2-d]pyrimidines and pyrazolo[4,3-d]pyrimidines were designed and synthesized as antiproliferative agents. The target compounds possessed selected substituents in analogous positions on the central scaffold that allowed the extraction of interesting SARs. The cytotoxic activity of the new derivatives was evaluated against prostatic (PC-3) and colon (HCT116) cell lines, and the most potent analogues showed IC50 values in the nM to low µM range, while they were found to be non-toxic against normal human fibroblasts (WI-38). Flow cytometric analysis of DNA content revealed that the most promising derivative 14b caused a statistically significant accumulation of PC-3 cells at G2/M phase and induced apoptosis in PC-3 cells.

Background: Globally, cancer is the leading cause of death, which causes 10 million deaths yearly. Clinically, several drugs are used in treatment but due to drug resistance and multidrug resistance, there occurs a failure in the cancer treatment., Objectives: The present review article is a comprehensive review of pyrazole and pyrimidine hybrids as potential anticancer agents., Methods: The review comprises more than 60 research works done in this field. The efficiency of the reported pyrazolopyrimidine fused heterocyclic with their biological data and the influence of the structural aspects of the molecule have been discussed., Results: This review highlighted pyrazolo-pyrimidines as targeted anticancer agents with effect on multiple targets., Conclusion: The review will be helpful for the researchers involved in targeted drugs for cancer therapy for designing new scaffolds with pyrazolo-pyrimidine moieties., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: Type-2 diabetes is a chronic progressive metabolic disease resulting in severe vascular complications and mortality risk. Recently, DPP-4 inhibitors had been conceived as a favorable class of agents for the treatment of type 2 diabetes due to the minimal side effects., Methods: Sitagliptin is the first medicine approved for the DPP-4 inhibitor. Its structure involved three fragments: 2,4,5-triflorophenyl fragment pharmacophore, enantiomerically β-amino carbonyl linker, and tetrahydrotriazolopyridine. Herein, we are drawn to the possibility of substituting tetrahydrotriazolopyridine motif present in Sitagliptin with a series of new fused pyrazolopyrimidine bicyclic fragment to investigate potency and safety., Results: Two series of fused 6-(aminomethyl)pyrazolopyrimidine and 6-(hydroxymethyl) pyrazolopyrimidine derivatives containing β-amino ester or amide as linkers were successfully designed for the new DPP-4 inhibitors. Most fused 6-methylpyrazolopyrimidines were evaluated against DPP-4 inhibition and selectivity capacity. Based on research study, β-amino carbonyl fused 6-(hydroxymethyl)pyrazolopyrimidine possesses the significant DPP-4 inhibition (IC 50 ≤ 59.8 nM) and presents similar with Sitagliptin (IC 50 = 28 nM). Particularly, they had satisfactory selectivity over DPP-8 and DPP-9, except for QPP., Conclusion: β-Amino esters and amides fused 6-(hydroxymethyl)pyrazolopyrimidine were developed as the new DPP-4 inhibitors. Those compounds with a methyl group or hydrogen in N -1 position and methyl substituted group in C-3 of pyrazolopyrimidine moiety showed better potent DPP-4 inhibition (IC 50 = 21.4-59.8 nM). Furthermore, they had satisfactory selectivity over DPP-8 and DPP-9 Finally, the docking results revealed that compound 9n was stabilized at DPP-4 active site and would be a potential lead drug., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

We have developed a new class of PDE10A inhibitor, a pyrazolo[1,5- a ]pyrimidine derivative MT-3014 (1). A previous compound introduced was deprioritized due to concerns for E/Z-isomerization and glutathione-adduct formation at the core stilbene structure. We discovered pyrazolo [1,5- a ] pyrimidine as a new lead scaffold by structure-based drug design utilizing a co-crystal structure with PDE10A. The lead compound was optimized for in vitro activity, solubility, and selectivity against human ether-á-go-go related gene cardiac channel binding. We observed that MT-3014 shows excellent efficacy in rat conditioned avoidance response test and suitable pharmacokinetic properties in rats, especially high brain penetration. [ABSTRACT FROM AUTHOR]

• Six 1-phenyl-1 H -pyrazolo[3,4- d ]pyrimidine derivatives with different substituents were synthesized. • Two compounds, 1 (R=H) and 6 (R=CF 3), showed arginase inhibition >70% and IC 50 values of 12 µM and 55 µM, respectively. • The molecular docking studies proposed that these two uncompetitive inhibitors interact with different La ARG binding sites. • The pyrazolopyridine system can be promising for the design of potential antileishmanial compounds. Arginase performs the first enzymatic step in polyamine biosynthesis in Leishmania and represents a promising target for drug development. Polyamines in Leishmania are involved in trypanothione synthesis, which neutralize the oxidative burst of reactive oxygen species (ROS) and nitric oxide (NO) that are produced by host macrophages to kill the parasite. In an attempt to synthesize arginase inhibitors, six 1-phenyl-1 H -pyrazolo[3,4- d ]pyrimidine derivatives with different substituents at the 4-position of the phenyl group were synthesized. All compounds were initially tested at 100 µM concentration against Leishmania amazonensis ARG (La ARG), showing inhibitory activity ranging from 36 to 74%. Two compounds, 1 (R=H) and 6 (R=CF 3), showed arginase inhibition >70% and IC 50 values of 12 µM and 47 µM, respectively. Thus, the kinetics of La ARG inhibition were analyzed for compounds 1 and 6 and revealed that these compounds inhibit the enzyme by an uncompetitive mechanism, showing K is values, and dissociation constants for ternary complex enzyme-substrate-inhibitor, of 8.5 ± 0.9 µM and 29 ± 5 µM, respectively. Additionally, the molecular docking studies proposed that these two uncompetitive inhibitors interact with different La ARG binding sites, where compound 1 forms more H-bond interactions with the enzyme than compound 6. These compounds showed low activity against L. amazonensis free amastigotes obtained from mice lesions when assayed with as much as 30 µM. The maximum growth inhibition reached was between 20 and 30% after 48 h of incubation. These results suggest that this system can be promising for the design of potential antileishmanial compounds. [ABSTRACT FROM AUTHOR]

Copyright of Revista de la Academia Colombiana de Ciencias Exactas, Físicas y Naturales is the property of Academia Colombiana de Ciencias Exactas, Fisicas y Naturales and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

In the title molecule, C19H16N4O, the planar pyrazolopyrimidine moiety is inclined to the attached phenyl rings by 35.42 (4) and 54.51 (6)°. In the crystal, adjacent molecules are linked into chains parallel to [110] and [110] by C-- H···O and C--H···N hydrogen bonds. Additional C--H···π(ring) interactions lead to the formation of the final three-dimensional network structure. The Hirshfeld surface analysis of the title compound suggests that the most significant contributions to the crystal packing are from H···H (48.2%), C···H/H···C (23.9%) and N···H/H···N (17.4%) contacts. [ABSTRACT FROM AUTHOR]