Anticancer effect evaluation in vitro and in vivo of iridium(III) polypyridyl complexes targeting DNA and mitochondria.

Int.J.Curr.Microbiol.App.Sci (2022) 11(01): 61-77 International Journal of Current Microbiology and Applied Sciences ISSN: 2319-7706 Volume 11 Number 01 (2022) Journal homepage: http://www.ijcmas.com Review Article https://doi.org/10.20546/ijcmas.2022.1101.009 Isatin: A Short Review of their Antimicrobial Activities Ashutosh Pathak 1 1,3* , P. Malairajan1, Arti Gautam1 and Shibu Das 2 Department of Pharmaceutical Sciences, Sam Higginbottom University of Agriculture, Technology and Sciences (SHUATS), Prayagraj, Uttar Pradesh - 211007, India 2 Department of Pharmacy, Maharishi University of Information Technology (MUIT), Lucknow, Uttar Pradesh - 226013, India 3 Department of Pharmaceutical Chemistry, Maharana Pratap School of Pharmacy, MohanLal Ganj Lucknow, Uttar Pradesh-226301 India *Corresponding author ABSTRACT Keywords Isatin, heterocyclic synthesis, analgesic, anti-inflammatory activity, ecofriendly Article Info Received: 08 December 2021 Accepted: 31 December 2021 Available Online: 10 January 2022 Isatin(2, 3-dioxindate), a particularly effective scaffold with a variety of pharmacological actions, has been developed due to its therapeutic significance in organic and medicinal chemistry. Many researchers have been drawn to this skeleton because of its diverse biological response profile and its multiple possibilities against a variety of activities. Sandmeyer's and Stolle processes are two typical ways for synthesizing isatin derivatives. Many researchers have taken advantage of the isatin moiety by using NH at the first position, C2 and C3 carbonyl positions for the creation of numerous derivatives with varying biological activities. Design strategies for the synthesis of isatin-containing heterocyclics have been discussed in this review paper using several approaches. The chemistry, synthesis, biological and pharmacological action, SAR, and advanced uses of the isatin moiety are all covered in this paper. The progress in the use of isatins for organic synthesis over the previous twenty-five years, as well as a study of their biological and pharmacological properties, are given, together with supplemental data. al., 2001). Isatin, also known as 1H-indole-2, 3dione, is an indole derivative and the first organic compound to be synthesised. It was discovered in 1841 by Bayer, Erdman, and Laurent as a product of the oxidation of indigo dye with nitric acid and chromic acids, resulting in bright orange coloured monoclinic crystals of isatin. Isatin is naturally present in plants of the genus Isatis. (Joaquim et al., Introduction In modern environment, microbial infections are a major cause of a variety of health problems. Heterocyclic compounds, which cross the gap between natural and synthetic, have recently been discovered to occur abundantly in nature and have proven to be extremely important to life (Elleby et 61 Int.J.Curr.Microbiol.App.Sci (2022) 11(01): 61-77 2001) Sumpter published the first overview of this compound's chemistry in 1954, followed by Popp in 1975 and a third review on the use of isatin as a precursor for the synthesis of other heterocyclic compounds in 1975. Isatin can be found in nature in plants of the genus Isatis, such as the melosatin alkaloids (methoxy phenylpentylisatins) obtained from the Caribbean tumorigenic plant Melochiatomentosa (Rastogi et al., 2011; Prasad, 2012), in Calanthe discolour LINDL (Varvounis et al., 2004) and in Couroupitaguianensis AubL (Silva et al., 2011), as well as in the secretion of the parotid gland (Yoshikawa et al., 1998; Ischia et al., 1988) 6-(3'-methylbuten-2'-yl) isatin was recovered from Streptomyces albus, and 5-(3'-methylbuten-2'yl) isatin was isolated from Chaetomium globosum. is then isolated and treated with concentrated sulphuric acid to give isatin in >75 percent of the time. Anilines having electron-withdrawing substituents, such as 2-fluoroaniline, and some heterocyclic amines, such as 2-aminophenoxathine, are good candidates for the procedure (Johansson et al., 2013; Anne et al., 2009). The Stolle isatin synthesis The Stolle approach is the most prominent alternative to Sandmeyer's procedure. Anilines are reacted with oxalyl chloride to produce an intermediate chlorooxalylanilide, which can be cyclized in the presence of a Lewis acid, typically aluminium chloride or BF3. Et2O has been used to make the equivalent isatin, but TiCl4 has also been employed (Loloiu and Maior, 1997). Isatin is also a component of coal tar and is used as a colour reagent for the amino acid proline, resulting in a blue derivative (Elliott and Gardner, 1976; 2012). Isatin can be found in mammalian tissues and the rat brain (mostly in the hippocampus and cerebellum), where it acts as a biochemical modulator (Hou et al., 2008). In vitro research have shown that isatin and its derivatives are extremely effective against genotoxic and mutagenic disorders, although the genotoxic and mutagenic potential of isatin has not been thoroughly proven or documented in vivo. Isatin was first identified as a selective inhibitor of monoamine oxidase (MAO) and was given the name "Tribulin" (Gang et al., 2011). Isatin is made up of a six-membered benzene ring and a nitrogen-containing five-membered ring. Although both rings are in the same plane, one is aromatic while the other is anti-aromatic. The Martinet isatin synthesis Isatin is made by reacting an amino aromatic molecule with an oxomalonate ester or its hydrate in the presence of an acid to produce a 3-(3-hydroxy-2oxindole) carboxylic acid derivative, which can then be further oxidatively decarboxylated to produce isatin (Gassman et al., 1977). The Gassmanisatin synthesis The synthesis and subsequent oxidation of an intermediate 3- methylthio-2- oxindole leads to the creation of substituted isatin (40-81 percent yield) (David et al., 2007). Metalation of anilideisatin synthesis Synthesis of Isatin derivatives The ortho-metalation (DoM) of N-pivaloyl- and N(t-butoxycarbonyl)-anilines is a new method for synthesising isatin. After deprotection and cyclization of the intermediate a-ketoesters, thedianions are treated with diethyl oxalate, and isatins are produced. For the synthesis of 4substituted isatins from meta-substituted anilines, this approach has the advantage of being regioselective (Nataša et al., 2013). Sandmeyer isatin synthesis The Sandmeyer method for isatin synthesis is the most ancient and widely used method for isatin synthesis. It's made by cyclizing aniline's condensation product with chloral hydrate and hydroxylamine hydrochloride in aqueous sodium sulphate to produce an isonitrosoacetanilide, which 62 Int.J.Curr.Microbiol.App.Sci (2022) 11(01): 61-77 gram-negative pathogens, all of the novel compounds showed considerable and improved antimicrobial efficacy (Trivedi et al., 2021). Chemistry of Isatin derivatives The pyrrole ring is fused with the benzene ring in the isatin ring system. The pyrrole ring is a fivemembered ring with one nitrogen in its ring structure. (Prasad, 2012) It was the first chemical to display the tautomerism phenomena. It is a lactamlactim tautomerism system in which the two forms are: Wang et al., in 2020 The inclusion of the natural substance moenomycin A, which inhibits the peptidoglycan transferase (PGT) enzyme, resulted in a variety of novel antimicrobial drugs. The most effective molecule was (V), which had MIC values of 6 g/mL for MSSA, MRSA, B. subtilis, and 12 g/mL for E. coli protein (PBP-1b). The hydrophilic part of the chemical interacts with the enzyme's active site, whereas the hydrophobic part interacts with the enzyme's transmembrane region in the cell wall (Wang et al., 2020). The production of N- and O alkyl Isatins proves the existence of the aforementioned tautomeric system in isatin. The former is made by reacting methyl iodide with the sodium salt of isatin, whereas the latter is made by reacting methyl iodide with the silver salt of isatin (Pal et al., 2011; Aggarwal, 2009). Mangasuli et al., (2020) Synthesized named compounds including Isatin-dithiocarbamate hybrids have emerged as a viable antimicrobial agent contender. He discovered that the majority of Compound had potent antibacterial action against A. flavus, T. harzianum, P. chrysogenum, and Candida albicans bacterial strains. In comparison to the commonly used Fluconazole, the chemical (3e) has showed excellent antifungal activity. These chemicals were created using both conventional and microwave irradiation methods. In addition to additional benefits such as gentle reaction conditions, high yields of products in a shorter reaction time, and a quick workup procedure, the microwave approach is cost-effective (Mangasuli et al., 2020). Synthetic methodologies of Isatin (1H-indole-2,3dione) For the conversion of Isatins to other heterocyclic methods, numerous synthetic techniques have been outlined. One of the following strategies can be used to generalise this method. Indoles and derivatives are formed by total or partial reduction of the heterocyclic ring. Heterocyclic ring oxidation, such as the conversion of isatin to isatoic anhydride, followed by conversion to various heterocyclic systems, as shown in Figure 1. Nucleophillic addition at position C-3, followed by a cyclization process (figure 2), with or without N1C2 bond cleavage, or spiroannelation at position C3, as shown in figure 2. A nucleophillic substitution at position C-2 causes the heterocyclic ring to open. As shown in Figures 3 and 4, this process can be followed by intramolecular or intermolecular exotrig cyclization. Bakht et al., (2020) Graphene oxide (GO) catalyst in deep eutectic solvent (DES) as a green media was used to synthesise isatin-thiazolidine hybrids. Antibacterial and cytotoxic properties of all produced compounds were tested in vitro. Compounds with higher antibacterial activity against Gram-positive bacteria than Gram-negative bacteria, he discovered. He also observed that chemicals with electron-withdrawing groups like bromo, fluoro, and nitro had stronger bacterial suppression than those with electron-donating substituents like methyl and hydroxyl groups. (Bakht et al., 2020) Antimicrobial Trivedi et al., (2021) The production of a ferroceneappended isatin 2,4-thiazolidinedione molecular hybrid connected by a triazole moiety has been reported. Against a number of gram-positive and 63 Int.J.Curr.Microbiol.App.Sci (2022) 11(01): 61-77 Pashirova et al., (2019) described the synthesis of Isatin-3-acylhydrazones with variable hydrophobicity quaternary ammonium moiety. The hydrophilic-lipophilic balance of -amphiphiles, as well as solvent polarity, influenced biological activity. Low hazardous ammonium salts showed selective antibacterial action against Gram-positive bacteria (S. aureus 209p and B. cereus 8035) and the fungus Candida albicans 855–653. hybrids exhibited significant activity against the pathogens studied. The structure-activity and structure-cytotoxicity relationships were also investigated, and it was discovered that (Gao et al., 2019). Substituents in the R1 position had a significant impact on activity. Electron-donating methyl performed better than electron-receiving fluoro. Antimicrobial agents and drug solubilization may be indicated for newly produced 1-dodecylisatin derivatives having a quaternary ammonium component, particularly for medications capable of stacking interactions (Pashirova et al., 2019). The antibacterial activity was similarly influenced by substituents on the phenyl ring. Substituted analogues at the C-5 position were more powerful than analogues at the C-7 position. Gao et al., (2019) Novel moxifloxacin-amide-1,2,3triazole-isatin hybrids have been synthesised. In vitro antibacterial activity against Gram-positive and Gram-negative bacteria, as well as drug-resistant diseases, was assessed for all produced compounds. The addition of methyloxime (R2) to the C-3 position of the isatin moiety could improve activity to some extent, however ethyloxime was found to be deleterious to activity in general. With MIC values ranging from 0.03 to 128 g/mL, all Fig.1 Fig.2 (a)4-Thiazolidinone 3D Model, (b) 4-Thiazolidinone's structure a b O 5 4 S N R2 …………………………… 64 3 2 R1 1 Int.J.Curr.Microbiol.App.Sci (2022) 11(01): 61-77 Fig.3 Isatin moiety structure, marketable medicines, and dyes. O O OH O N N H Lactim structure Lactum Structure HN COOH H N H N O N H N F N H O O Semaxanib N H Multiple Tyrosine Kinase inhibitor N H Sunitinib Orantinib Small molecule inhibitor Orally administared,tyrosine kinase inhibitor HO O N N N N O NH N H O N H MeOOC Isatin-3-Oxime/ isatin-O Ninetedanib-1 VEGFR, PDGFR, FGFR Inhibitor Anti cholinesterase Actvity O O N H N O HN O N H O O Indigo N O N H Indirubin Isoindigo 65 O NH N H Me Mesioindigo Int.J.Curr.Microbiol.App.Sci (2022) 11(01): 61-77 Fig.4 Sandmeyer isatin synthesis OH O N Chloral hydrate hydroxylamine HCl Sdium sulphate H H2SO4 O Heat water, Heat N N NH2 Phenylamine O H 1H-Indole-2,3-dione H 2-Hydroxyimino-N-phenyl-acetamide Isonitrosoacetanilide Aniline Isatin Fig.5 Common Routes to Synthesis of Substituted Isatin Derivatives Fig.6 Stolle isatin synthesis (COCl)2 O O N MeO NH2 MeO OMe OMe 5-Benzyl-2,3-dimethoxy-phenylamine H Melositin A 4-Benzyl-6,7-dimethoxy-1H-indole-2,3-dione Fig.7 Martinet isatin synthesis HO O CO2R O O O O O N NH2 O N O O R H 5,6-Dimethoxy-1H-indole-2,3-dione 3,4-Dimethoxyphenylamine 66 Int.J.Curr.Microbiol.App.Sci (2022) 11(01): 61-77 Fig.8 Gassmanisatin synthesis O O N-Chlorosuccinamide R R O R O N HgO/ BF3 N NH2 H H Fig.9 Metalation of anilideisatin synthesis 1. N-BuLi, THF O O R R 2. Diethyl Oxalate N N O O O H H HCl THF O OEt O O R N H Fig.10 Lactam-lactim tautomerism O O OH O N N H Lactim Lactam 67 Int.J.Curr.Microbiol.App.Sci (2022) 11(01): 61-77 Fig.11 Tautomeric system in Isatin O O OH O N N Lactim H Lactam silver salt sodium salt CH3I CH3I O O OMe O N N CH3 4 5 9 3 2 6 8 1 7 Fig.12 O H N S HO O N R Fe O N R Ferrocenylidene 2,4-thiazolidinedione Triazole Linker Isatine Oxame Triazole Linker 68 Ferrocenylidene 2,4-thiazolidinedione Int.J.Curr.Microbiol.App.Sci (2022) 11(01): 61-77 Fig.13 HN NH2 HN N R= O N R HN Hydrophilic Part NH2 HN Periplasm N Inhance Binding affinity O N Membrane Hydrophobic part Fig.14 69 Int.J.Curr.Microbiol.App.Sci (2022) 11(01): 61-77 Fig.15 H N O H N N S O O O O OH O R= Fig.16 N O + _ N Cl NH O quaternary ammonium moiety N R R= C10H29 , C12H25 , C14H29 , C16H33 , C18H37 , C20H41 70 Int.J.Curr.Microbiol.App.Sci (2022) 11(01): 61-77 Fig.17 Electronic effect Isatin moity with potential anti-bacterial activity Moxifloxacin with broad antibacterial activity R1 Amide linker O N N N N R2 F COOH O O H N N N OMe Control the lipophilicity H 1,2,3-triazole motif with diverse non -covalent iteractions O O Methylene linker O F N COOH N n H N N N N OMe R2 H R1= H, 5-F, 5-Me,7-F R2= O, NOMe, NOEt Fig.18 O O N H Isatin 71 Int.J.Curr.Microbiol.App.Sci (2022) 11(01): 61-77 Fig.19 Ciprofloacin moiety, responsible for the antimicrobial activity Isatin moiety with potential antimicrobial Activity O O F HO R2 O N N N N R1 Flexible Propylene Linker O O F HO N O N N N Fig.20 72 N O Int.J.Curr.Microbiol.App.Sci (2022) 11(01): 61-77 Fig.21 CH3 N N O O M N Cl H M= Ni (II) & Cu (II) Fig.22 Fig.23 COOH N X X= Br, R= Bn N R 73 Int.J.Curr.Microbiol.App.Sci (2022) 11(01): 61-77 Fig.24 N N F C H Ar O N N N OH F Ar = for 3C, 3H, 3K, 3I O O CH3 3C = 3K = OH N CH3 OCH3 3H 3I = = OCH3 OH OCH3 OCH3 Ganim et al., (2018) described the synthesis of isatin and thiosemicarbazone derivatives, which were then tested for DNA binding, including DNA protection studies using plasmid DNA (pUC19) and DNA interaction experiments with calf thymus DNA (CTDNA). They also used an in vitro experiment to test drugs' antibacterial properties against a variety of harmful bacterial species. DNA protection activity ranged from 23.5 to 59.5 percent in all isatin and thiosemicarbazone derivative compounds. The DNA-protective activity of I3-(N-2-MP)-TSC was the highest among them. With low concentrations, derivatives of isatin thiosemicarbazone showed substantial and specific antibacterial action. These chemicals were mostly efficient against Grampositive bacteria, but not against P. vulgaris or E. coli. These chemicals had the greatest impact on the Gram-positive methicillin-resistant S. aureus ATCC 43300 (MRSA) strain. The methyphenyl group at isatin was discovered to be critical for its antibacterial action against MRSA (Ganim et al., 2018). antibacterial activity against Gram-positive, Gramnegative, and mycobacterial infections. He discovered that all mono-isatin-ciprofloxacin hybrids had outstanding antibacterial activity against majority of the pathogens tested, with MICs ranging from 0.03 to 0.5 mg/mL. Ciprofloxacin-isatin hybrid (3d) was very effective against all Gram-positive and Gram-negative microorganisms tested, including clinically significant drug-resistant infections, and was comparable to or more effective than the parent ciprofloxacin and the reference levofloxacin (Wang et al., 2018). Ugale et al., (2017) N-(5 or 7 substituted-2oxoindolin-3-ylidene) benzofuran-2carbohydrazides were discovered. All of the produced compounds were tested for antimicrobial activity, and he discovered that 3o was effective against Escherichia coli and Pseudomonas vulgaris, while 3p was effective against Bacillus subtilis, E. coli and Pseudomonas vulgaris. Antifungal activity of 3o and 3p against Aspergillus niger was also observed (Ugale et al., 2017). Wang et al., (2018) A unique synthesis of twelve propylene-tethered ciprofloxacin-isatin hybrids was reported, and all hybrids were tested in vitro for Swathy et al., (2016) studied the synthesis of isatin complexes with manganese(II), cobalt(II), nickel(II), 74 Int.J.Curr.Microbiol.App.Sci (2022) 11(01): 61-77 copper(II), and zinc has been described (II). In comparison to S. typhi and S. aureus, all of the complexes have increased activity against E. coli. (CuLCl) > (NiLCl) > (MnL2) > (ZnLCl) > (CoL2) > L. Antibacterial activity order (CuLCl) > (NiLCl) > (MnL2) > (ZnLCl) > (CoL2) > L. When a chemical is coordinated with metal, its antifungal activity is increased by several times. Cu(II) > Ni(II) > Co(II) > Mn(II) > Zn(II) > L. The activity of these complexes and ligands is in this order: Cu(II) > Ni(II) > Co(II) > Mn(II) > Zn(II) > L. The copper complex is more active against R. stolonifer than the ligand, according to the comparison of activities. (Swathy et al., 2016). The synthesis of isatin-3-(4hydroxy) benzoylhydrazone was described by. He discovered that the C-3 position in isatin is particularly vulnerable to nucleophilic assault, whereas C-2 only reacts with nucleophiles under precise conditions due to the amido group's negative inductive impact. Antimicrobial activity was tested against Staphylococcus aureus, Serratia marcescens, Pseudomonas aeruginosa, Klebsiella pneumoniae, Enterococcus faecalis and Candida albicans in all produced compounds (Sandra et al., 2015; El-Faham et al., 2015). all microorganisms. In vitro antimicrobial activity against seven bacteria (four gramme positive and three gramme negative) and two fungal strains The antibacterial capabilities of electron donating group substituted derivatives were shown to be superior to those of electron withdrawing compounds (Prakash et al., 2013). References Aggarwal, O. P. Org Chemistry Reactions and Reagents. 46th ed., Meerut: Krishna Prakashan Media (P) Ltd, 2009; 658-60. 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European Journal of Medicinal Chemistry, 156, 580– 586. doi:10.1016/j.ejmech.2018.07.025 Yoshikawa, M., Murakami, T., Kishi, A., Sakurama, T., Matsuda, H., Nomura, M., Matsuda, H. and Kubo, M. “Novel indole S,Obisdesmoside, calanthoside, the precursor glycoside of tryptanthrin, indirubin, and isatin, with increasing skin blood flow promoting effects, from two calanthe species (orchidaceae)” Chem. Pharm. Bull. 1998, 46(5), 886-888. How to cite this article: Ashutosh Pathak, P. Malairajan, Arti Gautam and Shibu Das. 2022. Isatin: A Short Review of their Antimicrobial Activities. Int.J.Curr.Microbiol.App.Sci. 11(01): 61-77. doi: https://doi.org/10.20546/ijcmas.2022.1101.009 77