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A Convergent Multicomponent Synthesis, Spectral Analysis, Molecular Modelling and Docking Studies of Novel 2H-pyrido[1,2-a]pyrimidine-2,4(3H)-dione Derivatives as Potential Anti-Cervical Cancer Agents
Abstract
Abstract
A series of Novel hybrid 3,3-dimethyl-13-(substituted-phenyl)-3,4,5,13-tetrahydro-1H-pyrido[1′,2′:1,2]pyrimido[4,5-b]quinoline-1,12(2H)-dione derivatives were designed and chemically synthesized in useful yields. The newly synthesized compounds were characterized on the basis of spectral (FT-IR, 1H, 13C NMR, Mass spectral) analyses, and biologically screened in-vitro for their anti-cervical cancer activity against HeLa cancer cell line. The results of cytotoxic evaluation indicated that compounds 7a, 7b, 7c and 7e were appeared to have broad-spectrum cytotoxic activity with IC50 values of 270 μM, 320 μM, 330 μM, and 400 μM, against HeLa cell line. Compound 7a exhibited the most promising inhibitory activity against HeLa cell line as compared to 7b, 7c and 7e. Structural-Activity Relationship (SAR) results show that the presence of electron withdrawing substituents play an important role in the anti-cervical cancer activity of these tested compounds. Moreover, molecular docking studies were conducted to investigate the probable binding conformations of these anti-cancer agents and in-silico ADME (Absorption, Distribution, Metabolism, and Excretion) properties were calculated to predict physicochemical, lipophilicity, pharmacokinetics and medicinal properties of the target compounds.
... Cells without treatment were used as control. After exposure to various chemical doses, cell viability was evaluated using the MTT assay (Afza et al., 2023). This colorimetric assay measures the metabolic rate of treated cells, which is based on the reduction of a yellow tetrazolium salt, MTT [3-4,5-Dimethyl-2-thiazolyl]-2,5-diphenyl-2Htetrazolium bromide] (Sigma Aldrich, Darmstadt, Germany] to blue formazan product in metabolically active cells. ...
... After incubation, the media was removed and 100 μl DMSO was added to dissolve the blue formazan product. The optical density was measured at 540 nm in a Microplate Reader (BioTek, Winooski, VT, United States) after mixing for 15 min The following formula was used to calculate the proportion of viable cells (Afza et al., 2023): ...
Herein, present study mainly focuses on the synthesis and characterizations of boron nitride reinforced waste zirconia (wZrO2) with different concentrations. Composites were prepared via a scalable solid-state reaction method. Various physical parameters such as density, ionic concentration, polaron radius, and field strength were evaluated. XRD results reveal crystalline nature with a major phase of tetragonal zirconia and as boron nitride is reinforced, the tetragonal transforms into a monoclinic zirconia. Interconnected spherical grains and nanosheets were observed using FESEM. Mechanical characterizations revealed the highest compressive strength of 266 MPa. The latent fingerprints were visualized using a composite on different surfaces, implementing the powder dusting and solution techniques. MTT assay was performed and revealed good biocompatible nature. These results reveal that composite is suitable for fabrication of bioceramics with acceptable mechanical and biological performances. The composite can also be utilized for latent fingerprint detection in forensic science.
... In 96-well plates, SiHa cells were grown 1 × 10 4 cells in each well. Cell viability of both untreated and treated cells was assessed using the colorimetric reduction test with the tetrazolium dye 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) dye [22,23]. The cells were exposed to various concentrations of TGCs BG1, BG2, BG3, and BG4, ranging from 10 to 100 μg/ml, and then incubated for 24 h at 37 • C with 5 % CO 2 . ...
... Based on physicochemical and ADMET data, almost all compounds adhered to the Lipinski rule of five. Compounds 1, 4, 6 and 8 satisfied all criteria for physicochemical and ADMET data (Afza et al., 2023;Ouassaf et al., 2022). ...
Macromolecules i.e., carbohydrate derivatives are crucial to biochemical and medical research. Herein, we designed and synthesized eight methyl α-D-glucopyranoside (MGP) derivatives (2–8) in good yields following the regioselective direct acylation method. The structural configurations of the synthesized MGP derivatives were analyzed and verified using multiple physicochemical and spectroscopic techniques. Antimicrobial experiments revealed that almost all derivatives demonstrated noticeable antifungal and antibacterial efficacy. The synthesized derivatives showed minimum inhibitory concentration (MIC) values ranging from 0.75 µg/mL to 1.50 µg/mL and minimum bactericidal concentrations (MBCs) ranging from 8.00 µg/mL to 16.00 µg/mL. Compound 6 inhibited Ehrlich ascites carcinoma (EAC) cell proliferation by 10.36% with an IC50 of 2602.23 μg/mL in the MTT colorimetric assay. The obtained results were further rationalized by docking analysis of the synthesized derivatives against 4URO and 4XE3 receptors to explore the binding affinities and nonbonding interactions of MGP derivatives with target proteins. Compound 6 demonstrated the potential to bind with the target with the highest binding energy. In a stimulating environment, a molecular dynamics study showed that MGP derivatives have a stable conformation and binding pattern. The MGP derivatives were examined using POM (Petra/Osiris/Molinspiration) bioinformatics, and as a result, these derivatives showed good toxicity, bioavailability, and pharmacokinetics. Various antifungal/antiviral pharmacophore (Oδ−, O′δ−) sites were identified by using POM investigations, and compound 6 was further tested against other pathogenic fungi and viruses, such as Micron and Delta mutants of SARS-CoV-2.
... Molecular docking is a method for structure-based drug design that predicts the binding affinity between receptor and ligand by simulating molecular interactions [22,68]. The molecular docking investigation of [69,70]. ...
Several innovative materials' properties are predicted using in silicon investigations, a computer simulation technique. 1,2,4,5-tetraazaspiro[5.5]undecane-3-thione was synthesized and characterized by using a variety of spectroscopic approaches followed by in silicon studies. DFT at the B3LYP functional level and the basis set 6-311 ++G (d,p) was used. The title molecule was investigated for its electric dipole moment, polarizability, and static hyperpolarizability. In silicon studies of the compound were done and showed good result to predict pharmacokinetics, lipophilicity, physicochemical and medicinal properties of the target molecule. Molecular docking was done between receptors and ligand by simulating molecular interactions in BRD4 proteins. The compound was also bio-evaluated for its anti-lung cancer activity against A549 cancer cell line. Theoretical calculation of ADMET properties suggested that the synthesized compound shows good pharmacokinetic profile. The results of cytotoxic evaluation indicated that the compound has broad-spectrum cytotoxic activity with IC50 values of 300 μM against A549 cell line.
... The cells in culture media were exposed with various concentrations of CSE (10, 20, 30, 40, 50 and 60%) for 24 h. Cell viability assay was performed using MTT (3-(4, 5 dimethylthiazolyl-2)-2, 5-diphenyltetrazolium bromide) dye (Sigma-Aldrich®, USA) (Afza et al., 2023). After 24 h exposure 10 μL of MTT (5 mg/mL) was added in both control and exposed cells and incubated for another 4 h at 37 • C. The media was removed and 150 μL dimethyl sulphoxide (DMSO) was used to dissolve the formazan crystals. ...
Cigarette smoke is one of the leading causes of oxidative stress due to high levels of free radicals, which in turn leads to the degradation of alveolar cell walls and development of emphysema. Cigarette smoking has been linked to chronic bronchitis, Chronic Obstructive Pulmonary Disease (COPD) and lung cancer as well. The aim of the present study was to observe the effect of cigarette smoke extract (CSE) on TNF-α and MMPs mediated mucus hypersecretion in A549 cell line. The MTT experiments showed that CSE caused a dose-dependent decline in the level of viability of A549 cells. In addition, AO/PI and Mitotracker Red staining assays demonstrated that CSE caused the A549 cells to undergo apoptosis. This was determined by observing the reduction in mitochondrial membrane potential. CSE was found to be responsible for the formation of intracellular ROS, which was observed by DCFDA staining through fluorescence microscopy. Approximately 65% migration rate was decreased in 20% CSE exposed cells. CSE exposure led to the significantly increased mRNA levels of TNF-α, MMP-7, and MMP-12, in comparison to the control cells. Additionally, the expression of MUC5AC and MUC5B was provoked by CSE as well. Human epithelial cells are stimulated by TNF-α and MMPs secreted mucus, as shown by expression of MUC5AC and MUC5B. CSE could induce mucus in lungs through TNF-α and MMPs mediated pathways.
In the present research work, a series of novel (Z)-5-(cyclohexylidenehydrazono)-2-aryl-3H,5H-thiazolo[3,4-b][1,2,4]triazole derivatives were synthesized by Pellizzari reaction of (Z)-3-amino-2-(cyclo hexylidenehydrazono)thiazolidin-4-one with different aromatic amides. All the synthesized products were obtained in a good to excellent yields, and their structures were established based on UV-Vis, FT-IR, 1H NMR, 13C NMR, and HRMS analysis. To validate the experimental findings, in-silico studies of one synthesized compound (11a) were done with the help of density functional theory (DFT) at B3LYP/6-311++G(d,p) level. Frontier molecular orbitals, molecular electrostatic potential, and Reduced density gradient analysis were performed to better understand the electronic properties, and reactivity. Results of NLO, ELF, LOL, DOS, AIM, and vector analysis were reported. All the newly synthesized benzimidazole compounds had a cytotoxic impact, in some cases much more potent than the reference medication. The cytotoxicity of all the synthesized compounds were assessed against A549 cell lines using the MTT assay. Among them, compounds 11d and 11e showed more potent cytotoxicity having the IC50 value ∼90 and ∼80 µM respectively. The molecular docking studies revealed an excellent affinity for the active sites of the matching gene regulation-inhibitor complex (BDR4) protein. Additionally, the evaluation of ADMET parameters indicated good pharmacokinetic properties of all the investigated compounds.
Nucleoside analogs have been widely used as antiviral, antitumor, and antiparasitic agents due to their ability to inhibit nucleic acid synthesis. Adenosine, cytidine, guanosine, thymidine and uridine analogs such as didanosine, vidarabine, remdesivir, gemcitabine, lamivudine, acyclovir, abacavir, zidovusine, stavudine, and idoxuridine showed remarkable anticancer and antiviral activities. In our previously published articles, our main intention was to develop newer generation nucleoside analogs with acylation-induced modification of the hydroxyl group and showcase their biological potencies. In the process of developing nucleoside analogs, in silico studies play an important role and provide a scientific background for biological data. Molecular interactions between drugs and receptors followed by assessment of their stability in physiological environments, help to optimize the drug development process and minimize the burden of unwanted synthesis. Computational approaches, such as DFT, FMO, MEP, ADMET prediction, PASS prediction, POM analysis, molecular docking, and molecular dynamics simulation, are the most popular tools to culminate all preclinical study data and deliver a molecule with maximum bioactivity and minimum toxicity. Although clinical drug trials are crucial for providing dosage recommendations, they can only indirectly provide mechanistic information through researchers for pathological, physiological, and pharmacological determinants. As a result, in silico approaches are increasingly used in drug discovery and development to provide mechanistic information of clinical value. This article portrays the current status of these methods and highlights some remarkable contributions to the development of nucleoside analogs with optimized bioactivity.
Extensive investigation on the molecular and electronic structure of 2-amino-5-trifluoromethyl-1,3,4-thiadiazole in the
ground state and in the first excited state has been performed. The energy barrier corresponding to the conversion between imino
and amino tautomers has been calculated, which indicates the existence of amino tautomer in solid state for the title compound. The
FT−Raman and FT-IR spectra were recorded and compared with theoretical vibrational wavenumbers, and a good coherence has
been observed. The MESP map, dipole moment, polarizability, and hyperpolarizability have been calculated to comprehend the
properties of the title molecule. High polarizability value estimation of the title compound may enhance its bioactivity. Natural
bonding orbital analysis has been done on monomer and dimer to investigate the charge delocalization and strength of hydrogen
bonding, respectively. Strong hydrogen bonding interaction energies of 17.09/17.49 kcal mol−1 have been calculated at the B3LYP/
M06-2X functional. The UV−vis spectrum was recorded and related to the theoretical spectrum. The title compound was
biologically examined for anticancer activity by studying the cytotoxic performance against two human cancer cell lines (A549 and
HeLa) along with the molecular docking simulation. Both molecular docking and cytotoxic performance against cancer cell lines
show positive outcomes, and the title compound appears to be a promising anticancer agent.
Extensive investigation on the molecular and electronic structure of 2-amino-5-trifluoromethyl-1,3,4-thiadiazole in the ground state and in the first excited state has been performed. The energy barrier corresponding to the conversion between imino and amino tautomers has been calculated, which indicates the existence of amino tautomer in solid state for the title compound. The FT–Raman and FT-IR spectra were recorded and compared with theoretical vibrational wavenumbers, and a good coherence has been observed. The MESP map, dipole moment, polarizability, and hyperpolarizability have been calculated to comprehend the properties of the title molecule. High polarizability value estimation of the title compound may enhance its bioactivity. Natural bonding orbital analysis has been done on monomer and dimer to investigate the charge delocalization and strength of hydrogen bonding, respectively. Strong hydrogen bonding interaction energies of 17.09/17.49 kcal mol–1 have been calculated at the B3LYP/M06-2X functional. The UV–vis spectrum was recorded and related to the theoretical spectrum. The title compound was biologically examined for anticancer activity by studying the cytotoxic performance against two human cancer cell lines (A549 and HeLa) along with the molecular docking simulation. Both molecular docking and cytotoxic performance against cancer cell lines show positive outcomes, and the title compound appears to be a promising anticancer agent.
Human papillomaviruses (HPVs) are causative agents of various diseases associated with cellular hyperproliferation, including cervical cancer, one of the most prevalent tumors in women. E7 is one of the two HPV-encoded oncoproteins and directs recruitment and subsequent degradation of tumor-suppressive proteins such as retinoblastoma protein (pRb) via its LxCxE motif. E7 also triggers tumorigenesis in a pRb-independent pathway through its C-terminal domain, which has yet been largely undetermined, with a lack of structural information in a complex form with a host protein. Herein, we present the crystal structure of the E7 C-terminal domain of HPV18 belonging to the high-risk HPV genotypes bound to the catalytic domain of human nonreceptor-type protein tyrosine phosphatase 14 (PTPN14). They interact directly and potently with each other, with a dissociation constant of 18.2 nM. Ensuing structural analysis revealed the molecular basis of the PTPN14-binding specificity of E7 over other protein tyrosine phosphatases and also led to the identification of PTPN21 as a direct interacting partner of E7. Disruption of HPV18 E7 binding to PTPN14 by structure-based mutagenesis impaired E7's ability to promote keratinocyte proliferation and migration. Likewise, E7 binding-defective PTPN14 was resistant for degradation via proteasome, and it was much more effective than wild-type PTPN14 in attenuating the activity of downstream effectors of Hippo signaling and negatively regulating cell proliferation, migration, and invasion when examined in HPV18-positive HeLa cells. These results therefore demonstrated the significance and therapeutic potential of the intermolecular interaction between HPV E7 and host PTPN14 in HPV-mediated cell transformation and tumorigenesis.
Rescoring is a simple approach that theoretically could improve the original docking results. In this study AutoDock Vina was used as a docked engine and three other scoring functions besides the original scoring function, Vina, as well as their combinations as consensus scoring functions were employed to explore the effect of rescoring on virtual screenings that had been done on diverse targets. Rescoring by DrugScore produces the most number of cases with significant changes in screening power. Thus, the DrugScore results were used to build a simple model based on two binding site descriptors that could predict possible improvement by DrugScore rescoring. Furthermore, generally the screening power of all rescoring approach as well as original AutoDock Vina docking results correlated with the Maximum Theoretical Shape Complementarity (MTSC) and Maximum Distance from Center of Mass and all Alpha spheres (MDCMA). Therefore, it was suggested that, with a more complete set of binding site descriptors, it could be possible to find robust relationship between binding site descriptors and response to certain molecular docking programs and scoring functions. The results could be helpful for future researches aiming to do a virtual screening using AutoDock Vina and/or rescoring using DrugScore.
To be effective as a drug, a potent molecule must reach its target in the body in sufficient concentration, and stay there in a bioactive form long enough for the expected biologic events to occur. Drug development involves assessment of absorption, distribution, metabolism and excretion (ADME) increasingly earlier in the discovery process, at a stage when considered compounds are numerous but access to the physical samples is limited. In that context, computer models constitute valid alternatives to experiments. Here, we present the new SwissADME web tool that gives free access to a pool of fast yet robust predictive models for physicochemical properties, pharmacokinetics, drug-likeness and medicinal chemistry friendliness, among which in-house proficient methods such as the BOILED-Egg, iLOGP and Bioavailability Radar. Easy efficient input and interpretation are ensured thanks to a user-friendly interface through the login-free website http://www.swissadme.ch. Specialists, but also nonexpert in cheminformatics or computational chemistry can predict rapidly key parameters for a collection of molecules to support their drug discovery endeavours.
Free radicals are unpaired electrons on an open shell configuration & imbalance causes high reactivity which will lead to tissue damage and oxidative stress. Title molecules have been synthesized by using substituted aldehydes, barbituric acid and malanonitrile in DBN and study their antioxidant potential radical scavenging assay. Some of the tested compounds show moderate to good antioxidant activity. The structural elucidation of synthesized compounds ensured on the basis of their elemental and spectral studies.
Novel spiro derivatives of piperidone
A major concern of immunocompromised patients, in particular those with AIDS, is susceptibility to infection caused by opportunistic
pathogens such as Pneumocystis jirovecii, which is a leading cause of pneumonia in immunocompromised patients. We report the first kinetic and structural data for
2,4-diamino-6-[(2′,5′-dichloro anilino)methyl]pyrido[2,3-d]pyrimidine (OAAG324), a potent inhibitor of dihydrofolate reductase (DHFR) from P. jirovecii (pjDHFR), and also for trimethoprim (TMP) and methotrexate (MTX) with pjDHFR, Pneumocystis carinii DHFR (pcDHFR), and human DHFR (hDHFR). OAAG324 shows a 9.0-fold selectivity for pjDHFR (Ki, 2.7 nM) compared to its selectivity for hDHFR (Ki, 24.4 nM), whereas there is only a 2.3-fold selectivity for pcDHFR (Ki, 6.3 nM). In order to understand the determinants of inhibitory potency, active-site mutations of pj-, pc-, and hDHFR were
explored to make these enzymes more like each other. The most unexpected observations were that the variant pcDHFR forms with
K37Q and K37Q/F69N mutations, which made the enzyme more like the human form, also made these enzymes more sensitive to the
inhibitory activity of OAAG324, with Ki values of 0.26 and 0.71 nM, respectively. A similar gain in sensitivity was also observed for the hDHFR N64F variant, which
showed a lower Ki value (0.58 nM) than native hDHFR, pcDHFR, or pjDHFR. Structural data are reported for complexes of OAAG324 with hDHFR and
its Q35K and Q35S/N64F variants and for the complex of the K37S/F69N variant of pcDHFR with TMP. These results provide useful
insight into the role of these residues in the optimization of highly selective inhibitors of DHFR against the opportunistic
pathogen P. jirovecii.
Absorption, distribution, metabolism, excretion and toxicity (ADMET) properties play key roles in the discovery/development of drugs, pesticides, food additives, consumer products and industrial chemicals. This information is especially useful when to conduct environmental and human hazard assessment. The most critical rate limiting step in the chemical safety assessment workflow is the availability of high quality data. This paper describes an ADMET structure-activity relationship database, abbreviated as admetSAR. It is an open source, text and structure searchable, and continually updated database that collects curates and manages available ADMET-associated properties data from published literatures. In admetSAR, over 210,000 ADMET annotated data points for more than 96,000 unique compounds with 45 kinds of ADMET-associated properties, proteins, species or organisms have been carefully curated from a large number of diverse literatures. The database provides a user-friendly interface to query a specific chemical profile, using either CAS registry number, common name or structure similarity. In addition, the database includes 22 qualitative classification and 5 quantitative regression models with highly predictive accuracy, allowing to estimate ecological/mammalian ADMET properties for novel chemicals. The admetSAR is accessible free of charge at http://www.admetexp.org.
A series of pyrido[2,3-d]pyrimidine derivatives were designed and synthesized based on known CC chemokine receptor 4 (CCR4) antagonists. The activities of all the newly synthesized compounds were evaluated using a chemotaxis inhibition assay. Compound 6b was proven to be a potent CCR4 antagonist that can block cell chemotaxis induced by macrophage-derived chemokine (MDC), thymus and activation regulated chemokine (TARC), and CKLF1, the natural ligands of CCR4. In addition, compound 6b is more effective than budesonide in the murine rhinitis model. The intravenous injection LD₅₀ of compound 6b is 175 mg/kg and the oral LD₅₀ is greater than 2,000 mg/kg.
The design and synthesis of a small library of 4-aminopyrido[2,3-d]pyrimidine derivatives is reported. The potential activity of these compounds as CDK2/Cyclin A, CDK4/Cyclin D, EGFR and anti-tumor was evaluated by cytotoxicity studies in A431a, SNU638b, HCT116 and inhibition of CDK2-Cyclin A, CDK4/Cyclin D and EGFR enzyme activity in vitro. The anti-proliferative and CDK2-Cyclin A inhibitory activity of compounds 4c and 11a was significantly more active than roscovotine with IC(50) 0.3 and 0.09 μM respectively. Molecular modeling study, including fitting to a 3D-pharmacophore model, docking into cyclin dependant kinase2 (CDK2) active site and binding energy calculations were carried out and these studies suggested the same binding orientation inside the CDK2 binding pocket for these analogs compared to ATP.
Acute secretory diarrhea induced by infection with enterotoxigenic strains of Escherichia coli involves binding of stable toxin (STa) to its receptor on the intestinal brush border, guanylyl cyclase type C (GC-C). Intracellular cGMP is elevated, inducing increase in chloride efflux and subsequent accumulation of fluid in the intestinal lumen. We have screened a library of compounds and identified a pyridopyrimidine derivatives {5-(3-bromophenyl)-1,3-dimethyl-5,11-dihydro-1H-indeno[2′,1′:5,6]pyrido[2,3-d]pyrimidine-2,4,6-trione; BPIPP} as an inhibitor of GC-C that can suppress STa-stimulated cGMP accumulation by decreasing GC-C activation in intact T84 human colorectal carcinoma cells. BPIPP inhibited stimulation of guanylyl cyclases, including types A and B and soluble isoform in various cells. BPIPP suppressed stimulation of adenylyl cyclase and significantly decreased the activities of adenylyl cyclase toxin of Bordetella pertussis and edema toxin of Bacillus anthracis. The effects of BPIPP on cyclic nucleotide synthesis were observed only in intact cells. The mechanism of BPIPP-dependent inhibition appears to be complex and indirect, possibly associated with phospholipase C and tyrosine-specific phosphorylation. BPIPP inhibited chloride-ion transport stimulated by activation of guanylyl or adenylyl cyclases and suppressed STa-induced fluid accumulation in an in vivo rabbit intestinal loop model. Thus, BPIPP may be a promising lead compound for treatment of diarrhea and other diseases.
• adenylyl cyclase
• cGMP
• guanylyl cyclase
• cAMP
• toxin-induced diarrhea
An efficient multicomponent reaction (MCR) allows the creation of several chemical bonds in one sequence without labour-consuming reaction condition optimization and work-up procedures, minimizing the waste production and cost, thus multicomponent reactions (MCRs) have proved to be extremely beneficial in organic reactions. The salient features of the present protocol are mild reaction conditions, excellent yields and easy isolation of products. Herein, MCR of 5-Oxo-1-phenylpyrrolidine-3-carboxylic acid, substituted benzaldehydes and malononitrile were designed and the synthesized 2-Amino-7-(substituted- phenyl)-3-cyano-4-phenyl-4,5,6,7-tetrahydropyrano[2,3-b]pyrrole-5-carboxylic acid derivatives were evaluated for their antimicrobial activity. The structures of the synthesized compounds were assigned using different spectroscopic techniques such as FT-IR, ¹H NMR, ¹³C NMR and elemental analyses. Compound 5d containing -NO2 group showed incredible antimicrobial activity against Salmonella typhi (MTCC 537) as compared to reference drug (tetracycline), and also showed excellent activity against Bacillus licheniformis (MTCC 10341), Pseudomonas aeruginosa (MTCC 741) and Staphylococcus aureus (MTCC 10341). Structural activity relationship results displayed that the presence of nitro function or halogens plays an important role in the antimicrobial activities of these tested compounds. Theoretical calculation of ADME properties suggested that synthesized compounds showed good pharmacokinetic profile. The molecular docking study of compound 5d revealed that there were good interactions between the active sites of 7KW6, 5E68, 4EQA and 3IP4 protiens.
Novel pyridine derivative platinum complexes with the general formula [PtCl2L2]
(L1
: 2-fluoropyridine
, L2
:2-amino-3-methyl pyridine) were synthesized and their structural characterizations were made using FT-IR, UV-vis, ¹H-NMR, and ¹³C-NMR techniques as well as via the theoretical calculations. Using the DFT/MPW1PW91 method with LanL2DZ basis set the most probable molecular structure for the most stable complexes was determined. The potential energy distribution analysis was made for to confer the complexes their vibrational assignments. The molecular electrostatic potential, highest occupied molecular orbital and lowest occupied molecular orbital were also calculated. The thermal decomposition reactions of the complexes were investigated via DTA/TG combined system. The decomposition kinetics were calculated by using FWO and KAS methods. The average activation energies of the complexes were calculated to be 31.72-184.61 kJ/mol via FWO and 29.17-184.53 kJ/mol via KAS methods. The cytotoxicity of the complexes was tested against colon cancer cell line (DLD-1) and the [PtCl2L¹2] complex was found to be more effective than [PtCl2L²2] against over 24 h incubation period. The results showed that thus synthesized pyridine-derived platinum complexes may be used as effective chemotherapeutic agents in treatment of colon cancer.
Polyethylene glycol-400 (PEG-400) has been developed as an efficient and eco-friendly reaction medium for the synthesis of new isoxazolyl pyrido[2,3-d]pyrimidine derivatives 11 from isoxazolyl cyanoacetamide synthon 7. Compound 7 was employed with various aromatic aldehydes 8 and malononitrile 9 in the presence of triethylamine (Et3N) to afford the corresponding (E)-6-amino-1-(3-methyl-5-styrylisoxazol-4-yl)-2-oxo-4-phenyl-1,2-dihydro- pyridine-3,5-dicarbonitrile 10 at room temperature by using PEG-400 as a solvent medium as well as catalyst. The intermediate 10 on treatment with thiourea in the presence of PEG-400 at 90 °C to give the target compounds isoxazolyl pyrido[2,3-d]pyrimidines 11 in good to excellent yields. The newly synthesized compounds 10 and 11 were characterized by IR, ¹H NMR, ¹³C NMR, and HRMS analysis. The target compounds 11a-x was screened for their anti-inflammatory and analgesic activities. Among the tested compounds, the compounds 11s, 11t, 11u, 11v, 11w, and 11x showed significant anti-inflammatory and potent analgesic activities as that of reference drugs. The advantages of this protocol are operational simplicity, catalyst free, environmental safety, wide substrate scope, good yields, and PEG-400 can be recovered and reused. Most significant of all, this protocol is green.
The present investigation deals with the evaluation for the first time of the in vitro antimicrobial and α-glucosidase inhibitory potential of a series of 15 enantiopure cycloalkylglycines using agar well diffusion and spectrophotometric methods, respectively. The obtained results were compared to the positive controls. The antimicrobial results revealed that all compounds exerted strongly inhibitory activity, especially against Gram-positive bacterial strains with the most potent activity was ascribed to α-γ-hydroxy-α-amino acids 11–14 [minimum inhibitory concentration (MIC) = 1.58– 12.50 mg/ml, minimum bactericidal concentration (MBC) = 3.17–100 mg/ml, and minimum fungicidal concentration (MFC) = 6.25–50 mg/ml], followed by both isoxazolidine 5–9 (MIC = 1.58–12.50 mg/ml, MBC = 6.25–100 mg/ml, and MFC = 25–100 mg/ml) and isoxazine 10 (MIC = 3.17–12.50 mg/ml, MBC = 3.17–50 mg/ml, and MFC = 25–50 mg/ml) compounds, and slightly inhibitory effect with α-amino-γ-lactones series 1–4 (MIC = 3.17–25 mg/ml, MBC = 6.25–100 mg/ml, and MFC = 25–100 mg/ml). All the derivatives exhibited a potent α-glucosidase inhibitory activity with compound 10 (IC50 = 30.1 ± 0.6 μM) was found to be the most active. The druglikeness and pharmacokinetic profiles have been also predicted. The in silico results indicate that all derivatives showed a resemblance with several parameters of the antimicrobial standards, especially in terms of molecular property, bioavailability, lipophilicity, medicinal chemistry, and enzymatic inhibitory effects as well as they agree with the different drug discovery rules such as Lipinski (Pfizer), Ghose (Amgen), Veber (GlaxoSmithKline), Egan (Pharmacia), and Muegge (Bayer) displaying a higher druglikeness behavior.
A green 1,4-addition isocyanide-based three-component reaction was developed to synthesize chromanones via a facile, mild, and efficient one-pot protocol without a metal catalyst. The 1,4-addition of isocyanides occured at the C-2 position of chromones instead of the Schiff base in neat water. We found that the hydrogen bond can dictate the stereo-outcome of olefins, providing an effective method for the diastereomer-selective synthesis of this type of chromanones. The novel green synthetic protocol allowed the quick entry for the construction of complex chromanones in the environmental friendly manner.
A series of novel triazolothione, thiadiazole, triazole, and oxadiazole-functionalized pyrido[1,2-a]pyrimidin-4-ones 6a–6l and 7a–7f were prepared, starting from pyridine derivatives 1a and 1b. All the compounds 6a–6l and 7a–7f were screened against four human cancer cell lines (HeLa, COLO205, Hep G2, and MCF 7), among which compounds 6d, 6h, 6j, 7b, and 7e showed promising anticancer activity. Molecular docking studies showed good binding energy and exhibited interactions and better lower free energy values, indicating more thermodynamically favored interaction.
Background
In recent years, since the molecular docking technique can greatly improve the efficiency and reduce the research cost, it has become a key tool in computer-assisted drug design to predict the binding affinity and analyze the interactive mode.
Results
This study introduces the key principles, procedures and the widely-used applications for molecular docking. Also, it compares the commonly used docking applications and recommends which research areas are suitable for them. Lastly, it briefly reviews the latest progress in molecular docking such as the integrated method and deep learning.
Conclusion
Limited to the incomplete molecular structure and the shortcomings of the scoring function, current docking applications are not accurate enough to predict the binding affinity. However, we could improve the current molecular docking technique by integrating the big biological data into scoring function. Open image in new window
In the past decade, multicomponent reactions have experienced a renaissance as powerful peptide macrocyclization tools enabling the rapid creation of skeletal complexity and diversity with low synthetic cost. This review provides both a historical and modern overview of the development of the peptide multicomponent macrocyclization as a strategy capable to compete with the classic peptide cyclization methods in terms of chemical efficiency and synthetic scope. We prove that the utilization of multicomponent reactions for cyclizing peptides by either their termini or side chains provides a key advantage over those more established methods; that is, the possibility to explore the cyclic peptide chemotype space not only at the amino acid sequence but also at the ring-forming moiety. Owing to its multicomponent nature, this type of peptide cyclization process is well-suited to generate diversity at both the endo- and exo-cyclic fragments formed during the ring-closing step, which stands as a distinctive and useful characteristic for the creation and screening of cyclic peptide libraries. Examples of the novel multicomponent peptide stapling approach and heterocycle ring-forming macrocyclizations are included, along with multicomponent methods incorporating macrocyclization handles and the one-pot syntheses of macromulticyclic peptide cages. Interesting applications of this strategy in the field of drug discovery and chemical biology are provided.
Cancer is the second most important cause of death worldwide. There is always a demand for new anticancer drugs and continuously a wide variety of natural and synthetic compounds were developed by the researchers. Nowadays, a large number of drugs in clinical practice were found to have a high incidence of side effect and multidrug conflict. The development of novel less toxic, low cost and very energetic N-methylpicolinamide-bearing hybrids is a hot research topic in the community of medicinal chemistry. Herein we highlight the current advances in the synthesis of picolinamide-containing heterocyclic compounds as potent anticancer agents. In addition, briefly explore their structure-activity relationship studies for the inspiration of the innovation and development of more potent and effective drugs against various death-causing cancer diseases.
A series of novel furo[2,3-b]pyridine-2-carboxamide 4a-h/pyrido[3',2':4,5]furo[3,2-d] pyrimidin-4(3H)-one derivatives 5a-p were prepared from pyridin 2(1H) one 1 via selective O-alkylation with α-bromoethylester followed by cyclization, then reaction with different aliphatic primary amines to obtain 4 and further reaction with triethyl orthoacetate/triethyl orthoformate. Also prepared novel furo[2,3-b]pyridine-2-carbohydrazide Schiff’s bases 7a-h and pyrido [3',2':4,5]furo[3,2-d]pyrimidin-4(3H)-one derivatives 8a-h starting from furo[2,3-b]pyridine carboxylate derivatives 3 by reaction with hydrazine hydrate to form 6 and reaction with diverse substituted aldehydes and cyclization. Products 4a-h, 5a-p, 7a-h and 8a-h were screened against four human cancer cell lines (HeLa, COLO205, Hep G2 and MCF 7) and one normal cell line (HEK 293). Compounds 4e, 4f, 4g, 5h, 7c, 7d, 7e and 7f showed significant anticancer activity against all the cell lines at micro molar concentration and found to be non-toxic to normal cell line. Studies for HeLa, COLO205 and MCF-7 using CoMFA and CoMSIA. Models from 3D-QSAR provided a strong basis for future rational design of more active and selective HeLa, COLO205 and MCF-7 cell line inhibitors.
Three-component reactions of alkylglyoxals, 1,3-dicarbonyl compounds, and a nucleophile were performed under aqueous and catalyst-free conditions, which produced 1,4-diketone scaffolds in a straightforward way. Many compounds, such as indole, azaindole, pyrrole, 2-methylfuran, N,N-dimethylaniline, N-methylaniline, thiophenol, and benzyl mercaptan, were all able to act as nucleophiles to react with alkylglyoxal and 1,3-dicarbonyl compound. Mechanim of this reaction was also investigated. The obtained 1,4-diketones can be easily converted to many valuable chemicals.
Substituted lawsone Mannich bases 2a-e, 3a-e and 4a-e were prepared and tested for their biological activities. The new fatty alkyl substituted compounds 2a-c exhibited strong and selective growth inhibitory activities in the low one-digit micromolar and sub-micromolar range against a panel of human cancer cell lines associated with ROS formation. In addition, compounds 2a-c revealed sub-micromolar anti-trypanosomal activities against parasitic Trypanosoma brucei brucei cells via deformation of the microtubule cytoskeleton. The N-hexadecyl compound 2c was also highly active against locally isolated Entamoeba histolytica parasite samples exceeding the activity of metronidazole.
Quantum chemical calculations of geometrical structure, energy and vibrational wavenumbers of a novel functionalized pyrido-pyrimidine compound (a prospective antibacterial agent), chemically known as 6-Methyl,13,14,15-Trihydro-14-(4-Nitrophenyl)pyrido[1,2-a:1’,2’-a’] pyrido[2”,3”-d:6”,5”-d’]dipyrimidine-13,15-dione (C24H16N6O4), were carried out, using B3LYP/6311++G(d,p) method. Comprehensive interpretation of the infrared and Raman spectra of the compound under study is based on potential energy distribution. A good coherence between experimental and theoretical wavenumbers shows the preciseness of the assignments. NLO properties like the dipole moment, polarizability, first static hyperpolarizability and molecular electrostatic potential surface have been calculated to get a better cognizance of the properties of the title compound. Molecular docking results reveal that the title compound exhibit inhibitory activity against Staphylococcus aureus.
A series of thiazole derivatives 1–21 were prepared, characterized by EI-MS and 1 H NMR and evaluated for a-glucosidase inhibitory potential. All twenty one derivatives showed good a-glucosidase inhibitory activity with IC 50 value ranging between 18.23 ± 0.03 and 424.41 ± 0.94 lM when compared with the standard acarbose (IC 50 , 38.25 ± 0.12 lM). Compound (8) (IC 50 , 18.23 ± 0.03 lM) and compound (7) (IC 50 = 36.75 ± 0.05 lM) exhibited outstanding inhibitory potential much better than the standard acar-bose (IC 50 , 38.25 ± 0.12 lM). All other analogs also showed good to moderate enzyme inhibition. Molecular docking studies were carried out in order to find the binding affinity of thiazole derivatives with enzyme. Studies showed these thiazole analogs as a new class of a-glucosidase inhibitors.
An uncatalyzed efficient synthesis of bioactive pyridine derivatives has been investigated for the first time by a three-component sequential multicomponent reaction tackled with aromatic aldehydes, malononitrile, and 1,3-indandione via Knoevenagel condensation followed by Michael addition. The difference between the domino multicomponent and sequential multicomponent reaction is emphasized by this methodology. The reaction proceeds at ambient temperature without frequently useful N-source like ammonium salt for the construction of N-heterocycles, which makes this protocol a novel synthetic route for the preparation of the indenopyridine skeleton.
Graphical Abstract
Synthesis of novel 6-methylisoxazolo[5,4-d]isoxazol-3-yl-aryl-methanones 5 has been achieved via nitro-nitrite rearrangement by utilizing vinylogous nitroaldol adducts as synthons under mild conditions. Furthermore, the new series of compounds 5a-i were assessed for molecular properties prediction, drug-likeness by Molinspiration (Molinspiration, 2008) & MolSoft (MolSoft, 2007) softwares, lipophilicity and solubility parameters using ALOGPS 2.1 program. The new series of compounds 5a-i were screened for their anti-inflammatory activity.
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The n-octanol/water coefficient (log Po/w) is a key physicochemical parameter for drug discovery, design and development. Here, we present a physics-based approach that shows a strong linear correlation between the computed solvation free energy in implicit solvents and the experimental log Po/w on a cleansed data set of more than 17,500 molecules. After internal validation by five-fold cross-validation and data randomization, the predictive power of the most interesting multiple linear model, based on two GB/SA parameters solely, was tested on two different external sets of molecules. On the Martel druglike test set, the predictive power of the best model (N=706, r=0.64, MAE=1.18 and RMSE=1.40) is similar to six well established empirical methods. On the 17-drug test set, our model outperformed all compared empirical methodologies (N=17, r=0.94, MAE=0.38 and RMSE=0.52). The physical basis of our original GB/SA approach together with its predictive capacity, its computational efficiency (1 to 2 seconds per molecule) and its tridimensional molecular graphics capability lay the foundations for a promising predictor, the implicit log P method (iLOGP), to complement the portfolio of drug design tools developed and provided by SIB | Swiss Institute of Bioinformatics.
Our comparative assessment of scoring functions (CASF) benchmark is created to provide an objective evaluation of current scoring functions. The key idea of CASF is to compare the general performance of scoring functions on a diverse set of protein-ligand complexes. In order to avoid testing scoring functions in context of molecular docking, the scoring process is separated from the docking (or sampling) process by using ensembles of ligand binding poses that are generated in prior. Here, we describe the technical methods and evaluation results of the latest CASF-2013 study. The PDBbind core set (version 2013) was employed as the primary test set in this study, which consists of 195 protein-ligand complexes with high-quality 3D structures and reliable binding constants. A panel of 20 scoring functions, most of which are implemented in main-stream commercial software, were evaluated in terms of "scoring power" (binding affinity prediction), "ranking power" (relative ranking prediction), "docking power" (binding pose prediction), and "screening power" (discrimination of true binders from random molecules). Our results reveal that the performance of these scoring functions is generally more promising in the docking/screening power tests than in the scoring/ranking power tests. Top-ranked scoring functions in the scoring power test, such as X-ScoreHM, ChemScore@SYBYL, ChemPLP@GOLD, and PLP@DS, are also top-ranked in the ranking power test. Top-ranked scoring functions in the docking power test, such as ChemPLP@GOLD, Chemscore@GOLD, GlidScore-SP, LigScore@DS, and PLP@DS, are also top-ranked in the screening power test. Our results obtained on the entire test set and its subsets suggest that the real challenge in protein-ligand binding affinity prediction lies in polar interactions and the associated desolvation effect. Non-additive features observed among high-affinity protein-ligand complexes also need attention.
The reaction of several substituted 2-aminopyridines with ethyl malonate has been reported. It has been shown that two cyclic products may be obtained from this reaction, 1,8-naphthyridine derivatives being obtained as well as the previously reported pyridopyrimidine derivatives. The type of product obtained from a given 2-aminopyridine depends only on the substituents present in the pyridine ring.
The optimization of a potent and highly selective series of dual mTORC1 and mTORC2 inhibitors is described. An initial focus on improving cellular potency whilst maintaining or improving other key parameters, such as aqueous solubility and margins over hERG IC(50), led to the discovery of the clinical candidate AZD8055 (14). Further optimization, particularly aimed at reducing the rate of metabolism in human hepatocyte incubations, resulted in the discovery of the clinical candidate AZD2014 (21).
Very good yields of 4H-pyrido[1,2-a]pyrimidin-4-ones have been obtained in a one-stage synthesis by the condensation of 2-aminopyridines with β-keto esters or ethyl ethoxymethylenemalonate, and the corresponding 2,4-diones with diethyl malonate, in the presence of polyphosphoric acid (PPA). It is suggested that the cyclization of 2-acylacetamidopyridines with PPA to give pyrido[1,2-a]pyrimidin-4-ones involves the formation of N-(2-pyridyl)-β-(2′-pyridylamino)crotonamides since the latter on treatment with PPA give the same products.
L-Proline was utilized as an efficient organo-catalyst for the environmentally benign synthesis of 3-substituted coumarins by the Knoevenagel condensation of substituted 2-hydroxybenzaldehydes with reactive methylene compounds under solvent free conditions.
A study was conducted to investigate chemical and biological aspects of multicomponent reactions (MCRs). The high density of atoms of MCR-based compounds played an important role in their propensity for specific target classes where traditional non-MCR compounds had lower screening hit rates. Chemical transformations toward rare scaffold types annotated with unique physicochemical properties were amenable by MCR in a straightforward and short manner. X-ray diffraction investigations revealed that the bicyclic products contain varying degrees of pyramidalization of the bridgehead nitrogen atom. It was also demonstrated that another uniquely shaped scaffold, 3-azabicyclo[4.2.0]octan-4-one derivative was synthesized by combining the Ugi multicomponent reaction with [2 + 2] enone-olefin photochemical transformations.
The synthesis and biological evaluation of potent and selective inhibitors of the erbB2 kinase is presented. Based on the 4-anilinoquinazoline chemotype, the syntheses of several new series of erbB2 inhibitors are described with quinazoline and pyrido[4,3-d]pyrimidine cores. The vast majority of these compounds are found to be >100x selective over the closely related EGFR kinase. Two lead compounds are further shown to have low clearance and moderate bioavailability in rat.
The purpose of the study was to explore if cervical cancer information presented in a non-stigmatizing manner could promote screening in women living in a resource poor environment in Tshwane, South Africa.
An exploratory, contextual, quantitative door-to-door survey was conducted. The sampling method was convenience (n = 105). Structured interviews were used to gather self-reported data. Chi-square tests were used for secondary data analyses.
The study provided evidence that presenting information on cervical cancer in a non-stigmatizing manner based on the theme of self protection promoted cervical screening. The study further provided evidence that women preferred a cervical cancer message that does not focus on the sexual risk factors of this disease. More than a third of the sample preferring a message introducing cervical cancer as a sexually transmitted infection (n = 32) were of the opinion that this message were stigmatizing, blameful and displayed misunderstanding of their lives.
Cervical cancer screening is indeed not simple. The screening rate not only in South Africa but many other countries serves as proof. It can therefore not be afforded to add to the barriers by presenting information on cervical cancer in a way perceived as stigmatizing and blameful. Presenting information in way that women prefer might not only promote cervical screening, but might motivate them in such a way that they are screened.
Scoring functions are widely applied to the evaluation of protein-ligand binding in structure-based drug design. We have conducted a comparative assessment of 16 popular scoring functions implemented in main-stream commercial software or released by academic research groups. A set of 195 diverse protein-ligand complexes with high-resolution crystal structures and reliable binding constants were selected through a systematic nonredundant sampling of the PDBbind database and used as the primary test set in our study. All scoring functions were evaluated in three aspects, that is, "docking power", "ranking power", and "scoring power", and all evaluations were independent from the context of molecular docking or virtual screening. As for "docking power", six scoring functions, including GOLD::ASP, DS::PLP1, DrugScore(PDB), GlideScore-SP, DS::LigScore, and GOLD::ChemScore, achieved success rates over 70% when the acceptance cutoff was root-mean-square deviation < 2.0 A. Combining these scoring functions into consensus scoring schemes improved the success rates to 80% or even higher. As for "ranking power" and "scoring power", the top four scoring functions on the primary test set were X-Score, DrugScore(CSD), DS::PLP, and SYBYL::ChemScore. They were able to correctly rank the protein-ligand complexes containing the same type of protein with success rates around 50%. Correlation coefficients between the experimental binding constants and the binding scores computed by these scoring functions ranged from 0.545 to 0.644. Besides the primary test set, each scoring function was also tested on four additional test sets, each consisting of a certain number of protein-ligand complexes containing one particular type of protein. Our study serves as an updated benchmark for evaluating the general performance of today's scoring functions. Our results indicate that no single scoring function consistently outperforms others in all three aspects. Thus, it is important in practice to choose the appropriate scoring functions for different purposes.
NP506, the 3-{2,4-dimethyl-5-[2-oxo-5-(N'-phenylhydrazinocarbonyl)-1,2-dihydro-indol-3-ylidenemethyl]-1H-pyrrol-3-yl}-propionic acid, was designed as FGF receptor 1 inhibitor by computational study and found to be more active against endothelial proliferation of HUVEC after the rhFGF-2 stimulation than SU6668 with minimum effective dose of 10 microM. NP506 inhibited the tyrosine phosphorylation in FGF, VEGF, and PDGF receptors and the activation of extracellular signal-regulated kinase (ERK), c-Jun-N-terminal-kinase (JNK) and AKT after the rhFGF-2 stimulation. The introduction of the phenyl hydrazide motif to the position 5 of the pyrido[2,3-d]pyrimidine scaffold led to the inhibitory effect in two signaling pathways: inhibition of AKT activation in the phosphatidyl inositol 3'-kinase (PI13K)/AKT signaling pathway and the inhibition of ERK and JNK activation in MAPK pathway.
N9-substituted 2,4-diaminoquinazolines were synthesized and evaluated as inhibitors of Pneumocystis carinii (pc) and Toxoplasma gondii (tg) dihydrofolate reductase (DHFR). Reduction of commercially available 2,4-diamino-6-nitroquinazoline 14 with Raney nickel afforded 2,4,6-triaminoquinazoline 15. Reductive amination of 15 with the appropriate benzaldehydes or naphthaldehydes, followed by N9-alkylation, afforded the target compounds 5- 13. In the 2,5-dimethoxybenzylamino substituted quinazoline analogues, replacement of the N9-CH 3 group of 4 with the N9-C2H5 group of 8 resulted in a 9- and 8-fold increase in potency against pcDHFR and tgDHFR, respectively. The N9-C2H5 substituted compound 8 was highly potent, with IC50 values of 9.9 and 3.7 nM against pcDHFR and tgDHFR, respectively. N9-propyl and N9-cyclopropyl methyl substitutions did not afford further increases in potency. This study indicates that the N9-ethyl substitution is optimum for inhibitory activity against pcDHFR and tgDHFR for the 2,4-diaminoquinazolines. Selectivity was unaffected by N9 substitution.
Fifteen novel nonclassical and two classical 2,4-diamino-6-(benzylamino)pyrido[2,3-d]pyrimidine antifolates were synthesized as potential inhibitors of Pneumocystis carinii, (pc) Toxoplasma gondii, (tg) rat liver (rl), and human (h) recombinant dihydrofolate reductases (DHFR). These analogues lack a 5-methyl substitution which has been shown to be important for increased hDHFR inhibitory activity. In addition, they contain a reversal of the C9-N10 bridge present in folates and most antifolates. The synthesis of the compounds involved the reaction of 2,4,6-triaminopyrimidine with the sodium salt of nitromalonaldehyde to afford the key intermediate 2,4-diamino-6-nitropyrido[2,3-d]pyrimidine (7), in a single step. Reduction of 7 to the 2,4,6-triaminopyrido[2,3-d]pyrimidine (8), followed by reductive amination with the appropriate benzaldehydes or phenylacetaldehydes afforded the target compounds. N9 methylation of these analogues was carried out using formaldehyde and sodium cyanoborohydride. The analogues demonstrated significant inhibition of pcDHFR and tgDHFR. N9 methylation significantly increased DHFR inhibitory potency. Compound 11, the 3'4'5'-trimethoxy-substituted analogue with a selectivity ratio of 9.4 for tgDHFR (compared to rlDHFR) was the most selective analogue of the nonclassical series. Compound 22, the N9 methyl 2'5'-dimethoxy-substituted analogue was the most potent analogue against tgDHFR (IC 50 = 6.3 nM) and was the second most selective analogue for tgDHFR (compared to rlDHFR) in the nonclassical series. The naphthyl-substituted analogues 23-25 were generally more potent against rlDHFR than against pcDHFR and tgDHFR. Selected analogues were also evaluated against Streptococcus faecium (sf) DHFR, Escherichia coli (ec) DHFR, Lactobacillus casei (lc) DHFR and tgDHFR with hDHFR as the mammalian reference, under slightly different assay conditions than those employed for rlDHFR. Analogues 11 and 22 had selectivity ratios of greater than 100 for tgDHFR (compared to hDHFR). Analogue 22 in particular, was the most selective analogue of the nonclassical series against tgDHFR (selectivity ratio = 303.5) with excellent potency (28 nM). Analogue 11, also displayed significant selectivity for sfDHFR (selectivity ratio = 4902). Compound 22 was evaluated in vivo for the inhibition of the growth of T.gondii trophozoites in mice, where at 50 mg/kg orally, it demonstrated distinct prolongation of survival without toxicity. Compounds 11, 12 and 21-23 were evaluated as antitumor agents in the National Cancer Institutes preclinical in vitro screening program. Compounds 12, 22, and 23 showed GI50s for tumor growth inhibition in the 10 -6 - 10 -7 M range.
Oral bioavailability measurements in rats for over 1100 drug candidates studied at SmithKline Beecham Pharmaceuticals (now GlaxoSmithKline) have allowed us to analyze the relative importance of molecular properties considered to influence that drug property. Reduced molecular flexibility, as measured by the number of rotatable bonds, and low polar surface area or total hydrogen bond count (sum of donors and acceptors) are found to be important predictors of good oral bioavailability, independent of molecular weight. That on average both the number of rotatable bonds and polar surface area or hydrogen bond count tend to increase with molecular weight may in part explain the success of the molecular weight parameter in predicting oral bioavailability. The commonly applied molecular weight cutoff at 500 does not itself significantly separate compounds with poor oral bioavailability from those with acceptable values in this extensive data set. Our observations suggest that compounds which meet only the two criteria of (1) 10 or fewer rotatable bonds and (2) polar surface area equal to or less than 140 A(2) (or 12 or fewer H-bond donors and acceptors) will have a high probability of good oral bioavailability in the rat. Data sets for the artificial membrane permeation rate and for clearance in the rat were also examined. Reduced polar surface area correlates better with increased permeation rate than does lipophilicity (C log P), and increased rotatable bond count has a negative effect on the permeation rate. A threshold permeation rate is a prerequisite of oral bioavailability. The rotatable bond count does not correlate with the data examined here for the in vivo clearance rate in the rat.
4-Amino-5,7-disubstituted pyridopyrimidines are potent, non-nucleoside inhibitors of adenosine kinase (AK). We recently identified a potent, orally efficacious analog, 4 containing a 7-pyridylmorpholine substituted ring system as the key structural element of this template. In this report, we disclose the pharmacologic effects of five- and six-membered heterocyclic ring replacements for the pyridine ring in 4. These replacements were found to have interesting effects on in vivo efficacy and genotoxicity as well as in vitro potency. We discovered that the nitrogen in the heterocyclic ring at C(7) is important for the modulation of mutagenic side effects (Ames assay).
As part of a search for dihydrofolate reductase (DHFR) inhibitors combining the high potency of piritrexim (PTX) with the high antiparasitic vs mammalian selectivity of trimethoprim (TMP), the heretofore undescribed 2,4-diamino-6-(2',5'-disubstituted benzyl)pyrido[2,3-d]pyrimidines 6-14 with O-(omega-carboxyalkyl) or omega-carboxy-1-alkynyl groups on the benzyl moiety were synthesized and tested against Pneumocystis carinii, Toxoplasma gondii, and Mycobacterium avium DHFR vs rat DHFR. Three N-(2,4-diaminopteridin-6-yl)methyl)-2'-(omega-carboxy-1-alkynyl)dibenz[b,f]azepines (19-21) were also synthesized and tested. The pyridopyrimidine with the best combination of potency and selectivity was 2,4-diamino-5-methyl-6-[2'-(5-carboxy-1-butynyl)-5'-methoxy]benzyl]pyrimidine (13), with an IC(50) value of 0.65 nM against P. carinii DHFR, 0.57 nM against M. avium DHFR, and 55 nM against rat DHFR. The potency of 13 against P. carinii DHFR was 20-fold greater than that of PTX (IC(50) = 13 nM), and its selectivity index (SI) relative to rat DHFR was 85, whereas PTX was nonselective. The activity of 13 against P. carinii DHFR was 20 000 times greater than that of TMP, with an SI of 96, whereas that of TMP was only 14. However 13 was no more potent than PTX against M. avium DHFR, and its SI was no better than that of TMP. Molecular modeling dynamics studies using compounds 10 and 13 indicated a slight binding preference for the latter, in qualitative agreement with the IC(50) data. Among the pteridines, the most potent against P. carinii DHFR and M. avium DHFR was the 2'-(5-carboxy-1-butynyl)dibenz[b,f]azepinyl derivative 20 (IC(50) = 2.9 nM), whereas the most selective was the 2'-(5-carboxy-1-pentynyl) analogue 21, with SI values of >100 against both P. carinii and M. avium DHFR relative to rat DHFR. The final compound, 2,4-diamino-5-[3'-(4-carboxy-1-butynyl)-4'-bromo-5'-methoxybenzyl]pyrimidine (22), was both potent and selective against M. avium DHFR (IC(50) = 0.47 nM, SI = 1300) but was not potent or selective against either P. carinii or T. gondii DHFR.
Tyrosine kinases are used as important biomarkers in many tumor types. Preclinical and clinical anti-tumor studies have shown that broadly acting tyrosine kinase inhibitors may be more useful than specific inhibitors, since the former might overcome redundancies and crosstalk in tumor cell growth signaling pathways. Here, we aim to identify a novel potent tyrosine kinase inhibitor. Computer modeling of the pyrido-pyrimidine class compound, TKI-28(6-(2,6-dichlorophenyl)-8-methyl-2-phenylamino-8H-pyrido[2,3-d]pyrimidine-7-one), predicted that the compound would dock well in the ATP pocket of the ErbB-2 tyrosine kinase, yielding a high binding affinity for ErbB receptors. Biochemical studies revealed that TKI-28 potently inhibited the activities of tyrosine kinases such as ErbB-2, EGFR, KDR, PDGFRbeta, c-kit and c-Src, but had little effect on Flt-1 in cell-free system. TKI-28 also efficiently blocked autophosphorylation of the listed receptor tyrosine kinases, and subsequently downregulated phosphorylation of many downstream signaling proteins at the cellular level. TKI-28 exhibited a more potent anti-proliferative activity against EGF- and neuregulin-stimulated SK-OV-3 cells versus serum-stimulated cells, accompanied by apparent induction of apoptosis. Finally, TKI-28 was found to possess anti-angiogenic effects, characterized by inhibition of cell proliferation driven by EGF, VEGF and PDGF, as well as decreased cell migration and tube formation in HMECs. These results collectively highlight the pharmacological characteristics of TKI-28 as a broad-spectrum tyrosine kinase inhibitor, suggesting that it has great potential as an anti-cancer and anti-angiogenesis agent.
A series of dihydropyrido[2,3-d]pyrimidines have been synthesized and screened for its in vitro antileishmanial activity profile in promastigote and amastigote models. Compounds 2a-2l have shown 83-100% inhibition against promastigotes and 79-100% inhibition against amastigotes at a concentration of 50 microg/mL.
In order to obtain less toxic antitumoral compounds we have looked for novel compounds with anticancer activity based on proapoptotic mechanisms. The compounds studied in this work are derivatives of bicyclic aromatic systems like pyrido[2,3-d]pyrimidines. The potential antitumoral activity of the compounds was evaluated in vitro by examining their cytotoxic effects against human breast, colon, and bladder cancer lines (MD-MBA-231, HT-29, and T-24). The data indicate that HC-6 is a potent anticancer drug showing dose-dependent cytostatic and proapoptotic effects through activation of two different signaling pathways namely a pathway leading to cell cycle arrest and a transcription-independent route leading to rapid apoptosis.
A novel series of potent 2-aryl pyrido[2,3-d]pyrimidine mGlu5 receptor antagonists are described. The synthesis and pharmacological activities of these analogs are discussed.