Biological activities of isatin and its derivatives

Isatin is an endogenous compound identified in humans that possesses a wide range of biological activities. Isatin has anxiogenic, sedative, anticonvulsant activities and acts as a potent antagonist on atrial natriuretic peptide receptors in vitro. A series of p-substituted isatin semicarbazones have shown anticonvulsant activity in MES, scPTZ and scSTY tests. Various isatin-N-Mannich bases of isatin-3-thiosemicarbazones have shown antiviral and tuberculostatic activity. Methisazone is an effective compound against variola and vaccinia viruses. The N-dimethyl and morpholino derivative of 5-methyl isatin and trimethoprim exhibited an EC50 of more than 4.3 and 17.7 mg mL(-1), respectively. Isatin (3-o-nitrophenyl) hydrazone has shown activity against Walker carcinoma-256. Various substituted indolinones showed antitubercular activity against M. tuberculosis H37Rv with MIC ranging from 10-20 microg mL(-1). Isatin derivatives of Mannich bases had fibrinolytic, muscle relaxant, antiallergic, immunosuppressant, and antithrombotic activity. Isatin showed cardioinhibitory effect on frog heart, and hypotensive, respiratory depression and antidiuretic effects.     

Sedative-hypnotic profile of novel isatin ketals

Isatin (1H-indol-2,3-dione) is an endogenous compound found in many tissues and fluids. Isatin and its derivatives exert pharmacological effects on the central nervous system, including anxiogenic, sedative and anticonvulsant activities. Two new groups of isatin derivatives were synthesized (nine dioxolane ketals and nine dioxane ketals) and studied for their sedative, hypnotic and anesthetic effects using pentobarbital-induced sleeping time, locomotor activity evaluation and intravenous infusion. The dioxolane ketals were more potent than dioxane ketals for inducing sedative-hypnotic states, causing up to a three-fold increase in pentobarbital hypnosis. The dioxolane ketals produced sedation, demonstrated by decreased spontaneous locomotor activity in an open field. Hypnosis and anesthesia were observed during intravenous infusion of 5'-chlorospiro-[1,3-dioxolane-2,3'-indolin]-2'-one (T3) in conscious Wistar rats. Complete recovery from hypnosis and anesthesia required 39.1+/-7.3 and 6.8+/-2.4 min, respectively. Changes in hemodynamic parameters after infusion of 5.0 mg/kg/min were minimal. These findings suggest that these new isatin derivatives represent potential candidates for the development of new drugs that act on the central nervous system and may lead to a new centrally acting anesthetic with no toxic effects on the cardiovascular or respiratory systems.     

Isatin–azole hybrids and their anticancer activities

Isatin and azole moieties, which have the ability to form various noncovalent interactions with different therapeutic targets, are common pharmacophores in drug development. Isatin and azole derivatives possess promising in vitro and in vivo anticancer activity, and many of them, such as semaxanib, sunitinib, and carboxyamidotriazole, could be used to treat various cancers. Thus, it is conceivable that hybridization of the isatin moiety with azole may provide a valuable therapeutic intervention for the treatment of cancer. Substantial efforts have been made to develop isatin–azole hybrids as novel anticancer agents, and some of the isatin–azole hybrids exhibited considerable activity. This review emphasizes isatin–azole hybrids with potential anticancer activity, covering articles published between 2010 and 2019. The structure–activity relationships as well as the mechanisms of action are also discussed to provide insights for the rational design of more effective candidates.     

Synthesis and bioevaluation of Schiff and Mannich bases of isatin derivatives with 4-amino-5-benzyl-2,4-dihydro-3H-1,2,4-triazole-3-thione

Isatin (2,3-dioxindole) and its derivatives show a wide range of biological activities. In the present study, a series of Schiff and Mannich bases of isatin derivatives were prepared using 4-amino-5-benzyl-2,4-dihydro-3H-1,2,4-triazole-3-thione. The structures of these derivatives were characterized by IR, ¹H NMR and elemental analysis. In vitro antimicrobial activities were evaluated by agar dilution method and the zone of inhibition values of these derivatives were compared with ciprofloxacin and fluconazole. Chloro and Bromo groups at fifth position of isatin broaden the spectrum of antibacterial activity against S. aures, P. aeruginoa, and E. coli, respectively. For the antifungal activity, the compound 6h showed equipotent activity against A. niger. The remaining majority of the compounds were found active in the biological screening. The efforts were also made to establish structure activity relationships among synthesized compounds.     

Reaction of isatin with thiocarbohydrazide: a correction.

Heterocycles containing the indole ring system include some novel pharmacologically active compounds. Isatin and its N-acetylisatin are extremely versatile intermediates in the construction of a variety of heterocyclic systems when reacted with thiosemicarbazide derivatives. Literature survey revealed various interesting reactions of thiocarbohydrazide with cyclic ketones, cyclic 1,2-diketones and isatin.     

Isatins inhibit cyclooxygenase-2 and inducible nitric oxide synthase in a mouse macrophage cell line

Isatin is a versatile compound with a diversity of effects. We designed to investigate the inhibitory effect of isatin derivatives on lipopolysaccharide/interferon-gamma-induced expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) proteins, production of prostaglandin E(2) (PGE(2)), nitric oxide (NO), tumor necrosis factor (TNF-alpha), and their capacity to scavenge NO. Isatins inhibit TNF-alpha production and iNOS and COX-2 protein expression resulting on reduced levels of NO and PGE(2). Our results indicate isatin and it derivatives as inhibitors of iNOS and COX-2 enzymes, which might be used as anti-inflammatory and antitumoral agents.     

Pharmacological activity of novel 2-hydroxyacetophenone isatin derivatives on cardiac and vascular smooth muscles in rats

Isatin (1H-indole-2,3 dione) is an endogenous compound with biological activities. Many of its derivatives have pharmacological effects, including inhibition of cyclic guanosine monophosphate levels in cardiac tissue; sedative-hypnotic profiles; anticonvulsant, analgesic, antithermic, and anti-inflammatory activities; and anxiolytic, antimicrobial, and proapoptotic effects. Carbamates derived from isatin have a vasorelaxant profile. This study investigated the activity of 2 novel 2-hydroxyacetophenone derivatives of isatin (named MB101 and MB130) on the contractility of rat aorta and papillary muscles. Both compounds induced a concentration-dependent relaxation (5-100 μM) in the endothelium-intact aorta that was abolished by N-nitro-L-arginine methyl ester. Atropine, a muscarinic receptor antagonist, significantly prevented vasodilatation of 100 μM MB101. In contrast, atropine caused no significant alteration in MB130-induced vasorelaxation. Naloxone, a nonselective opioid receptor antagonist, completely prevented the relaxing effect of MB101 and MB130 at all concentrations. In papillary muscles, only MB130 induced a significant depression, and this contractile response was not altered by propranolol and atropine. Both the compounds reduced systolic and diastolic pressures in a dose-dependent manner in anesthetized rats. The 2-hydroxyacetophenones produced direct effects on vascular tonus through either muscarinic or opioid pathways. MB130 produced cardiac depression by opioid receptors and bradykinin because pretreatment HOE140 or with naloxone, an antagonist of type-2, bradykinin were able to partially block the decrease in twitch amplitude in papillary muscles induced by MB130. These findings provide information for designing new strategies for the treatment of cardiovascular disorders.     

Cyclic GMP excretion blocked by isatin administration under conditions of fluid overload

Isatin is a potent inhibitor of atrial natriuretic peptide (ANP) receptors and ANP-induced generation of cGMP in vitro. This study was designed to determine whether it had a similar effect in vivo, using a model of fluid overload known to induce ANP. We confirmed that this model increased urinary output of cGMP 3 hr after volume loading, and showed that this effect was blocked by i.p. injection of isatin (50 mg/kg). Isatin had no effect on urine volume or sodium output. However, isatin did have an effect on plasma protein concentration, both compared with control values, compatible with shifting fluid to the vascular compartment, and after volume overload, in which it normalised such a shift. Isatin thus affected both the generation of cGMP and fluid balance in vivo.     

Pharmacological role of isatin, an endogenous MAO inhibitor

Isatin (indole-2,3-dione) has been found in mammalian tissues as one of major components of tribulin, a postulated endogenous marker of stress and anxiety. I previously identified isatin as an endogenous inhibitor of monoamine oxidase (MAO) in the human urine and the brain of stroke-prone spontaneously hypertensive rats (SHRSP) using GC-MS. A single dose of isatin significantly increased norepinephrine (NE) and 5-hydroxytryptamine (5-HT) concentrations measured 2 h later in the various brain regions of normotensive Wistar Kyoto rats (WKY). Striatal acetylcholine (ACh) and dopamine (DA) levels significantly increased 2 h after the administration of isatin. Perfused through a microdialysis probe, isatin also produced a significant and concentration-dependent increase in the ACh and DA concentration in the perfusate from the rat striatum. In the patients with Parkinson's disease, urinary isatin concentrations tended to increase according to the severity of disease, as classified by the Hoehn and Yahr criteria. Isatin significantly increased striatal DA levels in a rat model of Parkinson's disease. Isatin may play a role in the regulation of the brain levels of ACh and DA. Furthermore, isatin has a wide spectrum of biological properties: (a) a marker of stress and anxiety, (b) an inhibitor of a number of enzymes, (c) an anti-seizure agent, (d) an inhibitor of benzodiazepin receptors and ANP binding to its receptors.     

Isatin dimers and their biological activities

Dimerization is a promising strategy to develop novel drug candidates that could extend the biological spectrum, enhance the activity, overcome drug resistance, as well as improve pharmacological, pharmacokinetic, and physicochemical profiles. Isatin dimers possess a broad spectrum of biological properties and the isatin dimer indirubin has already been used in the clinic, revealing the potential of isatin dimers as putative drugs. This review covers the recent advances of isatin dimers as pharmacologically significant scaffolds and the structure–activity relationship to set up the direction for the design and development of isatin dimers with higher efficiency and lower toxicity.     

Effects of isatin, an endogenous MAO inhibitor, on dopamine (DA) and acetylcholine (ACh) concentrations in rats

Isatin (indole-2,3-dione), an endogenous inhibitor of monoamine oxidase (MAO), has several physiological properties for stress and anxiety. We previously identified isatin in the brain of stroke-prone spontaneously hypertensive rats (SHRSP) using gas-chromatography mass spectrometry. This study elucidated the effects of isatin on the ACh and DA levels of brain tissues in rats. Furthermore, we evaluated the effect of isatin on DA levels in a rat model of Parkinson's disease induced by Japanese encephalitis virus. Striatal ACh and DA levels significantly increased at 2 hours after isatin (50-200 mg/kg, i.p.) administration. Perfused through a microdialysis probe, isatin (10(-6)-10(-4) M) also produced a significant and concentration-dependent increase in the ACh and DA concentrations in the perfusate from the rat striatum. Furthermore, urinary isatin concentrations in patients with Parkinson's disease tend to increase according to the severity of disease. Isatin (100 mg/kg, i.p.) significantly increased striatal DA levels in a rat model of Parkinson's disease. These results suggest that urinary isatin may become a diagnostic marker for the clinical severity of Parkinson's disease and that endogenous isatin, a new biological modulator, may play a role in the regulation of the brain levels of ACh by increasing the level of DA under stress.     

Effect of isatin on nitric oxide-stimulated soluble guanylate cyclase from human platelets

Isatin, an endogenous indole, has previously been shown to inhibit atrial natriuretic peptide (ANP)-stimulated particulate guanylate cyclase activity. Here, it was shown that it can be transported to human platelets where it inhibited nitric oxide (NO)-stimulated soluble guanylate cyclase activity obtained from human platelets. The effect was most pronounced at 10(-8)M isatin and is the most potent effect of isatin yet observed. The dose response curve was bell shaped with higher doses becoming less effective. The maximal inhibition observed was of 40%. Isatin had no effect on protoporphyrin IX-stimulated guanylate cyclase. Isatin-dependent regulation of ligand-stimulated guanylate cyclases is suggested to promote a stress-induced switch in metabolism.     

Inhibitory potency of some isatin analogues on human monoamine oxidase A and B.

Isatin is an endogenous compound which acts as a selective inhibitor of monoamine oxidase (MAO) B. In this study a range of isatin analogues were tested for their in vitro inhibition of human MAO A and B. Most of the analogues were less potent than isatin. Hydroxylation of the aromatic ring changed the inhibitory potency in favour of MAO A, with 5-hydroxyisatin being a potent and selective MAO A inhibitor (IC50 8 microM). Isatinic acid, which is formed reversibly from isatin at alkaline pH, showed no inhibition.     

Synthesis, antibacterial, antifungal and anti-HIV evaluation of Schiff and Mannich bases of isatin derivatives with 3-amino-2-methylmercapto quinazolin-4(3H)-one

Isatin (Indole 2,3-dione), its 5-chloro and 5-bromo derivatives were added to 3-amino-2-methylmercapto quinazolin-4(3H)-one to form Schiff bases and the N-Mannich bases of these compounds were synthesized by reacting with formaldehyde and several secondary amines. Their chemical structures have been confirmed by means of their IR, 1H-NMR data and by elemental analysis. Investigation of antimicrobial activity of compounds was done by an agar dilution method against 26 pathogenic bacteria, 8 pathogenic fungi and anti-HIV activity against replication of HIV-1 (III B) in MT-4 cells. Among the compounds tested 5-chloro-3-(3',4'-dihydro-2'-methylmercapto-4'-oxoquinazolin-3'-yl )- l-morpholino methyl imino isatin was the most active antimicrobial agent.     

Anxiogenic activity of isatin, a putative biological factor, in rodents

Isatin (2,3-dioxoindole) has been proposed as a new biological factor, responsible for at least part of the activity of tribulin, an endogenous monoamine oxidase and benzodiazepine receptor binding inhibitory factor, which may serve as an endocoid marker of stress and anxiety. The putative anxiogenic activity of isatin was investigated in rats and mice. The doses chosen for the study, namely 15 mg/kg i.p. in mice and 20 mg/kg i.p. in rats, were based on preliminary behavioural studies. Yohimbine, a well established anxiogenic agent, was used for comparison and used at doses of 2 and 2.5 mg/kg i.p. in mice and rats, respectively. The experimental paradigms chosen have been shown to stand the tests of validity and reliability. Isatin induced significant anxiogenic activity in the open-field and elevated plus-maze tests in mice, and the social interaction test in rats, which were comparable to those induced by yohimbine. In addition, both isatin and yohimbine attenuated the effects of the anxiolytic agent diazepam in the open-field test. The investigations indicate that isatin has significant anxiogenic effect and support the contention that it and/or its biotransformation products may be responsible for at least part of the activity of tribulin demonstrated previously in animal models and in clinical situations of stress and anxiety.     

Synthesis, antibacterial, antifungal and anti-HIV evaluation of Schiff and Mannich bases of isatin and its derivatives with triazole

Isatin (indole 2,3-dione) and its 5-chloro and 5-bromo derivatives have been reacted with 3-(4'-pyridyl)-4-amino-5-mercapto-4-(H)-1,2,4-triazole to form Schiff bases and the N-Mannich bases of these compounds were synthesised by reacting them with formaldehyde and several secondary amines. Their chemical structures have been confirmed by means of their IR, 1H-NMR data and by elemental analysis. Investigation of antimicrobial activity of compounds was done by agar dilution method against 27 pathogenic bacteria, 8 pathogenic fungi and anti-HIV activity against replication of HIV-1 (III B) in MT-4 cells. Among the compounds tested 1-(piperidinomethyl) 5-bromo 3-[3'-(4"-pyridyl)-5'-mercapto-4'-(H)-1',2',4'-triazol 4'-yl]imino isatin showed the most favourable antimicrobial activity.     

Synthesis, DNA-binding, and interferon-inducing properties of isatin and benzoisatin hydrazones

The ability of isatin derivatives (in particular, aminoacetylhydrazones) to intercalate into DNA and to induce interferon secretion is demonstrated for the first time. The toxicity of isatin derivatives is much lower and its interferon inducing activity is somewhat lower as compared to the analogous benzoisatin derivatives. The DNA affinity of benzoisatin derivatives is two orders of magnitude greater than that of isatin derivatives. __________ Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 40, No. 11, pp. 15–22, November, 2006.     

5-HT(2A/2C) receptor agonist-induced increase in urinary isatin excretion in rats: reversal by both diazepam and dexamethasone.

Isatin, a stress-related biological substance, increases in rat urine in association with elevated catecholamine biosynthesis during stress. The goal of this study was to unravel how the biosynthetic pathway of isatin is related to stress response. The importance of the serotonergic compounds in anxiety, which is the major emotional process of stress response, has emerged. m-Chlorophenylpiperazine (m-CPP), a 5-HT(1A/1B/2A/2C) receptor agonist, and (+/-)-1-(4-iodo-2,5-dimethoxyphenyl)-2-aminopropane hydrochloride [(+/-)-DOI], a 5-HT(2A/2C) agonist, both of which have anxiogenic properties, induced a marked increase in 24-hr urinary isatin excretion, whereas neither 1-(m-chlorophenyl)-biguanide (m-CPBG), a 5-HT3 agonist, nor 2-methyl-5-HT, a 5-HT(3,4) agonist, affected urinary isatin excretion. 5-HT(2A/2C) receptor antagonists such as ketanserin and ritanserin prevented the increase in urinary isatin excretion induced by the 5-HT(2A/2C) receptor agonist m-CPP. These findings are the first to provide evidence that pharmacological substances cause increases in urinary isatin excretion via specific 5-HT receptors, probably 5-HT(2A/2C) receptors. In addition, both the synthetic glucocorticoid dexamethasone and diazepam prevented the m-CPP-induced increase in urinary isatin excretion. These observations suggest that the mechanism by which m-CPP elicits enhancing effects on urinary isatin excretion has something in common with stress response involving activation of hypothalamic CRF cells and the sympathetic nervous system.     

2,3-吲哚醌对血管内皮细胞生长因子的影响及作用机制研究

目的:研究2,3-吲哚醌在体外对人神经母瘤细胞(SH-SY5Y)分泌血管内皮细胞生长因子(VEGF)的影响,探讨其作用机制。方法:采用酶联免疫吸附测定法检测VEGF蛋白分泌水平;反转录-聚合酶链反应测定VEGF信使核糖核酸(mRNA)的相对表达水平;Western-blot测定磷酸化的有丝分裂原激活的蛋白激酶(pp42/pp44)的相对表达量。结果:2,3-吲哚醌作用细胞24h后,VEGF分泌量明显降低,mRNA相对表达水平下降,pp42/pp44的相对表达量降低。结论:2,3-吲哚醌能抑制SH-SY5Y细胞分泌VEGF蛋白和mRNA的表达,其作用可能与改变有丝分裂原激活的蛋白激酶磷酸化水平有关。     

The structure-activity relationships of the antiviral chemotherapeutic activity of isatin β-thiosemicarbazone

As part of an investigation devoted to the development of new antiviral agents a compound of established antiviral activity has been subjected to systematic structural modification. The structure-activity data so obtained have been used in the design of new compounds, some of which are described. The compound chosen was isatin β-thiosemicarbazone, which has high activity against neurovaccinia infection in mice, and a 4-point parallel-line assay of in vivo chemotherapeutic activity has been developed, which has enabled the activity of the derivatives to be determined against isatin β-thiosemicarbazone as a standard. The overall dimensions of the isatin β-thiosemicarbazone molecule appear to be nearly maximal for the retention of high activity, as all substituents in the aromatic ring decrease the activity irrespective of their nature or position. The projection of the -CS.NH₂ group in relation to the ring nitrogen was found to be critical, as the α-thiosemicarbazone was inactive. A number of modifications of the side-chain were investigated:all led to reduction or loss of antiviral activity. The antiviral activity showed a positive correlation with chloroform solubility over a considerable range. The most active compound encountered was 1-ethylisatin β-thiosemicarbazone, with an activity of 286 (isatin β-thiosemicarbazone100). Isatin β-thiosemicarbazone showed no activity against 15 other viruses, and 20 related compounds showed on activity against ectromelia.