Medicinal and Biological Significance of Isoxazole A Highly Important Scaffold for Drug Discovery

 

S. Renuka1 and Rama Krishna Kota2

1D.No:27-5-10/1, Sreerampuram, Bhimavaram, 534202.

2Health Care and Science, Thomson Reuters, India

*Corresponding Author E-mail: renuka1020@yahoo.co.in,

 

ABSTRACT:

The article is a summary of the medicinal and biological significance of the most important pharmacophore among the heterocycles having many biological activities, the Isoxazole. The isoxazole is a highly active scaffold exhibiting a wide variety of medicinal and biological activities. An attempt is made in this article to cover medicinally active compounds along with the recent discoveries, which were reported to posses various biological activities. This might be helpful in developing the novel lead molecules to potential drug candidates

 

KEYWORDS: Hetrocycles, isoxazoles, scaffold, medicinal significance, biological significance.

 

 


INTRODUCTION:

Among the wide variety of heterocycles that have been explored for developing pharmaceutically important molecules, isoxazoles played an important role in medicinal chemistry, because of their diverse properties such as fairly accessible path of synthesis, wide range of therapeutic activities and variety of industrial applications, the isoxazole ring became a center of attraction for organic chemists.

 

Isoxazole (1) is an azole with an oxygen atom next to nitrogen. It has a molecular formula C3H3NO and molecular mass 69.06 g/mol. Isoxazole rings are found in natural products like ibotonic acid. They also form basis for a number of drugs like cox-2 inhibitors, nitric oxide donors like furan and appreciable number of five membered heterocycles containing nitrogen atom and oxygen atom obtained by laboratory synthesis.

 

Isoxazole derivatives are conferred with many biological activities such as anti-inflammatory2, anticonvulsant3, antibacterial4, antifungal 5, immunoregulatory 6, anticancer7, herbicidal8, neuroleptic9, antileukaemia10, antidepressant11 etc.

 

This moiety can be frequently recognized in the structure of numerous naturally occurring and synthetic compounds with interesting biological and pharmacological properties. Some of useful synthetic analogues with improved therapeutic activity can be obtained from single lead compound by structural modifications. A lot of modifications have been done during the last few years on Isoxazole nucleus. A survey of literature revealed that substituted isoxazoles possess different types of potent activities.

 

ANTIMICROBIAL ACTIVITY:

Antimicrobials cover a large spectrum of biological activities like antibacterial, antifungal, antiviral, antiprotozoal etc. Several derivatives of isoxazoles possessing potential antimicrobial activities have evolved.

Cloxacillin, dicloxacillin, oxacillin etc are being used as successful antibiotics by inhibiting b-lactamase enzyme and is used in many microbial infections12.

 

Cloxacillin    R = H; R1 = Cl

Dicloxacillin R = Cl; R1 = Cl

Oxacillin       R = H; R1 = H

Sulphamethoxazole, a derivative of sulphonamide with isoxazole ring is used as a successful bacteriostatic drug in the treatment of sinusitis and toxoplasmosis13.

 

V.V.Kachhadia et.al, worked on several isoxazoles bearing benzo(b)thiophene nucleus which were screened for antimicrobial activities against various strains of bacteria using amoxycillin, ampicillin, and ciprofloxacin as standards among which the following compounds were found to be potent14.

 

R = 3-Cl-C6H4-

R = 2-NO2-C6H4-

 

Anjani N. solankee worked on 2-phenylamino-4-(4’-chlorophenylamino)-6-[4’-{5’’-(4’’’-methoxyphenyl)-isoxazole-3”-yl}phenylamino]-5-triazine and evaluated for antibacterial activity in comparison to ciprofloxacin and the following compounds were found to be potent15.

S.No              R

7a.               2-methoxy phenyl

7d.               4-fluro phenyl

7e.               4-methyl phenyl

7g.               dimethoxy phenyl

 

Yogesh prajapathi worked on some new fluorine containing acetyl pyrazoline and isoxazole derivatives for their antibacterial activity compared to ciprofloxacin and among them the following compounds were found to be potent16.

 

R = 4 methoxy phenyl

 

Chirag Sharma et.al, worked on  2-{ 4-[5-(4-substituted phenyl)-4,5 dihydroisoxazol-3yl]phenoxy}- 4,6- bispthalimidoxy-1,3,5-triazine and evaluated for antibacterial and antifungal activities which were compared to ciprofloxacin and among them the following compound was found to be potent17.

 

Rajanarendar et.al, worked on 1-(5-methyl-3-isoxazolyl)-3,6-diadryl-4-thioxo-1,3,5-triazinan-2-ones which were evaluated for antimicrobial activity, particularly antibacterial and antifungal activities which were compared to nystatin  and the following compounds were found to be potent18.

S.No              Ar

3h.               C6H5

3j.               4-OCH3C6H4

3i.               4-ClC6H4

 

Vijay V.Dabholkar et.al, worked on several fused isoxazole and pyrazole derivatives which were evaluated for their antimicrobial activity against Staphylococcus aureus and cornybacterium diphtheriae using ampicillin as standard and the following compound was found to be potent19.

 

HERBICIDAL ACTIVITY:

Yuttanzhou et al synthesized novel 3-(substituted phenyl)-isoxazole derivatives which are inhibitors of porphyrinogen oxidase and subjected them for herbicidal activity, which is followed by reports of many researchers. Some of them such as JU-485 and KPP-314 have been commercialized. Many of these derivatives have been synthesized and they display herbicidal activities against various weeds like Echinochloa, Crusgalli, Setaria Viridis, Abutilon theoprastil 20.

 

R - OCH3

-OC2H5

-NHC6H5

-N (C2H5)2

 

ANTIOXIDANT ACTIVITY:

P.Manoj kumar et.al, synthesized some new series of 1-isonicotinyl 3, 5-dimethyl-4-arylazo isoxazoles which showed antioxidant activity and the activity is compared with standard drug ascorbic acid by DPPH method. Among them, the following compound is found to be potent21.

 

X- C or O

Y- N or O

Z- C or N

 

IMMUNOLOGICAL ACTIVITY:

Stanislaw ryng and Michael zimeki synthesized some new derivatives of isoxazoles including 4-substituted 3-(5-amino-3-methyl-4-isoxazole)-1,2,4-triazoline-5-trione, 5-substituted 2-(5-amino-3-methyl-4-isoxazole) and 1,3,4-thiadiazole derivatives which showed immunomodulatory with reference to cyclosporine22..

R- Aliphatic, Aromatic

 

ANTI CANCER ACTIVITY:

V. H. Bhaskar, B. Mohite synthesized 5-phenyl-1-(5-substituted phenyl isoxazol-3-yl)-1H-tetrazole (4a-h). Among the synthesized derivatives, eight compounds have been selected and evaluated for their anticancer activity at the National Cancer Institute in a panel of approximately 60 different human tumor cell lines derived from nine neoplastic cancer types. Relations between structure and activity are discussed and the most efficient anticancer compound (4b) was found to have selective influence on ovarian cancer cell lines, especially on SK-OV-3 with a percentage growth inhibition of 34.94.23

 

R- 2-chloro phenyl

 

Patrizia Diana et.al, synthesized a series of novel 2, 5-bis(3′-indolyl)furans and 3, 5-bis(3′-indolyl)isoxazoles which are antitumor agents. The antiproliferative activity was evaluated invitro in diverse human tumor cell lines. Initially 5 isoxazoles and 3 furan derivatives were tested against a panel of 10 human tumor cell lines and the most active derivatives 3c and 4a were selected to be evaluated in an extended panel of 29 cell lines. By exhibiting mean IC50 values of 17.4 μg/mL(3c) and 20.5 μg/mL(4a), in particular 4a showed a high level of tumor selectivity toward the 29 cell lines24.

 

X=O, Y=Z=CH;

X=CH, Y=Z=O

 

INVITRO METABOLISM STUDIES ON ISOXAZOLE RING SCISSION:

Amit S.kalgutkar, Hang T.Nguyen et.al, suggested that the lack of isoxazole ring opening in 3-methyl leflunamide strongly suggested that the hydrogen at 3-leflunamide is essential for ring opening. As a further evidence for P-450 mediated deprotanation of the C-3 hydrogen in the leflunamide, they examined the possibility of C-3 hydrogen/deuterium exchange in leflunamide recombinant P- 450/A2 incubated in phosphate buffer. The P-450 mediated isoxazole ring opening in a leflunamide is also catalyzed by the Fe (II) form of the enzyme, recombinant P450A/A2 incubations conducted in the presence of NADPH under anaerobic conditions and also in the presence of carbon monoxide. The presence of molecular oxygen in the incubation mixture greatly inhibited the formation of A7717225.

 

R - H Leflunamide

R -CH3 Methyl Leflunamide

 

ANTI NOCICEPTIVE ACTIVITY OF PYRAZOLYL ISXAZOLES:

K.Karthikeyan, T.veenuseelan et.al, developed a systematic procedure for the synthesis of pyrazolyl isoxazole and examined anti-nociceptive action by using various animal tissues. The lead molecule was synthesized by using 1, 3-dipolar cyclo addition of pyrazole derived nitric oxide with various dipolarophiles such as N-substituted maleimide, diethyl acetylene dicarboxylate and phenyl acetylene. The given structure of synthesized pyrazolyl isoxazoles shows maximum anti- nociceptive activity26.

 

ANTIPLATELET ACTIVITY:

Xue CB, Roderick J synthesized the novel isoxazole derivatives which show Antiplatelet activity. The Antiplatelet activity of labeled isoxazole derivative is due to glycoprotein 2b/3a antagonistic mechanism. The synthesized isoxazole derivatives show high antiplatelet activity in dogs27.

R - Aryl or Alkyl

R1 - Alkyl or Benzyl

 

ANTI INFLAMMATORY ACTIVITY:

K.Madhavi et.al, synthesized a series of 3-methyl-4-nitro-5-(substituted styryl) isoxazoles and evaluated for antioxidant, anti-inflammatory and analgesic activities with a view to evaluate effect of nitro substitution on styrylisoxazoles. Compounds with sterically hindered phenolic groups exhibited good anti-inflammatory activity with better antioxidant properties and are devoid of toxicity as well as ulcerogenic potential28.

 

ACTIVITY ON HUMAN B-ADRENERGIC RECEPTORS:

The three pairs of stereo isomeric 3- bromo isoxazolyl amino alcohols (S, R)- (-)-7a, (R, R)-(+)7b, (S, R)-(-)-8a, (R, R)-(+)-8b, (S, R)-(-)-9a and (S, R)-(+)-9b were synthesized by Clelia Dallonoce, Fabiofregerio and the labeled compounds shows the effect on B1, B2, B3 adrenergic receptors. They possess high affinity and efficacy towards the adrenergic receptors and this is tested in Chinese hamster ovary29.

MISSCELLANEOUS ACTIVITY:

3-Amino benz(d)isoxazoles acts as multi targeted inhibitors of receptor tyrosine kinase. SAR studies lead to identification of labeled compound and that potently inhibits both vascular endothelial growth factor receptor (VEGFR) and platelet derived growth factor receptor families of receptor tyrosine kinases (RTK) and this was demonstrated by in vivo studies also. The activity was done by Jiz, Ahmed AA et.al, Global pharmaceutical research and development30.

 

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Received on 15.05.2011        Modified on 25.05.2011

Accepted on 31.05.2011        © AJRC All right reserved

Asian J. Research Chem. 4(7): July, 2011; Page 1038-1042