drugs containing imidazoles and triazole heterocyclic ring in antifungal therapy

24 Pages·2016·0.5 MB·English

Gayathri P*et al. /International Journal Of Pharmacy & Technology
ISSN: 0975-766X
CODEN: IJPTFI
Available through Online Review Article
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A REVIEW ON “DRUGS CONTAINING IMIDAZOLES AND TRIAZOLE HETEROCYCLIC
RING IN ANTIFUNGAL THERAPY”
Rohit J. Bhor1*, C.J.Bhangale2, V.D.Wagh3
*1Department of Pharmaceutical Chemistry, PRES’s College of Pharmacy Chincholi, Tal-Sinner, Dist-Nasik, 422103,
Maharashtra, India.
2Department of Pharmaceutical Chemistry, PRES’s College of Pharmacy Chincholi, Tal-Sinner, Dist-Nasik, 422103,
Maharashtra, India.
3Department of Pharmaceutics, PRES’s College of Pharmacy Chincholi, Tal-Sinner, Dist-Nasik, 422103,
Maharashtra, India.
Email: [email protected]
Received on 20-07-2016 Accepted on 15-08-2016
Abstract
Writing investigation of different exploration papers and different distributions gives definite work on science of the
imidazole, triazole and its different pharmacological activities on different sorts of parasitic contaminations. Imidazole is
a substance which is being combined in a number of its subordinate structure from recent years. In the most recent couple
of decades, the science of imidazole, triazole and their combined heterocyclic subordinates has gotten significant
consideration attributable to their manufactured and viable natural exercises, for example, mitigating, CNS stimulants
narcotics, hostile to nervousness, antimicrobial specialists and against mycotic action, for example, fluconazole,
intraconazole, voriconazole and so on. Triazole ring framework and imidazole ring framework have pulled in a
persistently developing enthusiasm of manufactured natural scientific experts and those managing the therapeutic mixes
because of its adaptable potential to interface with organic frameworks. Amid the previous three decades, the frequencies
and sorts of systemic parasitic diseases have expanded significantly in patients endured with tumors, immuno
insufficiency or invulnerable concealment. The new antifungal operator gives promising movement, obtrusive parasitic
contaminations, positioning close by bacterial diseases. The triazole and imidazole mixes have an extensive variety of
natural exercises and are particularly engaged for antifungal conduct. The principle center was on the techniques which
manage the easy and advantageous combination.
Keywords: Antifungal therapy; Imidazole; Triazole;

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Introduction:
The investigation of organisms is called as "mycology". Mycology is a branch of natural science; it is separate kingdom in
organic scientific categorization. A growth assumes an essential part in decay of natural matter and in supplement
cycling1. Organisms are utilized as a part of maturation of different sustenance items, for example, wine, brew and soya
sauce. In 1940s, parasites are utilized for creation of anti-infection and at present, different sorts of proteins are delivered
from organisms and these compounds are utilized as a part of the business and in cleansers. Organisms are utilized as
pesticides to controlling the weeds, plant ailments and creepy crawlies. The kingdom of parasites contains 1.5 million to 5
million species2-5. Parasites are arranged or isolated into one sub-kingdom, and seven phyla and ten sub-phyla. At the
point when a gathering of parasites is found in range or geographic area, then it is known as "mycobiota". The name of
the organism is straightforwardly received or taken from the Latin word growth (mushroom). Mycology has been gotten
to be precise after the advancement of the magnifying lens in the sixteenth century6-7. The growths spores were presented
or watched firstly by Giambattista Della Porta in 1588. The researcher Dutch Christian Hendrik Persoon (1761-1836)
gives first characterization of mushroom. The researcher Elias Magnus Fries (1794-1878) gives arrangement of organisms
by utilizing spore shading and different tiny trademark. In world up to 5 to 10% of the considerable number of diseases
are brought on by growths. Contagious diseases in such a high hazard patients advance quickly and are hard to analyze
and treat8. Heterocyclic mixes are those mixes which are not by any stretch of the imagination made out of carbon iotas
yet one or a greater amount of different molecules in their ring, for example, nitrogen, sulfur, oxygen and so forth.
Carbocyclic or heterocyclic ring frameworks include the center of synthetic structures. Heterocyclic natural mixes
containing five or six membered ring with one or more nitrogen particles are of awesome importance9. Particularly in the
created nations parasitic contaminations have become quickly in most recent couple of decades. Parasitic diseases remain
a noteworthy reason for grimness and mortality regardless of advances in therapeutic science. Antifungal medication
revelation has recognized three classes of normal items like griseofulvin10, polyenes11 and echinocandins12 and four
classes of engineered chemicals like azoles13, allylamines14, and flucytosine15 and phenyl morpholines16 with clinical
quality against contagious diseases. They all work by obstructing the dynamic site of a compound differently known as
lanosterol 14α-demethylase or cytochrome P450DM17. The movement of the azole antifungal is not just dictated by the
liking of the nitrogen for the heme iron, additionally by that of the N-l substituent for the apoprotein moiety of P45018-19.

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More than whatever other antifungal class, the azoles have been consistently refined and enhanced through the span of
right around 50 years. The most punctual azole for clinical use, chlormidazole, was truly not a decent pharma-ceutical
drug because of its danger, however the straightforwardness with which variations on the chlormidazole synthetic
structure could be orchestrated and tried prompted unfaltering advancement with azole antifungal specialists20. For the
treatment of entrepreneurial parasitic contaminations, the advancement of new powerful and expansive range antifungal
operators is a vital test for present day prescription, with an intense, wide range of hostile to contagious action, great
pharmacokinetics, and fabulous bio-accessibility. Different azole antifungal specialists Ketoconazole, Fluconazole,
Voriconazole and Itraconazole have been produced for clinical use21.
Classification of fungi22-23:
The major fungal infections are as follows:
 Cutaneous infections: It includes infections of skin, hair, nails. For examples; ring worm infections, Athlete’s foot
and Tinea cruris. These infections are most commonly found in humans and animals also.
 Mucocutaneous infections: It includes infection of mucous membranes, moist skin infections and infection of
gastro intestinal infection, perianal and vulvovaginal infections. For examples; Candida albicans. These infections
are commonly found in humans and animals also.
 Systemic or pulmonary infections: For examples; Invasive Aspergillus, Cryptococcal meningitis, pulmonary
histoplasmosis, and systemic candidiasis. These infections are less found in humans and animals also.
For treatment different antifungal specialists are utilized, for example, Antibiotics, Azoles, Allylamines, and
Antimetabolites. Another orally dynamic antifungal operator is an imidazole and triazole subsidiary fundamentally
identified with Micronaozle and Clotrimazole. It disables the combination of ergosterol (the fundamental sterol in
contagious cell layers) in helpless living beings, including yeast, organisms, and dermatophytes24-25.
Imidazole has turned into an essential piece of numerous pharmaceuticals (Fig.1). Manufactured imidazoles are available
in numerous fungicides and antifungal, hostile to protozoal and antihypertensive meds. Imidazole is a piece of the
theophylline particle, found in tea leaves and espresso beans, which animates the focal sensory system. Separated of its
utilization for pharmaceutical reason it additionally have differing applications in commercial enterprises, the imidazole
has been utilized widely as an erosion inhibitor on certain move metals, for example, copper26. Averting copper

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consumption is essential, particularly in watery frameworks, where the conductivity of the copper diminishes because of
erosion. Numerous mixes of modern and mechanical significance contain imidazole subsidiaries. Imidazole (1,3-diaza-
2,4-cyclopentadiene) is a planar five-part ring framework with 3C and 2N particle in 1 and 3 positions. The most
straightforward individual from the imidazole family is imidazole itself, a compound with atomic recipe C H N . It is
3 4 2
dissolvable in water and other polar solvents. The compound is delegated fragrant because of the nearness of a sextet of π-
electrons, comprising of a couple of electrons from the protonated nitrogen molecule and one from each of the staying
four iotas of the ring. Imidazole is amphoteric, i.e. it can work as both a corrosive and as a base. It exists in two
comparable tautomeric shapes on the grounds that the hydrogen particle can be situated on both of the two nitrogen
molecules. Imidazole is a profoundly polar compound 27-28.

H H
1 1
N N

5 2 5 N 2
N N
4 3 4 3
Triazole
Imidazole
Fig.: 1 Structure containing imidazole and triazole heterocyclic ring
Triazole ring framework has significant notoriety because of the flexible natural exercises of countless subsidiaries.
Triazole mixes (Fig.1) have demonstrated an awesome adequacy against antifungal contaminations. In 1944, Wooly
found brilliant antifungal properties of azole subordinates which prompted the innovation of fluconazole, voriconazole,
albaconazole and intraconazole29. The instrument of hindrance of contagious development is entrenched and it is found
that azoles play out their antifungal activity in two stages: restraint of ergosterol amalgamation, a noteworthy part of
parasitic layer and second step includes the obstructing of P450-ward compound i.e., lanodterol 14-a-demethylase (CYP
51). Absence of ergosterol and amassing of 14-a-demethylase (CYP 51) disfunctionalize the smoothness of a few
chemicals which situated in layer so that outcome in hindrance of parasitic development and replication of its DNA30.
Antifungal Drugs31-33: An antifungal medication will be medicine utilized as a part of the treatment of parasitic diseases,
for example, competitor's foot, ringworm, candidiasis (thrush), genuine systemic contaminations, for example,
cryptococcal meningitis, and other, such medication are typically gotten by a specialist's solution or bought from
therapeutic.

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Classification of Anti-Fungal drugs:
Antifungal medication or drug is utilized as a part of counteractive action of mycoses, for example, ring worms and
candidiasis, systemic disease like cryptococcal meningitis contamination and competitor's foot. These medications can be
ordered into 4 bunch as demonstrated as follows (Fig.2)
I. Polyene Antifungals
II. Imidazole, Thiazoles and Triazole Antifungals
III. Allyl amines
IV. Echinocandins

Fig.2: Classification of Anti-Fungal drugs
Polyene Antifungal:
A polyene is atom which having various conjugated twofold bonds. The Polyene Antifungal medications have a
macrocyclic ring, one side of which has a few conjugated twofold bonds and is profoundly lipophilic, while the other side
is hydrophilic with numerous OH bunches. A polar amino sugar and a carboxylic corrosive gathering are available toward
one side in the structure of Polyene Antifungal medications. The Polyene Antifungal medications tie with sterols in the
contagious cell film, primarily ergosterol.
Examples of Polyene Antifungals are:
a) Natamycin
b) Rimcidin

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c) Filipin
d) Nystatin
e) Amphotericin
Imidazole, Thiazoles and Triazole Antifungals:
Azoles antifungal medication hinders the catalyst lanosterol 14 α-demethylase. This chemical is important to change over
lanosterol to ergosterol. It gives hindrance of contagious development. Azole hostile to parasitic medication incorporates
Imidazole, Triazole, and thiazole
Examples of Imidazole:
Examples:
a) Bifonazole
b) Butoconazole
c) Clotrimazole
d) Econazole
e) Fenticonazole
f) Isoconazole
g) Ketoconazole
h) Luliconazole
i) Miconazole
j) Omoconazole
k) Oxiconazole
l) Sertaconazole
m) Sulconazole
n) Tioconazole
Examples of Triazoles:
Examples:
I. Albaconazole

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II. Efinaconazole
III. Fluconazole
IV. Isavuconazole
V. Itraconazole
VI. Posaconazole
VII. Ravuconazole
VIII. Terconazole
IX. Voriconazole
Examples of Thiazoles:
Examples:
I. Abafungin
Allylamines:
Allylamines inhibit the enzyme squalene epoxidase, another enzyme required for ergosterol synthesis.
Examples of Allylamines:
a) Terbinafine
b) Amorolfine
c) Naftifine
d) Butenafine
Echincandins:
Echincoandins inhibit he synthesis of glucan in the cell wall probably via the enzyme 1, 3-β glucan synthase:
a. Anidulafungin
b. Caspofungin
c. Micafungin
Antifungal Spectrum and Drug Interactions with Antifungal Therapy34-36:
These mixes are assessed in vitro against pioneering pathogenic growths including Candida spp, Aspergillus spp.
furthermore, Cryptococcus spp. Exacerbates that demonstrated wide range of action were assessed in mice systemic

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disease models. Precise alteration on the piperazine moiety brought about the revelation of novel triazoles and imidazole
which showed wide range antifungal movement in vitro and in vivo action. A few mixes with various substituents were
combined and assessed for their antifungal movement in light of the remedial adequacy of specific compound.
Fluconazole is incapable against Aspergillus species and less movement against Candida krusei and Candida glabrata.
Itraconazole demonstrates antifungal movement against the Candida species, these medications are slightest dynamic
against C. glabrata. Itraconazole is additionally dynamic and worries about unusual bioavailability. Voriconazole,
Posaconazole, and Ravuconazole have prevalent in vitro action against Candida albicans, Candida parapsilosis, Candida
tropicalis, and C. krusei. Other in vitro examines propose that new operators may have movement against Blastomyces
dermatitidis, Histoplasma capsulatum, Coccoidioides immitis, and Fusarium solani.
Table 1: Some example of Antifungal drug and their drug interaction
Sr.no. Antifungals Involved Mechanism Effect
1 Ketoconazole, Decreased dissolution/oral Decreased serum concentration of azole
Itraconazole absorption of solid dosage Antacids, H2 blockers and Proton
form Pump Inhibitors, Sulcrafate,
Didanosine (oral).
2 Ketoconazole, Induction of mammalian Increased metabolism of azole and
Itraconazole, cytochrome-P450 mediated reduce its efficacy. Isoniazid, Rifampin
Fluconazole, metabolism of azole. Phenytoin Carbamazepine,
Voriconazole, Phenobarbital, Ritonavir
Posaconazole. (voriconazole).
3 Ketoconazole, Inhibition of cytochrome Increased serum concentration
Itraconazole, P450 enzyme, specially of co-administered drug or metabolite
Voriconazole, CYP3A4, thereby raised Oral hypoglycemic S-warfarin, R-
Fluconazole the blood level of these Wafarin, Cyclosporine, Tacrolimus,
(usual doses). drugs. Phenytoin, Carbamazepine, Triazolam,
Alprazolam, Midazolam, Diltiazem
Lovastatin, Isoniazid, Rifampin,
Rifabutin, Quinidine, Protease
inhibitors (Saquinavir, Ritonavir),
Vincristine, Cyclophosphamide,
Digoxin, Loratidine

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4 Amphotericin- B Decrease in glomerular Increased accumulation of renally-
Filtration. cleared drugs and/or drug vehicles
Flucytosine, Fluconazole,
Beta-lactam antibiotics.
5 Amphotericin- B Enhanced glomerular and Enhanced nephrotoxicity
tubular toxicity in the Aminoglycosides, Cyclosporine
kidney. Intravenous Contrast Dye
Foscarnet.
Drugs containing Azole nucleus 37-42:
Azoles are a class of five membered nitrogen heterocyclic rings. It contains no less than one other non-carbon iota of
nitrogen, sulfur, or oxygen. Azoles are fragrant and two twofold bonds. One and stand out credit pair of electrons from
each heteroatom in the ring is a piece of the fragrant holding in azoles. There are effectively decreased analogs are
azolines and azolidines. Azoles are five membered heterocyclic mixes with two or more heteroatom in which no less than
one is nitrogen. Azoles are discovered broadly in normal sources and there are a few medications accessible which
contain azole ring critical like Isoxazole, Thiazole, Pyrazole, Triazole, and Tetrazole. The noticeable quality on enthused a
few scientists and restorative scientific experts to plan more up to date triazole by various engineered courses while
joining an assortment of a known pharmacophore into their sub-atomic frameworks and assessing them for their
conceivable organic and pharmacological properties. Triazoles go about as pharmacophore for vital antifungal restorative
operators like Terconazole, Ketoconazole, Fluconazole, Voriconazole and Itraconazole. Here we will concentrate on
1,2,4-Triazoles, which are by a long shot the best-known class of triazoles five membered heteroatoms with three nitrogen
molecules in the ring and comprise wide assortment of restorative action. The activity of azole on mycotic natural
chemistry and physiology has been concentrated broadly. At high focuses (micromolar) the azoles are fungicidal and at
low fixations (nanomolar), they are parasites static. Triazole is a class of heterocyclic mixes. It was found and studies
following numerous a years. The five membered heterocyclic rings are arranged or exists in two isomeric structures
(Fig.3)
 1, 2, 3-triazole
H
 1, 2, 4-triazole 1 H
N
5 N2 N 1

5 N 2
4 N 3
N 3
1,2,3-Triazole 4
1,2,4-Triazole

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Fig.3. Triazole exists as two isomers, 1,2,3-triazoles and 1,2,4- triazoles
Table 2: Some example of Antifungal Drugs containing an Azole nucleus:
Sr.no. Azole Antifungal Drugs Category
1 Isoxazole Cycloserine Antibacterial Activity
Sulfisoaxazole Antibacterial Activity
2 Thiazole Thiabendazole Anthelmintic Activity
Thiamine Vitamin B1
3 Imidazole Clotrimazole Antifungal Activity
Ketoconazole Antifungal Activity
Pilocarpine Cholinergic Activity
4 Pyrrazole Betazole Histamine releasing drug
5 Thiadiazole Acetazolamide Carbonic anhydrase inhibitor drug
6 Triazole Fluconazole Antifungal Activity
Itraconazole Antifungal Activity
Trazodone Antidepressant Activity
The lipophilic imidazoles, for example, Clotrimazole (I), Econazole (II) and Miconazole (III) showed poor systemic
accessibility taking after oral organization because of both poor retention and broad first pass digestion system so their
utilization has been constrained to topical treatment of shallow contagious contamination. Ketoconazole (IV) a more polar
imidazole brought into treatment in the late 1970s.
Voriconazole:
N
N N

HO N N

F
F F

Voriconazole
(2R,3S)-2-(2,4-Difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol.

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