Compounds 1n Research Articles

Synthesis and anticancer evaluation of diaryl pyrido[2,3-d]pyrimidine /alkyl substituted pyrido[2,3-d]pyrimidine derivatives as thymidylate synthase inhibitors

Worldwide, colorectal cancer (CRC) is the third most common type of cancer and the second most common cause of cancer-related deaths. Thymidylate synthase (TS) is a crucial component of DNA biosynthesis and has drawn interest as an essential target for cancer treatment. In the current work, we have designed and synthesized twenty-eight new diaryl-based pyrido[2,3-d]pyrimidine/alkyl-substituted pyrido[2,3-d]pyrimidine derivatives and evaluated their anticancer activity against the HCT 116, MCF-7, Hep G2, and PC-3 cell lines cell lines. Additionally, we have carried out TS inhibitory activity and in silico studies for compounds 1n and 2j. All the synthesized compounds exhibited good anticancer activity, but among them, compounds 1n and 2j showed excellent anticancer activity, having IC50 values of 1.98 ± 0.69, 2.18 ± 0.93, 4.04 ± 1.06, and 4.18 ± 1.87 µM; and 1.48 ± 0.86, 3.18 ± 0.79, 3.44 ± 1.51, and 5.18 ± 1.85 µM, against the HCT 116, MCF-7, Hep G2, and PC-3 cell lines respectively with control raltitrexed (IC50 1.07 ± 1.08, 1.98 ± 0.72, 1.34 ± 1.0, and 3.09 ± 0.96 µM, respectively) and hTS inhibitory activity with IC50 values of 20.47 ± 1.09 and 13.48 ± 0.96 nM with control raltitrexed (IC50 14.95 ± 1.01 nM). Further, the mechanism of inhibition was revealed by molecular docking, which showed the binding pattern of 1n and 2j to the catalytic site of TS with docking scores of -10.6 and − 9.5 kcal/mol, respectively, with reference raltitrexed (-9.4 kcal/mol). Additionally, the assessment of physicochemical, biochemical, structural, and toxicological characteristics were also in the acceptable range for these compounds. Based on the anticancer activity of compounds, SAR was also performed for lead optimization.

Novel Benzylamine Derivatives: Synthesis, Anti-Mycobacterium Tuberculosis Evaluation and Predicted ADMET Properties

Background: Tuberculosis (TB), a disease caused by the bacillus bacteria Mycobacterium tuberculosis is one of the major contributors of ill health in the world. TB is ranked in the top 10 causes of death globally and it is the leading killer associated with a single infectious agent. According to the World Health Organization (WHO), global number of deaths associated with TB have been slowly declining with 1.3 million in reported 2016 and 2017, and 1.2 million reported in 2018 and 2019. Objective: The synthesis, characterisation, biological evaluations, and the prediction of ADMET properties of the novel benzylamine derivatives. Methods: Commercially available reagents and solvents were purchased from Sigma Aldrich and Merck (South Africa). All chemicals were used as received, unless otherwise stated. The synthesised crude compounds were purified by flash silica gel column chromatography (5 – 30% ethyl acetate in hexane). The successful formation and purity of the synthesised compounds was confirmed by NMR, HRMS and melting point. Results: The respective organic compounds were synthesised by treating 3-ethoxysalcyladehyde, 5-bromo-3-ethoxysalcyladehyde, 5-chloro-3-ethoxysalcyladehyde with various aromatic amines and the products were obtained in good to excellent yields. The 1H and 13C NMR spectra of all the products showed the appearance of the methylene signals ranging from 3.88 – 4.68 ppm and 42.25 – 52.57 ppm respectively. Additionally, most compounds showed anti-Mycobacterium tuberculosis activity that ranged between 20 and 28 µM. Conclusion: A total of 36 compounds were synthesised and successfully biologically evaluated against Mycobacterium tuberculosis (Mtb) H37RV strain. All compounds showed activity against Mtb at concentrations of > 20 µM < 28 µM with the exception of compound one that was active against Mtb at higher concentration (MIC90 > 125 µM).

Benzo[d]thiazole-2-carboxamides as new antituberculosis chemotypes inhibiting mycobacterial ATP phosphoribosyl transferase.

Aims: The screening of antimycobacterial benzo[d]thiazole-2-carboxamides against ATP-phosphoribosyl transferase (ATP-PRTase) was conducted. Materials & methods: The antitubercular potential of compounds1 and 2 against ATP-PRTase was assessed through the determination of half maximal effective concentration (EC50) andbinding constant (Kd), as well ascompetitive inhibitory studies and studies of perturbation of secondary structure, molecular modelingand L-histidine complementation assay. Results & conclusion:Compounds 1n and 2a significantly inhibited ATP-PRTaseas evidenced by their EC50 and Kdvaluesand the perturbation of thesecondary structure study. Compound 1n exhibitedstronger competitive inhibition toward ATP compared with 2a. The inhibition of the growth of Mycobacterium tuberculosis by targeting the L-histidine biosynthesis pathway and molecular modeling studies further supported theinhibition of ATP-PRTase.

Chemistry-oriented synthesis (ChOS) and target deconvolution on neuroprotective effect of a novel scaffold, oxaza spiroquinone

Here we first time report an unprecedented and unnatural six-membered 1,5-oxaza spiroquinone scaffold with structural novelty, a convenient and efficient synthetic route was developed for the synthesis of new 1,5-oxaza spiroquinone derivatives (1a-1r) in high yields from readily available starting materials. The logic of the present work consists of (1) the identification of a promising unprecedented scaffold from privileged scaffolds of biological active molecules through our ‘Chemistry-oriented Synthesis’ (ChOS) approach, a compensatory strategy for target-based drug discovery, (2) the positioning of the identified 1,5-oxaza spiroquinone scaffold on neuroinflammation and neurodegenerative disease through nitric oxide (NO) inhibitory activity without cytotoxicity in hyper-activated microglia (IC50 of NO production: 0.07–1.82 μM) to establish structure–activity relationship (SAR), (3) the investigation on the possibility as a selective kinase inhibitor related to neurodegenerative diseases (eg. JNK1, CDK2, DAPK1) through kinase full panel screening of the most potent compound 1n, and (4) the evaluation on in vivo efficacy of the compound 1n through Y-maze test.

Design, synthesis and evaluation of γ-turn mimetics as LSD1-selective inhibitors

Lysine-specific demethylase 1 (LSD1) is an attractive molecular target for cancer therapy. We have previously reported potent LSD1-selective inhibitors (i.e., NCD18, NCD38, and their analogs) consisting of trans-2-phenylcyclopropylamine (PCPA) or trans-2-arylcyclopropylamine (ACPA) and a lysine moiety that could form a γ-turn structure in the active site of LSD1. Herein we report the design, synthesis and evaluation of γ-turn mimetic compounds for further improvement of LSD1 inhibitory activity and anticancer activity. Among a series of γ-turn mimetic compounds synthesized by a Mitsunobu-reaction-based amination strategy, we identified 1n as a potent and selective LSD1 inhibitor. Compound 1n induced cell cycle arrest and apoptosis through histone methylation in human lung cancer cells. The γ-turn mimetics approach should offer new insights into drug design for LSD1-selective inhibitors.

A New Series of Cycloalkane‐fused Coumarin Sulfonates: Synthesis and In Vitro Antiproliferative Screening

In this paper, we report the synthesis of 14 new cycloalkane‐fused tricyclic coumarin sulfonate derivatives. They were examined for in vitro anticancer activity against NCI‐57 cancer cell line panel of nine different cancer types. Among all the target analogs, compounds 1c, 1e, and 1n showed the highest activities. Compound 1e exerted the highest percentage growth inhibition (91.91%) against SNB‐75 CNS cancer cell line at 10 μM concentration and was more active than carmustine against this cell line. Compound 1c also showed strong activity against HT29 colon, ACHN renal, and PC‐3 prostate cancer cell lines. Furthermore, compound 1n was selective toward the HT29 colon cancer cell line. Compounds 1c, 1e, and 1n showed superior selectivity against cancer cell lines compared to the noncancerous RAW 264.7 macrophages. The in silico predictions estimate the oral bioavailability, which is in compliance with Lipinski's rule of five.

Synthesis, DNA-binding study, and antioxidant activity of 14-aryl-14H-dibenzo[a,j]xanthene derivatives

A simple and efficient one-pot method for the synthesis of 14-aryl-14H-dibenzo[a,j]xanthene derivatives using Ni(ClO4)2·6H2O as a catalyst is described. DNA-binding properties of 14-aryl-14H-dibenzo[a,j]xanthene derivatives 1a, 1j, 1l, 1m, and 1n were investigated using calf thymus DNA by electronic absorption spectroscopy and fluorescence spectroscopy. Binding constant (K b) with DNA was calculated from the absorption measurements. The spectral changes observed such as hypochromicity, red shift, and isosbestic point are consistent with the intercalation mode of binding of the chromophore into the stack DNA base pairs. Among the five, compound 1n with strong electron donating substituents on the phenyl ring shows better intercalative binding with DNA. Investigations of antioxidant properties show that the dibenzo[a,j]xanthene 1m with –OH group substitution has high radical scavenging properties against DPPH and ABTS+.

Synthesis and Biological Evaluation of Substituted Desloratadines as Potent Arginine Vasopressin V2 Receptor Antagonists

Twenty-one non-peptide substituted desloratadine class compounds were synthesized as novel arginine vasopressin receptor antagonists from desloratadine via successive acylation, reduction and acylation reactions. Their structures were characterized by 1H-NMR and HRMS, their biological activity was evaluated by in vitro and in vivo studies. The in vitro binding assay and cAMP accumulation assay indicated that these compounds are potent selective V2 receptor antagonists. Among them compounds 1n, 1t and 1v exhibited both high affinity and promising selectivity for V2 receptors. The in vivo diuretic assay demonstrated that 1t presented remarkable diuretic activity. In conclusion, 1t is a potent novel AVP V2 receptor antagonist candidate.

Phenolic esters of O-desmethylvenlafaxine with improved oral bioavailability and brain uptake.

O-Desmethylvenlafaxine (desvenlafaxine, ODV) is a recently approved antidepressant which in some clinical studies failed to meet a satisfactory end-point. The aim of this study was to prepare a series of phenolic esters of ODV and evaluate their potential as ODV prodrugs with improved brain uptake. Fifteen phenolic esters (compounds 1a–o) were synthesized and their pharmacokinetic profiles evaluated in rat. The four compounds producing the highest relative bioavailability of ODV in rat (compounds 1c, 1e, 1n, 1o) were then studied to evaluate their brain uptake. Of these four compounds, compound 1n (the piperonylic acid ester of ODV) demonstrated the highest Cmax of ODV both in the rat hypothalamus and total brain. Finally the pharmacokinetics of 1n were evaluated in beagle dog where the increase in relative bioavailability of ODV was found to be as great as in rat. This high relative bioavailability of ODV coupled with its good brain penetration make 1n the most promising candidate for development as an ODV prodrug.

Oxazolopyridines and thiazolopyridines as monoamine oxidase B inhibitors for the treatment of Parkinson’s disease

In Parkinson’s disease, the motor impairments are mainly caused by the death of dopaminergic neurons. Among the enzymes which are involved in the biosynthesis and catabolism of dopamine, monoamine oxidase B (MAO-B) has been a therapeutic target of Parkinson’s disease. However, due to the undesirable adverse effects, development of alternative MAO-B inhibitors with greater optimal therapeutic potential towards Parkinson’s disease is urgently required. In this study, we designed and synthesized the oxazolopyridine and thiazolopyridine derivatives, and biologically evaluated their inhibitory activities against MAO-B. Structure–activity relationship study revealed that the piperidino group was the best choice for the R1 amino substituent to the oxazolopyridine core structure and the activities of the oxazolopyridines with various phenyl rings were between 267.1 and 889.5nM in IC50 values. Interestingly, by replacement of the core structure from oxazolopyrine to thiazolopyridine, the activities were significantly improved and the compound 1n with the thiazolopyridine core structure showed the most potent activity with the IC50 value of 26.5nM. Molecular docking study showed that van der Waals interaction in the human MAO-B active site could explain the enhanced inhibitory activities of thiazolopyridine derivatives.

2-Aminobenzothiazole derivatives: Search for new antifungal agents

A new series of 6-substituted 2-aminobenzothiazole derivatives were synthesized and screened in vitro as potential antimicrobials. Almost all the compounds showed antifungal activity. In particular, compounds 1n,o, designed on the basis of molecular modeling studies, were the best of the series, showing MIC values of 4–8 μg/mL against Candida albicans, Candida parapsilosis and Candida tropicalis. None of the two compounds did show any cytotoxicity effect on human THP-1 cells.

Nuclease activity and ultrastructural effects of new sulfonamides with anti-leishmanial and trypanocidal activities

Our aim was to evaluate the in vitro efficacy of a series of N-benzenesulfonamides of amine substituted aromatic rings, sulfonamides 1–6, against Trypanosoma cruzi and Leishmania spp. and to compare their trypanocidal and leishmanicidal profile. In order to elucidate the probable mechanism of action, the interaction of selected sulfonamides with pUC18 plasmid DNA was investigated by nuclease activity assays. In addition, the cellular targets of these sulfonamides in treated parasites were also searched by transmission and scanning electron microscopy.The most active compounds 4-nitro-N-pyrimidin-2-ylbenzenesulfonamide 1a and 4-chloro-N-5-methyl-thiazol-2-yl-benzenesulfonamide 2d displayed significant in vitro activity against Leishmania spp. promastigotes, without toxicity to J774 macrophages. Selected sulfonamides 1a, 4-nitro-N-pyrazin-2-yl-benzenesulfonamide 1n and 2d were also active against Leishmania infantum intracellular amastigotes. Compounds 1n and 2d showed nuclease activity in the presence of copper salt analogous to our previous results with sulfonamide 1a. Mechanistic data reveal the involvement of a redox process. Evidence for the formation of reactive oxygen species (ROS) responsible for DNA strand scission is provided for sulfonamides 1a, 1n and 2d. Transmission electron microscopic (TEM) analysis of L. infantum promastigotes treated with compounds 1a, 1n and 2d shows an overall cellular disorganization effects which are mainly addressed to DNA bearing structures such as the nucleus, mitochondria and kinetoplast. Disruption of double nuclear membrane and loss of cellular integrity along with accumulation of cytoplasmic electrodense bodies were also frequently observed.

Synthesis, characterization and pharmacological evaluation of (E)-N′-(substituted-benzylidene)isonicotinohydrazide derivatives as potent anticonvulsant agents

A series of (E)-N′-(substituted-benzylidene)isonicotinohydrazide derivatives were synthesized by coupling it with different substituted aldehydes, acetophenone, and benzophenones in presence of absolute ethanol along with catalytic amount of glacial acetic acid. All the synthesized compound were confirmed and characterized by using various spectral technique like IR, 1H NMR, 13C NMR, and mass spectroscopy studies. Anticonvulsant evaluations of all the synthesized compounds were done using various seizures models like maximal electroshock-induced seizure (MES) and subcutaneous pentylenetetrazole (scPTZ) at a dose of 30, 100, and 300 mg/kg body weight and anticonvulsant activity was noted at 0.5 h and 4 h time intervals after the drug administration. Compound 1a (E)-N′-2-benzylidene isonicotinohydrazide, 1g (E)-N′-2-ethoxybenzylidene isonicotinohydrazide, 1k (E)-N′-3-flourobenzylidene isonicotinohydrazide and 3a (E)-N′-diphenylmethylene isonicotinohydrazide showed protection in MES model, which indicates that these compounds have the ability to prevent the spread of seizure at 300 mg/kg dose and showed protection at 0.5 h duration. Compound 3a was also found to be active in scPTZ screen at a dose of 300 mg/kg. In neurotoxicity screen, all the synthesized compounds were found non-toxic except compounds 1n, 2a, and 3b. Further compounds 1a, 1g, 1k, and 3a were also evaluated in the minimal clonic seizure model and exhibited potent anticonvulsant activity with lower neurotoxicity. Among all synthesized derivatives, analogue 3a was found to exhibit protection in MES and scPTZ seizure models. This study proved that isonicotinoyl hydrazides synthesized by condensing isoniazid with various aldehydes and ketones displayed moderate to potent anticonvulsant activity.

Preparation of C-23 esterified silybin derivatives and evaluation of their lipid peroxidation inhibitory and DNA protective properties

A diverse series of C-23 esterified silybin derivatives ( 1a– n) were designed and synthesized. The antioxidative properties of these compounds were evaluated by 1,1-diphenyl-2-picrylhydrazyl (DPPH) and superoxide anion radical scavenging, ferrous ion chelation, and inhibition of rat liver homogenate lipid peroxidation. Their protective effects on the prevention of hydrogen peroxide induced DNA damage were also investigated. Most of the synthesized compounds exhibited more effective antioxidant activities than silybin. The esterified silybin analogues displayed satisfactory performance especially on iron chelation and antiperoxidative activity. Compound 1n in particular exhibited remarkable antiperoxidative effect with an IC 50 value of 0.2 ± 0.1 μM, which was stronger than that of quercetin (IC 50 = 1.8 ± 0.6 μM). Compounds 1c, 1e, 1g, 1h and 1k displayed potent, dose-dependent protective properties against DNA cleavage. The results of the bioassays support the antioxidative and DNA protective effects of these synthesized silybin derivatives.

Selective Oxidation and Reduction of Trinuclear Titanium(II) Hexaazatrinaphthylene ComplexesSynthesis, Structure, and Electrochemical Investigations

Titanocene complexes with chelating N-heterocyclic ligand bridges react with ferrocenium salts as selective oxidants to afford air-stable cationic complexes and allow the preparation of exceptional mixed valence hexaazatrinaphthylene complexes [(Cp2Ti)3(mu3-HATNMe6)]n+ (1n+) (n=1, 2, 3, 4). Cyclic voltammograms (CV) and differential pulse voltammograms (DPV) show that nine oxidation states of 1 are generated without decomposition. Comproportionation constants Kc have been calculated in order to determine the extent of electronic communication between the titanium centers. The Kc values of the mixed valence states are indicative of uncoupled (14+), moderately coupled (15+), and strongly coupled (1-, 1+, and 12+) systems. Small but significant structural changes occurring upon oxidation of neutral 1 are observed by X-ray structural analysis on 1+-14+. Anion-pi interactions between the electron-deficient central ring of the HATNMe6 moiety and PF6- and BF4- counterions, respectively, are found for 12+, 13+, and 14+. The short cation-anion contacts cause interesting molecular allignments in terms of molecular architecture. For 12+ the assembly of an one-dimensional (1D) polymer is observed. Electrochemical investigations on the mononuclear cationic titanocene complexes [(Cp2Ti)(L)]+ (L=2,2'-biquinoline (2+), 4,4'-dimethyl-2,2'-biquinoline (3+), and 5,8'-dimethyl-2,3'-biquinoxaline (4+)) showed similar oxidation and reduction characteristics among each other. Conversion to monoanionic, neutral, and dicationic states is enabled. As found for the trinuclear compounds 1n+, the molecular structures of 2+-4+ reveal significant differences compared to their neutral parents.

Novel T-type calcium channel blockers: Dioxoquinazoline carboxamide derivatives

T-type calcium channel is one of therapeutic targets for the treatment of cardiovascular diseases and neuropathic pains. Since the withdrawal of mibefradil, a T-type calcium channel blocker, there have been a lot of efforts to develop T-type calcium channel blockers. A small molecule library of dioxoquinazoline carboxamide derivatives containing 155 compounds was designed, synthesized, and biologically evaluated for T-type calcium channel blocking activity. Among those compounds synthesized, the compound 1n shows the most potent T-type calcium current blocking activity with an IC 50 value of 1.52 μM, which is comparable to that of mibefradil.

Structure−Activity Relationship of Triazafluorenone Derivatives as Potent and Selective mGluR1 Antagonists

SAR (structure-activity relationship) studies of triazafluorenone derivatives as potent mGluR1 antagonists are described. The triazafluorenone derivatives are non-amino acid derivatives and noncompetitive mGluR1 antagonists that bind at a putative allosteric recognition site located within the seven-transmembrane domain of the receptor. These triazafluorenone derivatives are potent, selective, and systemically active mGluR1 antagonists. Compound 1n, for example, was a very potent mGluR1 antagonist (IC50 = 3 nM) and demonstrated full efficacy in various in vivo animal pain models.

A solid-phase approach to mouse melanocortin receptor agonists derived from a novel thioether cyclized peptidomimetic scaffold.

The solid-phase synthesis of a novel thioether cyclized peptidomimetic scaffold, displaying functionality at the i to i + 3 positions, is reported. The thioether bridge is formed on-bead by an intramolecular reaction between a chloroacetylated reduced peptide bond and the free thiol from a cysteine. The crude products were obtained in moderate to very high purity. A series of 19 compounds were prepared and tested for agonist activity at the mouse melanocortin receptors 1, 3, 4, and 5 (mMC1-5R). From these results, several compounds were identified as having low micromolar agonist activity at the mMC1R and mMC4R. The former is involved in skin pigmentation and animal coat coloration. The latter is involved in the regulation of appetite and food intake and is currently a drug target for potential treatment of obesity. The most potent compound 1n with the pharmacophore motif "His-DPhe-Arg-Trp" was identified as having an EC(50) value of 165 nM at mMC1R, 7600 nM at mMC3R, 650 nM at mMC4R, and 335 nM at mMC5R. In addition, some of the compounds showed moderate selectivity for the mMC1R.

Why Do Nitroso Compounds Dimerize While Their Oxime Tautomers Do Not? A Structural Study of the Trans-Dimer of 2-Chloro-2-methyl-3-nitrosobutane and Higher Level ab Initio Study of Thermodynamic Stabilities and Electronic Structures of Isomers of Diazene Dioxides

NOCl addition to 2-methyl-2-butene produces a white crystalline solid which was shown by low-temperature X-ray diffraction to contain trans-dimers 2 of 2-chloro-2-methyl-3-nitrosobutane (1n): C10H20N2O2Cl2, Mr = 271.18, monoclinic, I2/a, a = 11.982(4), b = 7.1297(7), c = 15.735(5) Å, β = 90.20(2)°, V = 1344.2(6) Å3, Z = 4, Dx = 1.340(2) g cm-3, (Mo Kα) = 0.70930 Å, μ = 4.7 cm-1, F(000) = 1152, T = 173 K, R = 0.030, Rw = 0.032 for 791 observed reflections of 898 unique data. Diazene dioxide 2 also is the dominant species in solution although some spectroscopic and chemical observations indicate the presence of monomeric nitroso compound 1n and of the tautomeric oxime 1o at least in small quantities. In conjunction with the experimental study, conformational and configurational equilibrium structure preferences and the bonding in diazene dioxides R(O)NN(O)R‘ (3: R = R‘ = H, 4: R = H, R‘ = Me, 5: R = R‘ = Me) were studied at the MP2(full)/6-31G* level. The 1A‘ and 3A‘‘ states of HNO and MeNO and the oxime tautomer of MeNO were considered. Isomer energies, rotational barriers, excitation energies, tautomerization energies, and dimer formation energies were determined at levels up to QCISD(T)/6-311G**//MP2(full)/6-31G* + ΔVZPE(MP2(full)/6-31G*). The trans-isomer is favored in all cases, and the trans preference energy increases from 4.0 kcal/mol in (HNO)2 to 13.2 kcal/mol in (MeNO)2. The thermodynamic stabilities of the trans-configured diazene dioxides vary by less than 1 kcal/mol as the result of successive H/Me replacement; the calculated dimerization enthalpies for the trans-isomers are −9.0 (3), −9.9 (4), and −9.4 kcal/mol (5). Natural bond orbital analysis and dipole and quadrupole moments show dimer formation to increase the polarity of the NO bond, and this increase is only slightly larger for the Me-substituted NO bond. The driving force for dimer formation is the electron density transfer to the most electronegative element and this density transfer is made possible by N-rehybridization. The analogous dimerization of oximes via Nσ lone pair [2 + 2] addition would result in an unfavorable polarization reversal for the C-atom.