Compounds Exhibited IC50 Values Research Articles

Synthesis and antiprotozoal activities of benzyl phenyl ether diamidine derivatives

Sixty-two cationic benzyl phenyl ether derivatives (36 amidines and 26 prodrugs) were prepared and assayed for activities in vitro and in vivo against Trypanosoma brucei rhodesiense (STIB900), and in vitro against Plasmodium falciparum (K1) and Leishmania donovani axenic amastigotes. 3-Amidinobenzyl 4-amidino-2-iodo-6-methoxyphenyl ether dihydrochloride (55, IC50 = 3.0 nM) and seven other compounds exhibited IC50 values below 10 nM against T. b. rhodesiense in vitro. The 2-bromo-4,4′-diamidino analogue 19 (IC50 = 4.0 nM) and 12 other analogues were more potent than pentamidine (IC50 = 46 nM) against P. falciparum. The 3′,4-diamidino-2,6-diiodo analogue 49 (IC50 = 1.4 μM) and two other compounds were more effective than pentamidine (IC50 = 1.8 μM) against L. donovani. A prodrug, 3′,4-bis(N″-methoxy)amidino-2-bromo derivative 38, was the most efficacious against trypanosome infected mice, attaining 4/4 cures in four daily 25 mg/kg oral doses, and the 2-chloro-4,4′-diamidine 18 cured 3/4 mice in four daily 5 mg/kg intraperitoneal doses.

Virtual Screening Analysis and In-vitro Xanthine Oxidase Inhibitory Activity of Some Commercially Available Flavonoids.

Allopurinol, the xanthine oxidase inhibitor, is the only drug available for the treatment of gout. We examined the xanthine oxidase inhibitory activity of some commercially available flavonoids such asepigallocatechin, acacatechin, myricetin, naringenin, daidzein and glycitein by virtual screening and in-vitro studies. The interacting residues within the complex model and their contact types were identified. The virtual screening analysis were carried out using AutoDock 4.2 and in-vitro xanthine oxidase inhibitory activity was carried out using xanthine as the substrate. In addition, enzyme kinetics was performed using LineweaverBurkplot analysis. Allopurinol, a known xanthine oxidase inhibitor was used as the standard. The docking energy ofglycitein was found to be -8.49 kcal/mol which was less than that of the standard (-4.47 kcal/ mol). All the selected flavonoids were found to exhibit lower binding energy (-8.08 to -6.03 kcal/ mol) than allopurinol. The docking results confirm that flavonoids showed greater inhibition of xanthine oxidase due to their active binding sites and lesser binding energies compared to allopurinol. This may be attributed to the presence of benzopyran ring in the flavonoids. In the xanthine oxidase assay, IC50 value of glycitein was found to be 12±0.86 μg/mL, whereas that of allopurinol was 24±0.28 μg/mL. All the remaining compounds exhibited IC50 values ranging between 22±0.64 to 62±1.18 μg/mL. In the enzyme kinetic studies, flavonoids showed competitive type of enzyme inhibition. It can be concluded that flavonoids could be a promising remedy for the treatment of gout and related inflammatory disorders. Further in-vivo studies are required to develop potential compounds with lesser side effects.

Design and synthesis of some new heterocyclic benzylidene hydrazide derivatives for their antileishmanial activity

ABSTRACT: Benzylidene hydrazide is a highly active moiety against Leishmania donovani, and has become a core structure for the design of new antileishmanial agents. The 5-nitrothiophen-2-yl-benzylidene hydrazide derivative presents a potent IC50 value. With this background, it is attempted to discern the structural and physicochemical requirements for the inhibition of Leishmania donovani. The techniques of quantitative structure activity relationship and docking are valuable molecular modeling tools for drug design. In the present study, 3-DQSAR of some Leishmania donovani inhibitors was carried out using VLife MDS, while interaction studies were carried usind Schrodinger molecular modeling interface. The developed QSAR models showed q2 = 0.9849, pred_r2 = 0.6770 with kNN analysis by stepwise forward and backward method. Docking study revealed important interactions of designed compounds with the active binding site of Leishmania donovani. Designed compounds were synthesis and screened against Leishmania donovani. Three compounds exhibited IC50 values lower than standard drugs. Brief SAR analysis revealed that substitution is important to the activity. KEY WORDS: benzylidene hydrazide derivatives, antileishmanial activity, 3D-QSAR, docking

Phosphaplatins, next generation platinum antitumor agents: A paradigm shift in designing and defining molecular targets

Platinum(II)- and platinum(IV)-pyrophosphato-complexes (phosphaplatins) show excellent antitumor properties against a variety of human ovarian cancers, including cisplatin- and carboplatin-sensitive and resistant human cancers. To identify the lead compound of this class of non-DNA binding antitumor agents, stereoisomers of cis- and trans-1,2-cyclohexane-diamine(pyrophosphato)platinum(II) and of cis- and trans-1,2-cyclohexane-trans-dihydroxo-diamine(pyrophosphato)platinum(IV) were synthesized, and their in vitro efficacies were evaluated in a variety of human ovarian cancer cells including cisplatin- and carboplatin-resistant cancer cells. Some of these compounds exhibited IC50 values as low as 0.40μM, the lowest ever observed for any platinum anticancer drugs under identical conditions. More importantly, these compounds are highly active against cisplatin- and carboplatin-sensitive and resistant cancers; examples of these cancer cells include cisplatin-sensitive A2780, acquired cisplatin- and carboplatin-resistant A2780/C30, and inherent cisplatin-resistant OVCAR-10 cells. In vivo efficacy determined by using human ovarian xenografts indeed confirmed that phosphaplatins are quite effective in treating ovarian cancers. The superiority of phosphaplatins was observed in increased life span and tumor regression. These non-DNA binding compounds exhibit cytotoxicity in ovarian cancers primarily through apoptosis via cell cycle arrest both at S and G2 phases largely in a dose independent manner. Platinum(II) compounds showed reduced protein binding compared to either cisplatin or carboplatin. Furthermore, protein binding by phosphaplatins was largely limited to extracellular and cytosolic compartments. In vivo experiments revealed that platinum accumulations in kidney of mice were significantly less compared to cisplatin. The maximum tolerated dose was found be >60mg/kg via intravenous administration. Furthermore, rats treated with R,R-stereomer of the platinum(II) complex exhibited near normal white blood cell, platelet, and neutrophil counts indicating its non-toxic properties. Furthermore, the lead compound also stays in plasma for 24h giving ample time to reach desired targets. Taken together, these data indicate that phosphaplatins have the potential to treat resistant ovarian cancers, both acquired and de novo, without exhibiting severe toxic effects.

Study of potential xanthine oxidase inhibitors: In silico and in vitro biological activity

In an attempt to develop potent anti gout agents, coumarin derivatives and polyphenolic compounds were selected for present study. The docking energy of 2-benzyl coumarin was found to be -7.50 kcal/mol which was less than that of the standard allopurinol (-4.47 kcal/mol). All the selected compounds were found to exhibit lower binding energy (-7.50 to -4.68 kcal/mol) than allopurinol. Docking results confirm that selected compounds showed greater inhibition of xanthine oxidase due to their active binding sites. In xanthine oxidase assay, IC50 value of 2-benzyl coumarin was found to be 26 ± 1.16 µg/mL, whereas that of allopurinol was 24 ± 0.28 µg/mL. All the compounds exhibited IC50 values ranging between 26 ± 1.16 to 58 ± 0.74 µg/mL. In enzyme kinetic studies, coumarin derivatives showed competitive and polyphenolic compounds showed non competitive type of enzyme inhibition. It can be concluded that coumarin derivatives could be a remedy for the treatment of gout and related inflammatory disorders.

Structure‐activity optimization of 4H‐pyridopyrimidines: a class of selective bacterial protein synthesis inhibitors

IntroductionBacterial protein synthesis is the target for numerous natural and synthetic antibacterial agents. Previous screening of a focused chemical compound library using a polyU mRNA‐directed aminoacylation/translation protein synthesis system from Escherichia coli yielded a lead series of compounds that inhibit protein synthesis with IC50's ranging from 3 to14 μM (Ribble, et. al. (2010) AAC, 54, 4648–4657). This series of compounds all contained the same central scaffold composed of tetrahydropyrido[4,3‐d]pyrimidin‐4‐ol (e.g. 4H‐pyridopyrimidine). These compounds inhibited bacterial growth with minimum inhibitory concentrations (MICs) ranging from 0.25 to 32 μg/ml.ResultsOver 100 analogs of the initial compounds were designed and synthesized and assayed. In biochemical protein synthesis reactions nineteen of the compounds exhibited IC50 values less than 2.0 μM and seven less than 1.0 μM. These compounds were active against S. pneumoniae (MIC=2 μg/mL), H. influenzae (MIC=1 μg/mL), and M. catarrhalis (MIC≤0.12 μg/mL) and S. aureus (4= μg/ml). Macromolecular synthesis (MMS) assays in E. coli and S. aureus confirmed that antibacterial activity resulted from specific inhibition of protein synthesis.ConclusionOptimization of 4H‐pyridopyrimidines yields potent inhibitors of protein synthesis with good activity against respiratory pathogens.

Characterization of thiobarbituric acid derivatives as inhibitors of hepatitis C virus NS5B polymerase

In an effort to find chemicals inhibiting the enzymatic activity of the hepatitis C virus (HCV) NS5B polymerase, a series of thiobarbituric acid derivatives were selected from a library provided by Korea Research Institute of Chemical Technology and characterized. The selected compounds exhibited IC50 values ranging from 1.7 to 3.8 μM, and EC50 values ranging from 12.3 to 20.7 μM against NS5B polymerase of type 1b strain. They showed little effect against type 2a polymerase. One of the compounds, G05, was selected and further characterized. It inhibited the synthesis of RNA by recombinant HCV NS5B polymerase in a dose dependent manner. The CC50 value was 77 μM. The inhibition was in a noncompetitive manner with the substrate UTP. The compound did not inhibit the elongation step of RNA synthesis in a single-cycle processive polymerization assay. It inhibited the binding of NS5B polymerase to the template RNA in a dose-dependent manner.

Pharmacophore Modeling of Tyrosine Kinase Inhibitors: 4‐Anilinoquinazoline Derivatives

AbstractA pharmacophore model for the inhibition of Tyrosine Kinase is established that could serve as a guide for the rational design of high potent and selective inhibitors. Recently, quantitative structure‐activity relationships for 4‐anilinoquinazoline class of inhibitors to inhibit EGFR autophosphorylation are in great demand. We have developed a quantitatively predictive chemical function‐based pharmacophore model by using Discovery Studio 2.1 software. The optimal hypothesis consists of four features: three hydrophobic (HYD), and one hydrogen bond donor (HBD) functions. The input for HypoGen was a training set of 16 compounds exhibiting IC50 values ranging between 0.025 nM and 12000 nM, and having the output borne significant conventional coefficient of 0.97. To further validate our design rationale, protein‐ligand docking software was used to elucidate the intra‐molecular interactions. Therefore, the established pharmacophore model could help to a better understanding on how the substituents might influence the activity and afford important information for both ligand‐based and structure‐based drug designs.

257 Effects of Drug-X on cisplatin-resistant and cisplatin-sensitive ovarian cancer cells

Platinum(II)- and platinum(IV)-pyrophosphato-complexes (phosphaplatins) show excellent antitumor properties against a variety of human ovarian cancers, including cisplatin- and carboplatin-sensitive and resistant human cancers. To identify the lead compound of this class of non-DNA binding antitumor agents, stereoisomers of cis- and trans-1,2-cyclohexane-diamine(pyrophosphato)platinum(II) and of cis- and trans-1,2-cyclohexane-trans-dihydroxo-diamine(pyrophosphato)platinum(IV) were synthesized, and their in vitro efficacies were evaluated in a variety of human ovarian cancer cells including cisplatin- and carboplatin-resistant cancer cells. Some of these compounds exhibited IC50 values as low as 0.40 μM, the lowest ever observed for any platinum anticancer drugs under identical conditions. More importantly, these compounds are highly active against cisplatin- and carboplatin-sensitive and resistant cancers; examples of these cancer cells include cisplatin-sensitive A2780, acquired cisplatin- and carboplatin-resistant A2780/C30, and inherent cisplatin-resistant OVCAR-10 cells. In vivo efficacy determined by using human ovarian xenografts indeed confirmed that phosphaplatins are quite effective in treating ovarian cancers. The superiority of phosphaplatins was observed in increased life span and tumor regression. These non-DNA binding compounds exhibit cytotoxicity in ovarian cancers primarily through apoptosis via cell cycle arrest both at S and G2 phases largely in a dose independent manner. Platinum(II) compounds showed reduced protein binding compared to either cisplatin or carboplatin. Furthermore, protein binding by phosphaplatins was largely limited to extracellular and cytosolic compartments. In vivo experiments revealed that platinum accumulations in kidney of mice were significantly less compared to cisplatin. The maximum tolerated dose was found be >60 mg/kg via intravenous administration. Furthermore, rats treated with R,R-stereomer of the platinum(II) complex exhibited near normal white blood cell, platelet, and neutrophil counts indicating its non-toxic properties. Furthermore, the lead compound also stays in plasma for 24 h giving ample time to reach desired targets. Taken together, these data indicate that phosphaplatins have the potential to treat resistant ovarian cancers, both acquired and de novo, without exhibiting severe toxic effects.

Small Neutralizing Molecules to Inhibit Actions of the Chemokine CXCL12

The chemokine CXCL12 and the receptor CXCR4 play pivotal roles in normal vascular and neuronal development, in inflammatory responses, and in infectious diseases and cancer. For instance, CXCL12 has been shown to mediate human immunodeficiency virus-induced neurotoxicity, proliferative retinopathy and chronic inflammation, whereas its receptor CXCR4 is involved in human immunodeficiency virus infection, cancer metastasis and in the rare disease known as the warts, hypogammaglobulinemia, immunodeficiency, and myelokathexis (WHIM) syndrome. As we screened chemical libraries to find inhibitors of the interaction between CXCL12 and the receptor CXCR4, we identified synthetic compounds from the family of chalcones that reduce binding of CXCL12 to CXCR4, inhibit calcium responses mediated by the receptor, and prevent CXCR4 internalization in response to CXCL12. We found that the chemical compounds display an original mechanism of action as they bind to the chemokine but not to CXCR4. The highest affinity molecule blocked chemotaxis of human peripheral blood lymphocytes ex vivo. It was also active in vivo in a mouse model of allergic eosinophilic airway inflammation in which we detected inhibition of the inflammatory infiltrate. The compound showed selectivity for CXCL12 and not for CCL5 and CXCL8 chemokines and blocked CXCL12 binding to its second receptor, CXCR7. By analogy to the effect of neutralizing antibodies, this molecule behaves as a small organic neutralizing compound that may prove to have valuable pharmacological and therapeutic potential.

First Gallamine−Tacrine Hybrid: Design and Characterization at Cholinesterases and the M2 Muscarinic Receptor

Gallamine and tacrine are allosteric antagonists at muscarinic M2 acetylcholine receptors and inhibitors of acetylcholinesterase. At both acetylcholine-binding proteins, gallamine and tacrine are known to occupy two different binding sites: in M2 receptors within the allosteric binding area and in acetylcholinesterase at its catalytic and its peripheral site. To find new ligands of both targets, we designed a gallamine-tacrine dimer and several derived hybrid compounds to address the two binding sites. Their M2 receptor allosteric and acetylcholinesterase inhibitory potential was determined. The hybrid compounds revealed an allosteric potency in the low nanomolar range exceeding the allosteric potency of gallamine and tacrine by factors of 100 and 4800, respectively. Cholinesterase inhibition was augmented by hybrid formation, and all compounds exhibited IC50 values in the lower nanomolar range. Thus, gallamine-tacrine hybrid formation is a valuable approach toward high affinity ligands concurrently targeting these acetylcholine-binding proteins.

Solid-Phase Combinatorial Synthesis of Peptide−Biphenyl Hybrids as Calpain Inhibitors,

[structure: see text] The combinatorial parallel synthesis of peptide-biphenyl hybrids on solid support using state of the art of peptide synthesis is reported. Key steps were the N to C addition of an amino moiety, hydrolysis of the methyl ester, and the absence of cross-linked compounds when the 2,2'-diamino-1,1'-biphenyl was incorporated. When tested for activity as calpain inhibitors, some of the compounds exhibited IC(50) values in the nanomolar range.

Substituted 2-iminopiperidines as inhibitors of human nitric oxide synthase isoforms.

A series of analogues of 2-iminopiperidine have been prepared and shown to be potent inhibitors of the human nitric oxide synthase (NOS) isoforms. Methyl substitutions on the 4-position (3) or 4- and 6-positions (8) afforded the most potent analogues. These compounds exhibited IC50 values of 0.1 and 0.08 microM, respectively, for hiNOS inhibition. Substitution with cyclohexylmethyl at the 6-position (13) afforded an inhibitor that showed the best selectivity for hiNOS versus heNOS (heNOS IC50/hiNOS IC50 = 64). Following oral administration, inhibitors were found to decrease serum nitrite/nitrate levels in an in vivo rat endotoxin assay. This series of 2-iminopiperidines were prepared via the described synthetic methodologies. The effect of ring substitutions on potency and selectivity for this class of cyclic amidines as NOS inhibitors is described.

Novel spirodihydrobenzofuranlactams as antagonists of endothelin and as inhibitors of HIV-1 protease produced by Stachybotrys Sp. I. Fermentation, isolation and biological activity.

Six novel spirodihydrobenzofuranlactams I - VI (1 - 6) and a related spirodihydrobenzofuranalcohol, the previously described natural compound L-671,776 (7), were isolated from cultures of two different Stachybotrys species. These secondary metabolites showed antagonistic effects in the endothelin receptor binding assay and inhibited HIV-1 protease. Both biological activities are novel for L-671,776 (7). The pseudosymmetric spirodihydrobenzofuranlactam VI (6) is the most potent representative of this class of compounds exhibiting IC50 values of 1.5 microM in the ET-A receptor binding assay and 11 microM in the HIV-1 protease inhibition assay.

Novel spirodihydrobenzofuranlactams as antagonists of endothelin and as inhibitors of HIV-1 protease produced by Stachybotrys sp. II. Structure determination.

Six novel Spirodihydrobenzofuranlactams I-VI (1-6) and a related spirodihydrobenzofuranalcohol, the previously described natural compound L-671, 776 (7), were isolated from cultures of two different Stachybotrys species. These secondary metabolites showed antagonistic effects in the endothelin receptor binding assay and inhibited HIV-1 protease. Both biological activities are novel for L-671, 776 (7). The pseudosymmetric spirodihydrobenzofuranlactam VI (6) is the most potent representative of this class of compounds exhibiting IC50 values of 1.5 μm in the ET-A receptor binding assay and 11 μM in the HIV-1 protease inhibition assay.

Non-peptide renin inhibitors containing 2-(((3-phenylpropyl)phosphoryl)oxy)alkanoic acid moieties as P2-P3 replacements.

A series of novel renin inhibitors containing 2-(((3-phenylpropyl)phosphoryl)oxy)alkanoic acid moieties as P2-P3 surrogates are presented. The P2-P3 mimetics were obtained from (omega-phenylalkyl)-phosphinic acids 1a-c and 2-hydroxyalkanoic acid benzyl esters 2a-f by N,N'-dicyclohexylcarbodiimide-mediated coupling and subsequent oxidation with sodium metaperjodate. Ester cleavage of these derivatives and coupling with P1-P1' transition-state mimetics I-VII provided highly selective compounds with inhibitory potencies in the lower nanomolar range. Small renin inhibitors, such as analogues 8c and 8h with molecular weights of 539 and 537, respectively, could be prepared. These compounds exhibited IC50 values of about 20 nM against human plasma renin. Compound 7i was examined in vivo for its hypotensive effect. In salt-depleted cynomolgus monkeys, 7i inhibited plasma renin activity almost completely and lowered blood pressure after oral administration of a dose of 30 mg/kg.