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ISSN 0974-4169 www.ajrconline.org REVIEW ARTICLE

Oxindoles and Their Pharmaceutical Significance- an Overview

Shashi Ravi Suman Rudrangi1*, Vijaya Kumar Bontha2, Venkata Reddy Manda3 and Srinivas Bethi4

1Department of Pharmaceutical Sciences, School of Sciences, University of Greenwich, Chatham Maritime, Kent, United Kingdom, ME4 4TB

2Department of Pharmaceutics, Jangaon Institute of Pharmaceutical Sciences, Kakatiya University, Yeshwanthapur, Jangaon- 506167, India

3Former Director, Drugs Control Administration, A.P., Director, Sree Dattha Institute of Pharmacy, Sheriguda, Ibrahimpatnam-501510, India

4Department of Medicinal Chemistry, Talla Padamavathi College of Pharmacy, Urus, Kareemabad-506002, India *Corresponding Author E-mail: suman_rudrangijips@yahoo.com

ABSTRACT: Oxindoles are credited to have a wide range of applications and are reported to exhibit an extensive range of biological effects which include the antiviral, antifungal, antibacterial, antiproliferative, anticancer, anti-inflammatory antihypertensive and the anticonvulsant activities. The chemistry of oxindoles is very interesting and the biological activity of the oxindoles and their derivatives has made them very important in synthetic organic and medicinal chemistry. This review provides insight into various applications of oxindoles and their derivatives to date.

KEYWORDS: Oxindoles, Oxindole derivatives, Applications, Biological Activity

INTRODUCTION: Oxindoles (Fig.-1) are endogenous aromatic organic compounds that are found in the tissues and body fluids of mammals, and in the natural products of some plants. They are aromatic heterocyclic organic compounds with a bicyclic structure. An oxindole molecule consists of a six-membered benzene ring that is fused to a five-membered ring containing nitrogen. Oxindole's structure is based on the indoline structure but where a carbonyl is situated at the 2-position of the 5 membered ring.1 This review provides insight into various applications of oxindoles and their derivatives to date. Examples of some bioactive oxindoles are shown in Fig.2. 2-3 Applications of Oxindoles: Oxindoles are credited to have a wide range of applications and are reported to exhibit an extensive range of biological effects which include the antiviral, antifungal, antibacterial, antiproliferative, anticancer, anti-inflammatory antihypertensive and the anticonvulsant activities. Received on 10.10.2010 Modified on 28.10.2010 Accepted on 04.11.2010 © AJRC All right reserved Asian J. Research Chem. 4(3): March 2011; Page 335-338

Oxindoles as Anti-HIV agents: The Human Immunodeficiency Virus (HIV) is a global health threat and infects millions of people. It has been reported that nearly 40 million adults and children are living with HIV/AIDS worldwide and more than 20 million people have died of AIDS since the first reported cases in 1981.In 2001, there were 3 million adult and children deaths due to HIV/AIDS whereas 3.1 million deaths were reported in 2004. Oxindoles are used to inhibit the replication of HIV and combat the infections that are caused by drug-resistant, drug-sensitive, and mutant strains of HIV.4 Some novel oxindoles (Fig.-3) were found to act as the HIV non-nucleoside reverse transcriptase inhibitors (NNRTIs) which are among the most common classes of drugs prescribed for antiviral therapy5. The anti-viral activity of the oxindoles is found to be due to its interactions with the reverse transcriptase. Oxindoles act by effectively docking into the HIV-1 NNRTI site. The mechanism of action is depicted in Fig. 4. Oxindoles as Anti-cancer agents: Oxindoles have also been credited with exhibiting antitumor activity by inhibiting tyrosine kinase receptors such as PDGF-R �, VEGF-R or CDK. One of the most important examples is the indolin-2-one (sunitinib) which has been widely used in the treatment of gastrointestinal stromal tumors, and metastatic renal cell cancer. 2 It was reported by the in-pharma technologist website that

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sunitinib has generated nearly $847 millions in the global sales in 2008.

Fig.1. Oxindole’s structure

2 (tenidap)

3 (Indolidan)

4 (Adibendan)

Fig.2. Examples of some bioactive oxindoles 2-3 Substituted arylsulfoanilides are used as antiproliferatives. Studies of the relationship between their structure and activity have resulted in the identification of compounds that possesses micromolar activity against lung cancer cells. A potent Aryl-sulfoanilide-oxindole (Fig.-5) hybrid resulted from incorporating the substitution pattern of aryl-sulfoanilide onto a 3-phenyloxindole scaffold. The aryl-

sulfoanilide -oxindole hybrid inhibits the growth of cancer cells by partial depletion of intracellular calcium stores and phosphorylation of elF2�. The hybrid also inhibits the initiation of translation. 6

Fig.3. Novel HIV-1 inhibitors 5 Oxindoles as Anti-inflammatory agents: Some non-steroidal oxindoles have been reported to show analgesic and anti-inflammatory activity. Certain ketone-containing 1-substituted oxindole-3-carboxamide and 3-substituted 2-oxindole-1-carboxamide compounds act as analgesic and anti-inflammatory agents. They act by inhibiting the enzymes lipoxygenase (LO) and cyclooxygenase (CO). The oxindoles derivatives are used in ameliorating the symptoms of the chronic diseases such as osteo-arthritis and rheumatoid arthritis. 7-8

Oxindoles that show cyclooxygenase- inhibiting activity and cytokine- modulating properties have been developed for treating rheumatoid arthritis and osteoarthritis. Tenidap ((Z)-5-chloro-3-[1-hydroxy-1-(2-thienyl) methylene]-2-oxo-2, 3-dihydro-1H-indole-1-carboxamide), is one of the outstanding representatives of the antirheumatic oxindoles. Oxindole-1-carboxamides and oxindole-1, 3-dicarboxamides are also used in arthritis and are considered to be interesting targets in medicinal chemistry.

Fig.4. Docking of the oxindoles into the HIV-1 NNRTI site 5

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Fig.5. Aryl-sulfoanilide resulting in arylsulfoanilide-oxindole hybrid 6 Oxindoles as potential CVS agents: Oxindole derivatives are also used as cardiotonics and anti-hypertensives. The non-steroidal oxindole derivatives Indolidan and Adibendan are used in the treatment of congestive heart failure which is a very debilitating and malignant disease. Indolidan is a highly potent inotropic cardiotonic, which has the dihydropyridazinone moiety attached to a benzo-fused heterocycle, whereas dihydropyridazinone moiety is attached tricyclic 5-6-5 fused heterocycle in the case of Adibendan. These compounds mainly act by inhibiting the cAMP, a secondary messenger which mediates the cell responses to many neurotransmitters and hormones. These oxindole derivatives also have potent vasodilatory, positive inotropic and inodilatory actions3. It has been reported that aminomethylene oxindole derivatives (Fig.6.) are useful as antihypertensive agents.9

O

C H 3

O

C H 3

NH

O

N

R1

R

Fig.6. Aminomethylene oxindole derivatives 9

Oxindoles as Protein tyrosine kinase and Protein serine/Threonine kinase inhibitors: Protein kinases play a vital role in control of growth and differentiation of cell and are the key mediators of the cellular signalling which leads to the production of cytokines and growth factors. Some of the examples of protein kinases include CDK1, CDK2, CDK3, CDK4, EGFR, ERK, ERK1, ERK2, VEGF-R1, VEGFR-2, FGF-R1, FGF-R2, JAK1 and JAK2. 10 They have also been implicated as targets in central nervous system disorders like pain sensation, Alzheimer’s disease, bone diseases like osteoporosis, inflammatory diseases like arthritis, chronic obstructive pulmonary disease and psoriasis, cancer, restenosis, atherosclerosis, angiogenesis. 11-18

3-(Anilinomethylene) oxindoles (Fig.7.) are some novel amine substituted oxindole derivatives that have been reported to inhibit the protein serine kinase and protein

tyrosine kinase receptors and also inhibit growth of tumor by inhibiting tumor-related angiogenesis. They are also used in treating many pathological diseases like atherosclerosis, thrombosis, restenosis that involve cellular proliferation. Some oxindoles have also been credited to exhibit the antitumor activity by inhibiting the tyrosine kinase receptors such as PDGF-R �, VEGF-R or CDK. 19

Fig.7. 3-(Anilinomethylene) oxindoles 19 Oxindoles as Sleep inducers: Oxindoles are also credited for their anti-convulsant and CNS-depressant activities. Some alkoxy-substituted oxindoles are used as sedatives and analgesics. It has been disclosed that N-ethyl oxindole and N-methyl oxindole have CNS depressant and anti-convulsant actions. Various alkoxy-substituted oxindoles were pharmacologically evaluated with results that include analgetic and sedative activities. Some examples of the oxindoles that were reported to exhibit sleep inducing are 5-fluoro oxindole, 6-chloro oxindole, 6-fluoro oxindole, 7-chloro oxindole, 5-fluoro-1-methyl oxindole, 5-chloro-1-ethyl oxindole. Structures of some alkoxy-substituted oxindoles are depicted in Fig.8. 20

Fig.8. Oxindole derivatives as sleep inducers 20

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Oxindoles as Anti-bacterial agents: Resistance to antibacterial drugs has become a global, clinical and public health problem, which has emerged with startling rapidity in the recent years and will increase in future undoubtedly. Multiple drug resistance is a growing problem and hence the doctors and scientists are now challenged with the infections for which there is no effective therapy. Many structurally novel antibacterials with a new mode of action have gained a lot of importance in treating bacterial infections. Oxindole- oxazolidinone derivatives are the most recent synthetic class of antimicrobials, used as the antibacterial agents. The oxindole oxazolidinone derivative (Fig.9.) is reported to act as an antibacterial by inhibiting bacterial protein synthesis, and is used for treatment of many serious infections that are caused by veterinary and human pathogens and multiple resistant strains of bacteria.21

Fig.9. Oxindole oxazolidinone derivative as an antibacterial agent 21

Oxindoles as potential CNS agents: Some 3-substituted-2-oxindole-1-carboxamides and their pharmaceutically acceptable base salts are credited for their use in prevention and treatment of Alzheimer’s disease in humans and mammals, and the symptoms of such disease like impairment of memory and Alzheimer’s dementia. It was believed that Tenidap would be suited for treating Alzheimer’s disease, because of its cytokine modulating properties and cyclooxygenase inhibiting properties. Some substituted 2-oxindole-1-carboxamide compounds

that are believed to be used in treatment and prevention of Alzheimer’s disease are as follows: 5-chloro-3-(2-thenoyl)-2-oxindole-1-carboxamide; 6-chloro-3-(2-phenylacetyl)-2-oxindole-1-carboxamide; 5, 6-difluoro-3-(2-furoyl)-2-oxindole-1-carboxamide. 22 CONCLUSION: The chemistry of oxindoles is very interesting and the biological activity of the oxindoles and their derivatives has made them very important in synthetic organic and medicinal chemistry. The future potential of Oxindoles is very immense and the vast range of applications offered makes them ‘Legendary magic bullets in Bio-medicinal Chemistry’.

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