Significance of Fluorine in Medicinal Chemistry: A Review
SR Pattan*, NS Dighe, HV Shinde, MB Hole and VM Gaware
Department of Medicinal Chemistry, Pravara Rural College of Pharmacy, Pravaranagar, M.S, India
*Corresponding Author E-mail: shashipattan@yahoo.com
ABSTRACT
Fluorine is second smallest element in periodic table. It has many pharmacological activities with different substituted heterocycles. It has attracted the attention of Medicinal Chemist for its versatile and significant activities. This review explains the significance of presence of fluorine in various Medicinal compounds. The medicinal importance, use of the drugs containing fluorine is listed.
KEYWORDS: Fluorine, Haloperidol , Progabide
INTRODUCTION:
The reasons forever increasing importance of fluorine[1] incorporated bioactive molecules may be listed below.
1) Fluorine being the second smallest atom next to hydrogen closely mimics hydrogen in enzyme interactions.
2) Fluorine can replace H or O in enzyme substrate without a significant change in the shape and it is often recognized by target enzyme.
3) The substitution of fluorine to hydrogen increases Lipid Solubility, which in turn increases transport and absorption of drug in vivo.
4) Fluorine is most electronegative element. The strong electron withdrawing effect (I effect) of fluorine influences stability and reactivity of functional groups which may dramatically change the electronic profile of whole molecule.
5) C-F bonds are particularly susceptible to stereo electronic effects. They likely to orientate very specifically relative to C=O and C-N bonds thus influence the conformation of biomolecules such as Peptides.
6) The replacement of “hydrogen” by fluorine at or near active sites causes inhibition due to high C-F bond energy.
Thus fluorine can be used as “design tool” in tuning molecules for particular purposes. This leads us into medicinal chemistry where we design active drugs on the specific disease target.
Antibacterial Agents
Gatifloxacin [2] which is exceptional in being fluorinated quinolone with a methyl piperazine substitute is a antibacterial, active than ciprofloxacin.A derivative of quinazoline carboxylic acid [3] that posses a wide range of antibacterial activity is A 86719-I which is shown to inhibit enzyme DNA gyrase.
Antifungal Agents
A new triazole antifungal agent, Voriconazole [4] formerly UK-109,496, in treating the opportunistic fungal infections in AIDS patients has shown outstanding fungicidal activity.
Antiviral Agents
A fluorinated derivative identified as R-71762[5] has shown to inhibit the viral production in cells infected with HIV-I induced cytopathological changes.
Antistroke Agents: (glutamate relese inhibitors)
A new bezithioazolyl derivative Lubeluzole [6] has been reported by Diener may present stroke and might also be useful in Alzheimer’s patients.
Antidepressant Agents
The selective serotonin re-uptake inhibitors [7] (SRRIs) increase the activity of 5HT by presenting it reabsorption. Escitalapram is the 5-isomer of the Citalopram developed in forest lab US is an antidepressant.
Antisteoarthritis and Antirhemactic Agents
The degenerative changes in the joints and inflammation is controlled by the Cox-2 inhibitor Celecoxib [8], is fluro derivative.
The isoxazole derivative Leflunomide [9] was already used as an immunomodulator in transplant surgery and can suppress the inflammation related to the Rheumatoid arthritis.
Antidiabetic Agents
A fluorinated benzothiazole derivative Zoporestat[10] was highly active and found to present the accumulation of sorbitol in nerves hence controls the neuropathy in diabetic patients.
Vasodilators
Nebivolol [11] described as a,a’-{ iminodimethylene}bis{6-fluoro-2-chromanmethanol} was reported by Bowman et al, is a beta- adrenoreceptor blocking agent used in the treated of hypertension.
Anti Androgen Agents- Anti prostate cancer agents
Furr et al reported bicalutamide [12] a non steroidal fluoro benzene antiandrogen which is used against the carcinoma of the prostate gland.
Anti- Schizophrenic Agents
Hoperidone was discovered by titan pharmaceuticals and Novartis pharma, is a 5-HT2A/D2 antagonist, is also a fluorobenzene derivative.
Fluorobenzoyl derivative have shown potential psychoactive properties.
Anti Peptic Ulcer Agents
Brunner and Harke [13] investigated pentaprazole a fluorinated molecule is the inhibitor of Hydrogen/potassium- adenosine triphosphate enzyme system inhibitor.
Cytotoxic Agents
The synthesis of novel fluorobenzene molecule Brequinar[14] (DUP-785) identified as 2-(2-fluoro-1,1-biphenyl-4-yl) -6- fluoro-3-methylquinoline-H- carboxylic acid sodium salt was effectively used against lung carcinoma cell lines by Dexter et al.
FTC-092 [15] synthesized from Tekeda Company Japan chemically 1-(3-0-benzyle-2-deoxy-beta-O-riofuronosyl)-5-trifluoro-methyl-2, 4—(1H, 3H) pyrimidinedione has shown a very good cytotoxicity on cancer cell lines.
Hypolipidaemic Agents
A fluorinated derivative of phenylcarbaimoyl pyrrolidine atrovastatin [16] was reported by Brower for effective cholesterol synthesis inhibitor.
Allergic Rhinitis
A derivative S-(fluoromethyl-1)-6-alpha, 9-difluoro-II-beta, 17-dihydroxy-16alpha-methyl-3-oxotandrosta-1,4-diene-17-beta-carbothiate was shown to passes anti-inflammatory activity used in rhinitis.
Cardiac Stimulant
A new class of fluoroquinolines represented by flourquinan described chemically as 7-fluoro-1-methyl-3-(methyl-sulphinyl-4 (1H)-qunolinone was reported as an cardiac stimulant17.
Anticonvulsants:
Fluorophenyl moiety containing drugs like Progabide have anticonvulsant activity.
CONCLUSION:
The presence of fluorine in medicinal compounds has the greater pharmacological profile. As fluorine has strong electron withdrawing effect which influences best ability and reactivity of functional groups will lead to the change of electronic profile of the whole molecule. Fluorine is considered as Design Tool in synthesizing newer medicinal compounds. The fluorine is often associated in the derivatives of Ciprofloxacin, Norfloxacin, Gatifloxacin and other higher antibiotics. Fluorine is very effective for the treatment of fungal infections in AIDS patient. The fluorine derivative inhibits viral productions in cells with HIV I and HIV II. It is useful in Alzheimer’s disease to prevent stroke. Fluorine work as selective serotonin re-uptake inhibitors (SSRIs). It also helps in COX-2 inhibition. The fluorine plays important role rheumatoid arthritis, diabetes patients, hypertension, carcinoma causes toxicity to cancer cells, lowers cholesterol level, effective anti inflammatory agent, flouroquninolinone was reported as a cardiac stimulant. Fluorophenyl has anticonvulsant activity. Thus the present review helps and encourages for the search of many more medicinal compounds having as the essential.
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Received on 29.08.2009 Modified on 30.09.2009
Accepted on 20.10.2009 © AJRC All right reserved
Asian J. Research Chem. 2(4):Oct.-Dec. 2009 page 376-379