Synthesis and characterization of quinazoline derivatives: search for hybrid molecule as diuretic and antihypertensive agents

Abstract

To explore the pharmacological and structure–activity relationship of a series of N-substituted-(4-oxo-2-substituted-phenylquinazolin-3-(4H)-yl), substituted benzene sulfonamide derivatives (1–25) were synthesized from substituted anthranilic acids derived amino quinazolines and substituted benzene sulphonamides. All the synthesized compounds were evaluated for their diuretic (by Lipschitz et al. method), antihypertensive activity by non-invasive blood pressure (NIBP) using the tail-cuff method and anti-diabetic potential in rats. Six compounds showing significantly excellent activity were compared with metolazone, prazosin and diazoxide as standards. Compound N-[7-chloro-2-(4-methoxyphenyl)-4-oxoquinazolin-3(4H)-yl]-4 nitrobenzenesulfonamide (20) exhibited most potent of the series.     

Synthesis and Structure-activity Relationships of Amastatin Analogues,Inhibitors of Aminopeptidase A

Stereoisomers and analogues of amastatin, [(2S,3R)-3-amino-2-hydroxy-5-methylhexanoyl]-l-Val-l-Val-l-Asp, were synthesized and their inhibitory activities towards aminopeptidase A (AP-A) and other arylamidases tested. Among the four stereoisomers of a new amino acid residue in amastatin, the 2S stereoisomers exhibited strong activity. In a series of compounds in which the C-terminal amino acid of amastatin was substituted by other amino acids, the one containing Asp or Glu showed the strongest activity towards AP-A. In a series of compounds in which the second or third residue from the amino terminal of amastatin was substituted by other amino acids, the one containing hydrophobic amino acids showed strong activity. In the study of the relationship of the length of the peptide chain and inhibitory activity, the activity towards AP-A was seen to increase until the length of the peptide reached that of a tetrapeptide.     

Design, synthesis and pharmacological screening of a series of N1-(substituted) aryl-5,7-dimethyl-2-(substituted)pyrido(2,3-d)-pyrimidin-4(3H)-ones as potential histamine H1-receptor antagonists

A series of N1-(substituted)aryl-5,7-dimethyl-2-(substituted)pyrido(2,3-d)pyrimidin-4(3H)-one was designed on the basis of the triangular pharmacophoric requirement of histamine H1-receptor antagonists. The designed series was synthesized by cyclo-condensation of monoaryl thiourea with ethyl cyanoacetate in the presence of dry HCl gas to give N1-(substituted aryl)-2-mercaptopyrimidine-4(3H)-one, which on cyclo-condensation with acetylacetone gave the pyridopyrimidinone. Further methylation of the mercapto group at C-2 with methyl iodide followed by nucleophilic displacement of the methylmercapto group by various amines gave the targeted compounds. All the synthesized compounds were screened for histamine H1-receptor antagonistic activity by the in vitro method of inhibition of the isotonic contraction induced by histamine on isolated guinea pig ileum using cetirizine as a standard drug. All the compounds exhibited potent histamine H1-receptor antagonistic activity with pA2 values from 7.30- 9.75 (cetirizine, pA2 value 9.40). The potent compounds were screened for their in vivo antihistaminic activity by protection of animal from asphyxic shock. The sedative potential of potent compounds was checked on albino mice by photoactometer and they had comparative sedative potential to the standard drug cetirizine. None of the compound exhibited anticholinergic activity in the in vitro rat ileum model.     

Anti-HIV-1 peptides derived from partial amino acid sequences of CC-chemokine RANTES. Regulated upon activation,normal T-cell expressed and secreted

Fifteen acetyl-peptide-amides with partial amino acid sequences of RANTES (regulated upon activation, normal T-cell expressed and secreted), all Cys residues of which were substituted by Ala, were synthesized, and screened for anti-HIV-1 activity. Peptides corresponding to 1-10, 37-46, and 57-68 showed marked activity against CC-chemokine receptor 5-using HIV-1(JR-CSF) (% inhibition at 100 nM 69, 82, 76%, respectively). The results indicate that multiple regions, including the N-terminal part responsible for chemotactic activity, are involved in anti-HIV-1 activity of RANTES, yielding possible lead compounds for anti-HIV-1 agents.     

Synthesis, pharmacological evaluation and docking studies of N-(benzo[d]thiazol-2-yl)-2-(piperazin-1-yl)acetamide analogs as COX-2 inhibitors

The existing NSAIDs having number of toxicities emphasises the need for discovery of new non-toxic anti-inflammatory agents. In this Letter, we present the simple two step chemical synthesis, in vivo pharmacological screening and docking study of few N-(benzo[d]thiazol-2-yl)-2-(piperazin-1-yl)acetamide analogs. Different amino benzothiazoles were chloroacetylated and further reacted with substituted piperazines in presence of a base to get N-(benzo[d]thiazol-2-yl)-2-(piperazin-1-yl)acetamide analogs (A1-C4). These compounds were evaluated for anti-inflammatory activity by carragenan induced paw oedema method. Promising compounds were screened for toxicity by evaluating the ulcerogenic potential. Molecular docking experiments were carried out against COX-2 enzyme using Surflex-Dock GeomX programme of Sybyl software on Dell T-1500 workstation to confirm the mechanism of action of active compounds among the series. In silico study reveal the binding interactions of N-(benzo[d]thiazol-2-yl)-2-(piperazin-1-yl)acetamide analogs with COX-2 protein and is in agreement with the in vivo anti-inflammatory activity.     

Inhibition of Src kinase activity by 7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-heteroaryl-thieno[3,2-b]pyridine-6-carbonitriles

7-[(2,4-Dichloro-5-methoxyphenyl)amino]thieno[3,2-b]pyridine-6-carbonitriles with various heteroaryl groups at C-2 are inhibitors of Src kinase activity. Of these new analogs, compounds substituted at C-2 by a 3,5-furan or a 2,5-pyridine had the best activity in the Src enzyme and cell assays.     

Synthesis and biological evaluation of 2-aminothiazole derivatives as antimycobacterial and antiplasmodial agents

A series of compounds derived from the 2-amino-4-(2-pyridyl) thiazole scaffold was synthesized and tested for in vitro antimycobacterial activity against the Mycobacterium tuberculosis H37Rv strain, antiplasmodial activity against the chloroquine sensitive NF54 Plasmodium falciparum strain and cytotoxicity on a mammalian cell line. Optimal antimycobacterial activity was found with compounds with a 2-pyridyl ring at position 4 of the thiazole scaffold, a substituted phenyl ring at the 2-amino position, and an amide linker between the scaffold and the substituted phenyl. The antiplasmodial activity was best with compounds that had the phenyl ring substituted with hydrophobic electron withdrawing groups.     

2-(Substituted phenyl)amino analogs of 1-methoxyspirobrassinol methyl ether: Synthesis and anticancer activity

New analogs of indole phytoalexin 1-methoxyspirobrassinol methyl ether have been designed by replacement of its 2-methoxy group with 2-(substituted phenyl)amino group. Synthesized by spirocyclization methodology, trans- and cis-diastereoisomers of target compounds were isolated and evaluated as potential anticancer and antimicrobial agents. Their molecular geometries were refined by ab initio minimizations. Pharmacophore modeling and QSAR studies were performed in order to correlate their molecular structure and biological activity.     

Synthesis and NMR properties of novel 5,6-dihydroborauracil derivatives

Novel boron compounds - 5,6-saturated borauracil derivatives (4-bromo-5,6-dihydroborauracil, 4-hydroxy-5,6-dihydroborauracil and 4-methoxy-5,6-dihydroborauracil) are presented along with other boron compounds obtained from N-vinylurea: N-substituted β-boronic amino acid - 2-{[(dihydroxyborano-amino)(dihydroxyboranooxy)methyl]-amino}ethylboronic acid and substituted methoxy-borane O-[(1-amino-1-N-vinylamino)methyl]dihydroxyboronate.     

Synthesis, structural elucidation, DNA-PK inhibition, homology modelling and anti-platelet activity of morpholino-substituted-1,3-naphth-oxazines

A number of new angular 2-morpholino-(substituted)-naphth-1,3-oxazines (compound 10b), linear 2-morpholino-(substituted)-naphth-1,3-oxazines (compounds 13b-c), linear 6, 7 and 9-O-substituted-2-morpholino-(substituted)-naphth-1,3-oxazines (compounds 17-22, 24, and 25) and angular compounds 14-16 and 23 were synthesised. The O-substituent was pyridin-2yl-methyl (15, 18, and 21) pyridin-3yl-methyl (16, 19, and 22) and 4-methylpipreazin-1-yl-ethoxy (23-25). Twelve compounds were tested for their inhibitory effect on collagen induced platelet aggregation and it was found that the most active compounds were compounds 19 and 22 with IC(50)=55±4 and 85±4 μM, respectively. Furthermore, the compounds were also assayed for their ability to inhibit DNA-dependent protein kinase (DNA-PK) activity. The most active compounds were 18 IC(50)=0.091 μM, 24 IC(50)=0.191 μM, and 22 IC(50)=0.331 μM. Homology modelling was used to build a 3D model of DNA-PK based on the X-ray structure of phosphatidylinositol 3-kinases (PI3Ks). Docking of synthesised compounds within the binding pocket and structure-activity relationships (SAR) analyses of the poses were performed and results agreed well with observed activity.     

Synthesis and evaluation of uterine relaxant activity for a novel series of substituted p-hydroxyphenylethanolamines

Novel racemic 1-(4-hydroxyphenyl)-2-[3-(substituted phenoxy)-2-hydroxy-1-propyl]aminopropan-1-ol hydrochlorides (9a-h) were synthesized by condensing racemic 1-(p-hydroxyphenyl)-2-aminopropan-1-ol hydrochloride (6) with substituted aryloxymethyloxiranes (8a-h) in DMF in presence of anhydrous potassium carbonate and then reacting with dry hydrogen chloride gas. They were evaluated for uterine relaxant activity in vitro on isolated rat uterus and in vivo in pregnant rats. Their cAMP releasing potential was studied using rat uterus tissue homogenates by cAMP [3H] assay and cardiac stimulant potential was evaluated in dog. All compounds exhibited potent uterine relaxant activity in vitro and produced a significant delay in the onset of labour in pregnant rats; their cAMP releasing potential was higher than isoxsuprine hydrochloride except for 9b and 9c. Finally insignificant cardiac stimulant potential was noted for these compounds when compared to isoxsuprine hydrochloride.     

Synthesis of benzamide derivatives and their evaluation as antiprion agents

A new set of 5-(2-(pyrrolidin-1-yl)acetamido)-N-butyl-2-(substituted)benzamide and 5-(2-(piperidin-1-yl)acetamido)-N-butyl-2-(substituted) benzamide derivatives were synthesized in which as structural features the 2-(1-pyrrolidinyl)- or 2-(1-piperidyl)acetylamino group or a diphenylether moiety are associated to a benzamide scaffold. Their binding affinity for human PrP(C) and inhibition of its conversion into PrP(Sc) were determined in vitro; moreover, the antiprion activity was assayed by inhibition of PrP(Sc) accumulation in scrapie-infected mouse neuroblastoma cells (ScN2a) and scrapie mouse brain (SMB) cells. The results clearly indicate the benzamide derivatives as attractive lead compounds for the development of potential therapeutic agents against prion disease.     

Synthesis and antispasmodic activity of lidocaine derivatives endowed with reduced local anesthetic action

The present structure-activity relationship (SAR) study focused on chemical modifications of the structure of the local anesthetic lidocaine, and indicated analogues having reduced anesthetic potency, but with superior potency relative to the prototype in preventing anaphylactic or histamine-evoked ileum contraction. From the SAR analysis, 2-(diethylamino)-N-(trifluoromethyl-phenyl) and 2-(diethylamino)-N-(dimethyl-phenyl) acetamides were selected as the most promising compounds. New insights into the applicability of non-anesthetic lidocaine derivatives as templates in drug discovery for allergic syndromes are provided.     

Synthesis and QSAR studies on hypotensive 1-[3-(4-substituted phenylthio) propyl]-4-(substituted phenyl) piperazines

A series of 1-[3-(4-substituted phenylthio) propyl]-4-(substituted phenyl) piperazines has been synthesized and evaluated for hypotensive activity. The QSAR studies indicate that resonance and hydrophobic parameters of the aryl substituents are important for hypotensive activity. The similar role of resonance parameter in describing the variance of 5-HT(2A) receptor binding affinities of these compounds suggests a possible role of 5-HT(2A) receptors in mediating the hypotensive action of title compounds.     

Design,synthesis and pharmacological evaluation of omeprazole-like agents with anti-inflammatory activity

A new series of novel benzimidazole derivatives containing substituted pyrid-2-yl moiety and polyhydroxy sugar conjugated to the N-benzimidazole moiety has been synthesized and evaluated as orally bioavailable anti-inflammatory agents with anti-ulcerogenic activity. The anti-inflammatory and anti-ulcerogenic activities of these compounds were compared to diclofenac and omeprazole, respectively. In carrageenan-induced paw oedema assay, 2-methyl-N-((3,4-dimethoxypyridin-2-yl)methyl)-1H-benzimidazol-5-amine (12d) and 1-(1,2,3,5-tetrahydroxy-α-d-mannofuranose)-5-(((3,4-dimethoxypyridin-2yl)methyl)amino)-2-methyl-1H-benzimidazole (15d) displayed dose-dependent anti-inflammatory activities by decreasing the inflammation by 62% and 72%, respectively which is comparable to that of diclofenac (73%). In contrast to diclofenac, the anti-inflammatory activity of these compounds was not only free from any side effects on the gastric mucosa but also showed significant anti-ulcerogenic activity in rat pyloric ligation and ethanol-induced gastric ulcer models similar to that of omeprazole. Together, these findings suggest that 12d and 15d are potent anti-inflammatory agents with concurrent anti-ulcerogenic activity and support its clinical promise as a component of therapeutic strategies for inflammation, for which the gastric side effects are always a major limitation.     

Bacteriostatic, Fungistatic, and Algistatic Activity of Fatty Nitrogen Compounds

A total of 164 fatty nitrogen compounds, consisting of quaternary ammonium compounds, alkylamines, N-alkyl-1, 3-propylene diamines, substituted amino hydroxystearonitriles, substituted amino hydroxystearyl amines, and nitrogen-containing surfactants, were screened for bacteriostatic, fungistatic, and algistatic activity. The most active compounds were dodecylamine and dodecylamine acetate. A number of compounds were very active against gram-negative bacteria. Most of the surfactants were virtually nontoxic to all of the test organisms.     

Contrasting membrane localization and behavior of halogenated cyclobutanes that follow or violate the Meyer-Overton hypothesis of general anesthetic potency.

The membrane localization and properties of two halogenated cyclobutanes were examined using 2H and 19F NMR. The common predictors of potency indicate that these two compounds will have anesthetic activity; however, 1,2-dichlorohexafluorocyclobutane (c(CCIFCCIFCF2CF2)) is not an effective anesthetic, whereas 1-chloro-1,2,2-trifluorocyclobutane (c(CCIFCF2CH2CH2)) is an effective general anesthetic. Using 2H NMR, the effect of these compounds on the acyl chain packing in palmitoyl (d31) oleoylphosphatidylcholine membranes was examined. The addition of the anesthetic c(CCIFCF2CH2CH2) results in small increases in the segmental order near the headgroup, whereas segments deeper in the bilayer show decreases in order. These results are consistent with those obtained previously for halothane, isoflurane, and enflurane. On the addition of the nonanesthetic c(CCIFCCIFCF2CF2), the segmental order in vitually unchanged, except for a slightly changed order near the segents 10-12 of the palmitoyl chains. These results, and the 19F chemical shifts, indicate that the anesthetic c(CCIFCF2CH2CH2) exhibits a preference for the membrane interface, as do the other general anesthetics, whereas the nonanesthetic c(CCIFCIFCF2CF2) resides within the membrane hydrocarbon core. The compound c(CCIFCCIFCF2CF2) and other nonanesthetic halocarbons have lower molecular dipole moments compared to effective anesthetic halocarbons, which may account for their altered distribution within the membrane. These data strongly suggest that preferential localization of a halocarbon within the membrane interface is a predictor of anesthetic potency. Furthermore, the data indicate that the properties and forces in the membrane interface deserve consideration as mediators of anesthetic activity.     

Synthesis and preliminary screening of novel N-{2-[4-(substituted)piperazin-1-yl]-2-oxoethyl}acetamides as potential atypical antipsychotic agents

A series of N-{2-[4-(substituted)piperazin-1-yl]-2-oxoethyl}acetamides were synthesized as prospective novel atypical antipsychotic agents. Microwave irradiation of acetyl glycine (I) with substituted piperazines in the presence of DCC in DMF for about 3-5 min gave the titled compounds (P:1-7). All the synthesized compounds were screened for their in vivo pharmacological activity in Swiss albino mice. D(2) antagonism studies were performed using the climbing mouse assay model and 5-HT(2A) antagonism studies were performed using quipazine induced head twitches in mice. Among the synthesized compounds P4 was found to be the most active compound.