Synthesis and structure–activity relationships evaluation of benzothiazinone derivatives as potential anti-tubercular agents

N-Alkyl and heterocycle substituted 1,3-benzothiazin-4-one (BTZ) derivatives were synthesized. The anti-mycobacterial activities of these compounds were evaluated by determination of minimal inhibitory concentration (MIC) for Mycobacterium tuberculosis H37Ra and M. tuberculosis H37Rv. It was found that an extended or branched alkyl chain analog could enhance the potency, and activities of N-alkyl substituted BTZs were not affected by either nitro or trifluoromethyl at 6-position. Trifluoromethyl plays an important role in maintaining anti-tubercular activity in the piperazine or piperidine analogs. Compound 8o, which contains an azaspirodithiolane group, showed a MIC of 0.0001 μM against M. tuberculosis H37Rv, 20-fold more potent than BTZ043 racemate. These results suggested that the volume and lipophilicity of the substituents were important in maintaining activity. In addition, compound 8o was nontoxic to Vero cells and orally bioavailable in a preliminary pharmacokinetics study.     

Synthesis and structure–activity relationships of cassiarin A as potential antimalarials with vasorelaxant activity

Cassiarin A 1, a tricyclic alkaloid, isolated from the leaves of Cassia siamea (Leguminosae), shows powerful antimalarial activity against Plasmodium falciparum in vitro as well as P. berghei in vivo, which may be valuable leads for novel antimalarials. Interactions of parasitized red blood cells (pRBCs) with endothelium in aorta are especially important in the processes contribute to the pathogenesis of severe malaria. Nitric oxide (NO) reduces endothelial expression of receptors/adhesion molecules used by pRBC to adhere to vascular endothelium, and reduces cytoadherence of pRBC to vascular endothelium. Cassiarin A 1 showed vasorelaxation activity against rat aortic ring, which may be related with NO production. A series of a hydroxyl and a nitrogen-substituted derivatives and a dehydroxy derivative of 1 have been synthesized as having potent antimalarials against P. falciparum with vasodilator activity, which may reduce cytoadherence of pRBC to vascular endothelium. Cassiarin A 1 exhibited a potent antimalarial activity and a high selectivity index in vitro, suggesting that the presence of a hydroxyl and a nitrogen atom without any substituents may be important to show antimalarial activity. Relative to cassiarin A, a methoxy derivative showed more potent vasorelaxant activity, although it did not show improvement for inhibition of P. falciparum in vitro. These cassiarin derivatives may be promising candidates as antimalarials with different mode of actions.     

Synthesis and structure–activity relationships of novel benzofuran farnesyltransferase inhibitors

A series of benzofuran-based farnesyltransferase inhibitors have been designed and synthesized as antitumor agents. Among them, 11f showed the most potent enzyme inhibitory activity (IC₅₀ = 1.1 nM) and antitumor activity in human cancer xenografts in mice.     

Peptide deformylase inhibitors with retro-amide scaffold: Synthesis and structure–activity relationships

Peptide deformylase (PDF) is a metalloprotease catalyzing the removal of a formyl group from newly synthesized proteins. Thus inhibition of PDF activity is considered to be one of the most effective antibiotic strategies. Reported herein are the synthesis and structure–activity relationship studies of retro-amide inhibitors based on actinonin, a naturally occurring PDF inhibitor. Analysis of the structure–activity relationships led to the discovery of 7a, which exhibits potent enzyme inhibition and antibacterial activity against Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis.     

Synthesis,characterization, antimicrobial activity and structure–activity relationships of new aryldisulfonamides

A series of aromatic disulfonamide (1-8) derivatives and 4-methylbenzenesulfonyl hydrazide (9) were synthesized and characterized. All compounds were evaluated in vitro for their antimicrobial activity against Staphylococcus aureus ATCC 25953, Bacillus cereus ATCC 6633, Bacillus magaterium RSKK 5117, Escherichia coli ATCC 11230, Salmonella enterititis ATCC 13076 by microdilution and disc diffusion methods. Antimicrobial activity of the aromatic disulfonamides decreased as the length of the carbon chain increased. An analysis of the structure- activity relationship (SAR) along with computational studies showed that the most active compound (9) possessed low lipophilicity (AlogP=0.59) and high solubility (logS = -1.33).     

Synthesis and structure–activity relationships of C-glycosylated oxadiazoles as inhibitors of glycogen phosphorylase

A series of per-O-benzoylated 5-β-d-glucopyranosyl-2-substituted-1,3,4-oxadiazoles was prepared by acylation of the corresponding 5-(β-d-glucopyranosyl)tetrazole. As an alternative, oxidation of 2,6-anhydro-aldose benzoylhydrazones by iodobenzene I,I-diacetate afforded the same oxadiazoles. 1,3-Dipolar cycloaddition of nitrile oxides to per-O-benzoylated β-d-glucopyranosyl cyanide gave the corresponding 5-β-d-glucopyranosyl-3-substituted-1,2,4-oxadiazoles. The O-benzoyl protecting groups were removed by base-catalyzed transesterification. The 1,3,4-oxadiazoles were practically inefficient as inhibitors of rabbit muscle glycogen phosphorylase b while the 1,2,4-oxadiazoles displayed inhibitory activities in the micromolar range. The best inhibitors were the 5-β-d-glucopyranosyl-3-(4-methylphenyl- and -2-naphthyl)-1,2,4-oxadiazoles (K_i = 8.8 and 11.6 μM, respectively). A detailed analysis of the structure–activity relationships is presented.     

Synthesis and structure–activity relationships of novel indazolyl glucocorticoid receptor partial agonists

SAR was used to further develop an indazole class of non-steroidal glucocorticoid receptor agonists aided by a GR LBD (ligand-binding domain)-agonist co-crystal structure described in the accompanying paper. Progress towards discovering a dissociated GR agonist guided by human in vitro assays biased the optimization of this compound series towards partial agonists that possessed excellent selectivity against other nuclear hormone receptors.     

Ruthenium complexes endowed with potent anti-Trypanosoma cruzi activity: Synthesis,biological characterization and structure–activity relationships

Although effective against epimastigotes (proliferative form) and of low cytotoxicity in mammals, the aryl-4-oxothiazolylhydrazones (ATZ) display only limited activity against trypomastigotes (bloodstream form) of Trypanosoma cruzi. Considering the metal complexation approach with bioactive ligands as one possible strategy for improving the biological efficacy of ATZ, a set of eight new ruthenium–ATZ complexes (RuCl₂ATZCOD, COD is 1,5-cyclooctadiene) were prepared, chemically and biologically characterized, including in vitro assays against epimastigotes and trypomastigote forms of the parasite and also assessment of cytotoxicity in mammals. Two of these complexes presented antitrypanosomal activity at non-cytotoxic concentrations on mammalian cells and of higher potency than its metal–free ligands, while the metallic precursor [RuCl₂COD(MeCN)₂] showed only moderate antitrypanosomal activity. Comparative analysis between the ruthenium complexes and metal–free ligands demonstrated the usefulness of this approach, with the establishment of new SAR data. Additional pharmacological tests, including a DNA bond assay, gave rise to the proposal of a single preliminary explanation for the molecular origin of the bioactivity.     

Synthesis and structure–activity relationships of dehydroaltenusin derivatives as selective DNA polymerase α inhibitors

Herein, we describe the synthesis and structure–activity relationships of dehydroaltenusin derivatives as inhibitors of a mammalian DNA polymerase α. We have newly synthesized nine dehydroaltenusin derivatives modified at the side chains or benzoquinone moiety. We also achieved the first synthesis of desmethylaltenusin and desmethyldehydroaltenusin, metabolites of Alternaria sp. or Talaromyces flavus, respectively. Among all synthesized derivatives, demethoxydehydroaltenusin was the most selective inhibitor of DNA polymerase α. The o-hydroxy-p-benzoquinone (2-hydroxycyclohexa-2,5-dienone) moiety is essential for the inhibition of DNA polymerases. Substitution at the 5-position of dehydroaltenusin is important for the inhibitory potency. Because dehydroaltenusin is conjugated with N-acetylcysteine methyl ester at the o-hydroxy-p-benzoquinone moiety, one or more cysteine residues of DNA polymerase α may act as a target for this compound.     

Assessing the structure–activity relationships of fluorotelomer unsaturated acids and aldehydes with glutathione

Fluorotelomer alcohols (FTOHs) have been shown to degrade via abiotic and biotic mechanisms to perfluorocarboxylates (PFCAs) which are environmentally persistent and bioaccumulate in humans and wildlife depending on their chain length. Fluorotelomer unsaturated aldehydes (FTUALs) and acids (FTUCAs) are intermediate metabolites that form from the degradation of FTOHs. Their potential for toxicity is not yet defined and may be more significant compared to PFCAs. Past studies have shown that these intermediates form adducts with glutathione (GSH). The purpose of this study was to further assess the reactivity of these intermediate compounds. In vitro experiments were carried out in an aqueous buffer system (pH 7.4) where FTUCAs and FTUALs of varying chain lengths were reacted with GSH. To quantify the reactivity of FTUCAs and FTUALs, unreacted free GSH was derivatized with 5,5′-dithiobis(2-nitrobenzoic acid), its absorbance measured at 412 nm, and the percentage of unconjugated free GSH evaluated over time. EC₅₀ values were obtained for the reactions of GSH with acrolein and methyl methacrylate to assess the accuracy of the method, as well as for acrylic acid, FTUCAs, and FTUALs. The results of this study indicated that α,β-unsaturated aldehydes are comparatively the most reactive and reaction with GSH may be influenced by the length of the fluorinated tail. This is the first study to examine the relationship of FTUCAs and FTUALs with biological nucleophiles by quantifying their intrinsic reactivity.     

Synthesis and structure–activity relationships of sinenxan A derivatives as multidrug resistance reversal agents

Two types of sinenxan A derivatives with different side chains at C-5 were synthesized and evaluated for their in vitro multidrug resistant reversal activities. Several derivatives exhibited better activities than the positive control verapamil. The structure–activity relationships of these derivatives suggested that a carbonyl group at C-13 and the length of side chain at C-5 are important for the activity.     

Synthesis and structure–activity relationships of γ-carboline derivatives as potent and selective cysLT1 antagonists

A γ-carboline series of cysLT₁ receptor antagonists has been prepared. Some of the compounds show good potencies both, in vitro and in vivo, compared to the standard compounds.     

Synthesis,structure–activity relationships and biological evaluation of barbigerone analogues as anti-proliferative and anti-angiogenesis agents

A series of barbigerone analogues (7a–7w, 13a–13x) were designed, synthesized and biologically evaluated for their anti-proliferative and anti-angiogenic activities. Among these compounds, compound 13a exhibited the most potent inhibitory effect on the proliferation of HUVECs, HepG2, A375, U251, B16, and HCT116 cells (IC₅₀ = 3.80, 0.28, 1.58, 3.50, 1.09 and 0.68 μM, respectively). Compound 13a inhibited the angiogenesis in zebrafish embryo assay in a concentration-dependent manner. Furthermore, 13a also effectively inhibited the migration and capillary like tube formation of human umbilical vein endothelial cell in vitro. These results support the further investigation of this class of compounds as potential anti-proliferative and anti-angiogenesis agents.     

Synthesis and structure–activity relationships of novel furazan-3,4-diamide analogs as potent anti-cancer agents

This study describes the synthesis and structure–activity relationships of a series of furazan-3,4-diamide analogs. 1,2,5-Oxadiazole ring and electron-withdrawing substituent on the phenyl ring are proposed to be the important elements which contribute to a significant extent maximal potency of anti-proliferation effect.     

Redox-active dinitrodiphenylthioethers against Leishmania: Synthesis,structure–activity relationships and mechanism of action studies

BTB 06237 (2-[(2,4-dichloro-5-methylphenyl)sulfanyl]-1,3-dinitro-5-(trifluoromethyl) benzene), a compound previously identified through QSAR pharmacophore development and a virtual screen of the Maybridge database, possesses potent and selective activity against Leishmania parasites. In the present study, several analogs of BTB 06237 were synthesized and analyzed for activity against Leishmania axenic amastigotes, their ability to reduce the level of parasitemia in peritoneal macrophages, and their ability to generate reactive oxygen species (ROS) in L. donovani promastigotes. It was found that an aromatic ring must be present in the position occupied by the 2,4-dichloro-5-methylphenyl group in the lead compound, but changing the functional groups generally has little effect on the antileishmanial potency. Alterations to the 1,3-dinitro-5-(trifluoromethyl)benzene ring have more influence on antiparasitic activity with two aromatic nitro groups and a third electron-withdrawing group being required. This structural requirement corresponds with redox potential, the ability to generate ROS in the parasites, and dissipation of the mitochondrial membrane potential. Finally, we used this collection of data to design a new antileishmanial compound with strong activity in vitro and improved properties as an antileishmanial candidate.     

Synthesis and structure–activity relationships of N-substituted spiropiperidines as nociceptin receptor ligands: Part 2

A series of N-8 substituted analogs based upon the spiropiperidine core of the original lead compound 1 was synthesized. This lead has been elaborated to compounds to give compounds 2 and 3 (R = H) that exhibited high NOP binding affinity as well as selectivity against other known opioid receptors. These two series have been further functionalized at the amido nitrogen. The synthesis and structure–activity relationship (SAR) of these and related compounds are discussed.     

Synthesis and structure–activity relationships of carboxylic acid derivatives of pyridoxal as P2X receptor antagonists

Carboxylic acid derivatives of pyridoxal were developed as potent P2X₁ and P2X₃ receptor antagonists with modifications of a lead compound, pyridoxal-5′-phosphate-6-azophenyl-2′,5′-disulfonate (5b, iso-PPADS). The designing strategies included the modifications of aldehyde, phosphate or sulfonate groups of 5b, which may be interacted with lysine residues of the receptor binding pocket, to weak anionic carboxylic acid groups. The corresponding carboxylic acid analogs of pyridoxal-5′-phosphate (1), 13 and 14, showed parallel antagonistic potencies. Also, most of 6-azophenyl derivatives (24–28) of compound 13 or 14 showed potent antagonistic activities similar to that of 5b at human P2X₃ receptors with 100 nM range of IC₅₀ values in two-electrode voltage clamp (TEVC) assay system on the Xenopus oocyte. The results indicated that aldehyde and phosphoric or sulfonic acids in 5b could be changed to a carboxylic acid without affecting antagonistic potency at mouse P2X₁ and human P2X₃ receptors.     

Synthesis and structure–activity relationships of 2-acylamino-4,6-diphenylpyridine derivatives as novel antagonists of GPR54

GPR54 is a G protein-coupled receptor (GPCR) which was formerly an orphan receptor. Recent functional study of GPR54 revealed that the receptor has an essential role to modulate sex-hormones including GnRH. Though antagonists of GPR54 are expected to be novel drugs for sex-hormone dependent diseases such as prostate cancer or endometriosis, small molecule GPR54 antagonists have not been reported. We have synthesized a series of 2-acylamino-4,6-diphenylpyridines to identify potent GPR54 antagonists. Detailed structure–activity relationship studies led to compound 9l with an IC₅₀ value of 3.7 nM in a GPR54 binding assay, and apparent antagonistic activity in a cellular functional assay.     

Melatonin analogue new indole hydrazide/hydrazone derivatives with antioxidant behavior: Synthesis and structure–activity relationships

Melatonin (MLT) is a hormone produced in the brain by the pineal gland, from the amino acid tryptophan. It is also an antioxidant hormone with a particular role in the protection of nuclear and mitochondrial DNA. In recent years, many physiological properties of MLT have been described resulting in much attention in the development of synthetic compounds possessing the indole ring. Sixteen MLT analogue indole hydrazide/hydrazone derivatives were synthesized and in vitro antioxidant activity was investigated. Most of the compounds showed significantly higher activity than MLT at 10^{? 3} M and 10^{? 4} M concentrations.     

Synthesis and structure–activity relationships of 2-hydrazinyladenosine derivatives as A2A adenosine receptor ligands

A series of 2-hydrazinyladenosine derivatives was synthesized and investigated in radioligand binding studies for their affinity at the adenosine receptor subtypes with the goal to obtain potent and A_2AAR selective agonists and to explore the structure–activity relationships of this class of compounds at A_2AAR. Modifications included introduction of a second sugar moiety at position 2 of adenosine to form new bis-sugar nucleosides and/or modifications of the 2-position linker in different ways. The performed modifications were found to produce compounds with relatively high A_2AAR affinity and very high selectivity toward A_2AAR. The most potent bis-sugar nucleoside was obtained with the d-galactose derivative 16 which exhibited a K_i value of 329 nM at A_2AAR with marked selectivity against the other AR subtypes. In another set of compounds, compound 3 was modified via replacement of its cyclic structure with mono- and disubstituted phenyl moieties and the resulting hydrazones 10–14 were found to have low nanomolar affinity for A_2AAR. In addition to 3, compounds 10, 11 and 13 have been identified as the most potent compounds in the present series with K_i values of 16.1, 24.4, and 12.0 nM, respectively, at rat A_2AAR. Species differences were tested and found to exist in different rates. Functional properties of the most potent compounds 10, 11, 13 and 16 were assessed showing that the compounds acted as agonists at A_2AAR.