QUINAZOLINONE, IMPORTANCE & MALARIA DRUG DISCOVERY

Sharad et al. World Journal of Pharmaceutical Research

www.wjpr.net Vol 8, Issue 2, 2019.

1457

QUINAZOLINONE, IMPORTANCE & MALARIA DRUG DISCOVERY

*Bhujbal Pooja Sharad, Shinde Vishakha Vikas, Tajane Arti Shantaram, Shitole

Pratiksha Balasaheb, S. S. Kadam, M. V. Gadhave, S. L. Jadhav and D. D. Gaikwad

VJSM‘s Vishal Institute of Pharmaceutical Education and Research, Ale, Pune.

ABSTRACT

Quinazolin-4-(3H)-one is a heterocyclic compounds, and its

derivatives are synthetically important molecule, thus used for the

synthesis of a large variety of compounds. The compound was first

prepared condensation products of anthranillic acid and amides by

Niementowski quinazolinone synthesis, named after its discoverer

Stefan Niementowski (1866-1925). The original work was published in

1895. The first quinazoline 2-cyano-3, 4-dihydro-4-oxoquinazoline by

griess at 1869. From literature survey states that most of the methods

used for the synthesis of quinazolinone compounds make use of

anthranillic acid or one of their functional derivatives as the starting materials. Quinazolin-4-

(3H)-one is synthesized when keto group is introduced in the pyrimidine ring of quinazoline.

Quinazolinone and its derivatives possess a large class of biologically active compounds that

exhibited broad spectrum of biological activities such as anti-HIV, anticancer, antifungal,

antibacterial, anti mutagenic, anticoccidial, anticonvulsant, anti-inflammatory, antidepressant,

anti malarial, antioxidant, anti leukemic, and antileishmanial activities and other activities.

Literature review state that quinazolinone derivatives have attracted strong interest in organic

and medicinal chemistry due to their potent biological and pharmacological activities. The

present review provides a brief overview on the recent advances and future perspectives on

pharmacological aspects of quinazolinone and its derivatives reported in the last decade.

KEYWORDS: Quinazolin-4-(3H)-one, Anti Fungal activity, Anti-inflammatory &

Antioxidant activity, Anti Malerial Activity, Anti cancer Activity, Maleria Drug Discovery.

INTRODUCTION

These compounds have been isolated from several families in the plant kingdom, as well as

from bacteria and animal species, and many are bio –synthetically derived from anthranillic

World Journal of Pharmaceutical Research SJIF Impact Factor 8.074

Volume 8, Issue 2, 1457-1484. Review Article ISSN 2277– 7105

Article Received on

20 Dec. 2018,

Revised on 10 Jan. 2019,

Accepted on 30 Jan. 2019

DOI: 10.20959/wjpr20192-14172

*Corresponding Author

Bhujbal Pooja Sharad

VJSM‘s Vishal Institute of

Pharmaceutical Education

and Research, Ale, Pune.



1458

acid. The first quinazoline alkaloid isolated was Vasicine (peganine) in 1888, produced by

Adhatoda vasica. Some other quinazoline alkaloids that have been isolated, characterized,

and synthesized are Chrysogine, Febrifugine, and Isofebrifugine.[1]

Important classes of fused

heterocyclic compound of quinazoline are found in more than 200 naturally occurring

alkaloids.

In plants Indol quinazolinones are mainly found in polygonum tinctorium lour,

strobilanthescusia, isatistinctoria and other blue dye producing plants. In micro organisms,

these compounds are isolated from fusariumlateritium nees, the marine bacterium bacillus

cereus 041381, the entomopathogenic fungus isaria farinose, streptomyces sp., chaetomium

species IFB-EO15, aspergillus nidulans MA-143 and penicllium aurantiogriseum.[2]

The

heterocyclic class of quinazoline nucleus is composed of two fused six membered aromatic

rings a benzene ring and pyrimidine ring. its chemical formula C8 H6 N2. Fused bicyclic

compound of quinazoline earlier called as benzo-1, 3 diazine was first prepared in the

laboratory in 1903 by Gabriel[3]

, although one of its derivatives was known much earlier.[4]

based on the position of keto or oxo group it may be classified into three types: 4(3H)

quinazolinone, 2(1H) quinazolinone, 4(1H,3H) Quinazolinone.[5]

From the above (fig: 1) three Quinazolinone structures, 4(3H)- quinazolinone are most

prevalent, either as natural products or as intermediates in various proposed biosynthetic

pathways.[6]

this is partly due to the structure being derived from the anthranillic acid or

different esters, anthranilamide and anthranilonitrile, (isatoicanhydride) anthranilates while

the 2(1H)-quinazolinone is predominantly a product of benzamides with nitriles or

anthranilonitrile.[7]

4(3H)Quinazolinone 2(1H) Quinazolinone



1459

Chemistry and Chemical Properties

Heterocyclic compound of quinazolinone having two structural isomers, 4-quinazolninoe and

2-quinazolinone.4-isomers are more common.

Chemical name of 4-quinazolinone is found to be quinazolin-4(3H)-one or 4-oxo-3, 4-

dihydroquinazoline or 4-oxoquinazolinol or (3H) quinazoline or 3, 4-dihydroquinazolin-4-

one or 4-quinazolinone. Two nitrogen atoms are incorporated in chemicals with two

conjoined aromatic rings, one of the carbon which is oxidized with keto oxygen. A strong

lactam-lactim tautomeric interaction is present in quinazolinones.[8]

this tautomeric

interaction can occur when a 4(3H)-quinazolinone containing a methyl in the 3-position when

chlorination with POCl3, the methyl group is lost and chlorination proceeds.[9]

When the methyl group is present in the 2-position, the tautomeric effect is extended

generating an exo methylene carbon. This compound can be condensed with aldehydes

producing 2-styryl-4-(3H)- quinazolinone. the result of tautomeric effects, increases the

reactivity effect of substituted -4- (3H)-quinazolinones.[10]

hence, the quinazolinone are

documented to be a ―privileged structure ― for drug development and discovery.[11]

moreover,

based on various literature, the quinazolinone ring system revealed that,[12]

the positions 2,6

and 8 of the ring system much more important for structural activity studies and also

chemotherapeutic activity could be increased by the inclusion of different heterocyclic

moieties at position 3 of the quinazolinone ring system.[13]



1460

General Methods For Synthesis Of Quinazolin-4-(3h) One

Quinazolin-4-(3H)-one have been synthesized from 2 amino benzoic acid on reaction with

foramide when heated at 1200c for 6hrs. the reaction takes place with elimination of water

and process through o-amido benzamides intermediate. This is known as Niementowski

synthesis.[19]

3, 1, 4-Benoxazones react with amines to form 3, 4-dihydro-4-oxoquinazolines. primary

aliphatic amines, anilines react with 2-methyl-5-nitro-4-oxoquinazolines. Anthranillic acid

fused and react with urea to produce the 1, 2, 3, 4-tertrahydro-2, 4-dioxoquinazoline.



1461

The most effective conversion of urethane derivatives. In this anilines are condensation with

urethane to form a quinazolin-4-(3H)-one. The substituted 2 methyl quinazolinone

derivatives was synthesized by heating urethane and acetanilide for 3hrs in the presence of

phosphorous pentoxide in tolune.

The synthesis of quinazolinone involves the reaction of N-acyl anthranillic acid by heating

with ammonia or substituted amines (Fig.8). the condensation of various primary amines and

N-acyl-5-nitroanthranilic acid to form the 2-methyl-3-aikyl-6-nitro-quinazolin-4-(3H)-one in

good yield.

Quinazolin-4-Ones As Antifungal Agents

Quinazolinone derivatives are one of the most active classes of compounds possessing a wide

spectrum of biological activity. Recently several scientists have been reported that

introduction of various heterocyclic moieties at 2 and 3 position of quinazolinone nucleus

modulate the antifungal activity. Various derivatives of quinazolinone have been synthesized

and evaluated for their antifungal activity against Candida Albicans, Aspergilles Niger,

Aspergillus Clavatus, Aspergillus Fumigatus, Aspergillus Parasiticus at various

concentrations. This article is sincere attempt to review chemistry and antifungal activity of

quinazolinones for last 20 year (1991-2011).[21]



1462

Fungi are heterotrophic microorganisms that are dependent upon organic compounds for their

nutrition. These are characterized by absorptive type of nutrition i.e. these feed by excretion

of enzymes into the substrate and by subsequent take up of digested compounds through the

cell wall. These differ from the bacteria in being ‗eukaryotes‘ because their genome is

organized in a nucleus surrounded by a cell wall. The word ‗fungi‘ is a general term which

includes both yeasts and molds and occupy an amazing variety and number of ecological

niches. They fulfill a critical function in nature by converting such polymers lignin, chitin,

and cellulose into humus. Fungal infections pose major problem in immunecompromised

patients. Problems have continued to aggreviate during past 20 years and are now significant

causes of morbidity and mortality.

This is particularly true in patients with hematological malignancies undergoing induction or

consolidation chemotherapy, in patients with acquired immunodeficiency secondary to

infection by human immunodeficiency viruses, and in immunosuppresed organ transplant

recipients. Patients with diabetic ketoacidosis are also at great risk. These infections also

occur in some iatrogenic or nosocomial settings. Some of these compounds showed good

antifungal activity than reference drug.[22]

Priya et al (2011) synthesized 4-(3H)-quinazolinone derivative (Fig. 1) from the reaction of

anthranilic acid and primary aromatic amines with Vilsmeier reagent in a few minutes under

microwave irradiation providing good yields. All the synthesized quinazolinones were

screened for their In vitro anti fungal activity against Candida Albicans, Aspergilles Niger.[23]

A series of 3-[3-(2-Substituted-4-oxo-4Hquinazolin-3-yl)-guanidino] propionic acid

derivatives (Fig. 2) have been synthesied by Palani and Vijay 2011. All the synthesized

compounds were characterized by IR, 1HNMR and mass spectra. Some of synthesized

compounds were more potent against Monascus puppures, Aspergillus fumigates, Aspergillus

parasiticus and Microsporum gypseum than the reference drug Clotrimazole.[24]



1463

A condensation of four different 3-formylchromones with 2-methyl/phenyl-3-amino-4(3H)-

quinazolinone and their dibromo analogs has resulted in twelve new compounds which have

been characterized as their respective 3-[N-(4-oxo-2-methyl/phenyl-3-quinazolinyl)-

formimidoyl]-chromones (Fig3), base on their spectro-analytical properties. These

compounds have been investigated as antifungal agent by Achaiah etal 1991.[25]

Quinazolinones As Anti-Microbial Activity

The number of life-threatening infectious diseases caused by multidrug -resistant bacteria has

reached an alarming level in many countries around the world. Severe Acute Respiratory

Syndrome (SARS) caused by the novel corona v irus SARS-CoV and bird flu caused by

avian influenza (H5N1) virus have emerged as two important infectious diseases with

pandemic potential. Both infections crossed the species barrier to infect humans This review

focused on the antimicrobial activity of quinazolinones and its derivative which can deal with

the increasing resistance by microbes and also having significant antimicrobial activity for

the effective treatment of various types of microbial diseases.[26]

Quinazolinones are classes of fused heterocycles that are of considerable interest because of

the diverse range of their biological properties, for example, anticancer, diuretic, anti-

inflammatory, anticonvulsant and antihyper tensive antimicrobial activities1 Quinazolinone

(fig.1) is a building block for approximately 150 naturally occur ring alkaloids isolated to

Figure 3



1464

date from a number of families of the plant kingdom, from animals and from

microorganisms. The first quinazolinone was synthesized1 in the late 1860s from anthranilic

acid and cyanogens to give 2-cyanoquinazolinone (1) 2 Methaqualone (2) was synthesized

for the first time in 1951 and it is the most well - known synthetic quinazolinone drug,

famous for its sedative–hypnotic effects.[27]

The synthesis of quinazolinones and will be

classified into the following five categories, based on the substitution patterns of the ring

system:

2-Substituted-4(3H)-quinazolinonesand –quinazolines

3-Substituted-4(3H)-quinazolinones

4-Substituted-quinazolines

2,3-Disubstituted-4(3H)-quinazolinones

2,4-Disubstituted-4(3H)-quinazolinones and quinazolines

Charansingh H. Gill et al (2010) synthesized a series of new quinazolinone derivatives.

Elemental analysis, IR, 1H NMR and mass spectral data elucidated the structures of all newly

synthesized compounds. In vitro antimicrobial activities of the synthesized compounds were

investigated against Gram-positive Bacillus subtilis (ATCC No. 6633), Staphylococcus

aureus (ATCC No. 25923), Gram-negative Salmonella typhimurium (ATCC No. 23564),

Pseudomonas aeruginosa (ATCC No. 27853) and fungi Candida albicans and Aspergillus

niger. Among all the tested compounds, some of the tested compounds showed equipotent



1465

activity with standard. The antibacterial activities of the synthesized compounds 8a–j were

det ermined by the well –diffusion method.[28]

Adnan A. Kadi etal (2009) synthesized a new series of 6-i odo-2-phen ylquinazolin -4(3H)-

one derivatives was prepared and screened for antimicrobial activity. The thioureide

derivatives, the carbohydrazide derivatives displayed excellent broadspectrum antimicrobial

activity. Some compounds showed moderate activity against Candida albicans and

Pseudomonas aeruginosa. None of the tested compounds was as active as the reference

standard drugs ampicillin and clotrimazole. The detailed synthesis, antimicrobial activit y,

and the minimum inhibitor concentrations (MIC) are reported.[29]

Quinazolinone As Anti-Inflammatory And Antioxidant Activity

Inflammation is the result of concerted participation of a large number of vasoactive, chemo

tactic and proliferative factors at different stages and there are many targets for anti

inflammatory action Irrespective of the type of injury the inflammatory response is

suppressed by glucocorticoids. This is the basis of most of their clinical uses. Glucocorticoids

interfere on several steps in the inflammatoryresponse. Corticoids are only palliative, do not

remove the cause of inflammation, the underlying disease continues to progress while



1466

manifestations are dampened. They favor spread of infections as capacity of defensive Cells

to kill microorganisms is impaired. They also interfere with healing and scar formation.

Peptic ulcer may perforate asymptomatically. Indiscriminate use of corticoids is hazardous.

Other than corticosteroids the NSAIDs are also used to treat inflammation. The major

mechanism of action of the NSAIDs is the inhibition of prostaglandin (PG) synthesis or

preferential or selective cox-2 inhibition.[30-31]

Due to inhibition of PG synthesis it may produce toxicities like gastric mucosal damage,

bleeding, inhibition of platelet function, delay/prolongation of labour, asthma and

anaphylactoid reaction in some individuals. The inhibition of cox-2 may enhance the

cardiovascular risk. The search for new molecules with anti-oxidant properties is a very

active domain of research, since they can protect the human body from free radicals and

retard the progress of many chronic diseases, such as vascular diseases, some forms of cancer

and oxidative stress responsible for DNA, protein and membrane damage. Reactive oxygen

species (ROS) such as superoxide anions, hydrogen peroxide, hydroxyl and nitric oxide

radicals, play an important role in oxidative stress related to the pathogenesis of various

important diseases.[32-33]

Anti-oxidants act as a major defense against radical mediated toxicity by protecting the

damages caused by free radicals. Anti-oxidants agents are effective in the prevention and

treatment of complex diseases, like atherosclerosis, stroke, diabetes, Alzheimer‘s disease and

cancer. Flavonoids and phenolic compounds are widely distributed in plants which have been

reported to exert multiple biological effects including antioxidants, free radical scavenging

abilities, anti-inflammatory and anticarcinogenic. It has attracted a great deal of research

interest in natural antioxidants. A number of synthetic compounds such as quinazolinones

have also been extremely exploited for antioxidants activity. The above observation

stimulated our interest to synthesize a series of compounds containing quinazolin-4 (3H) -one

ring system associated with various primary aromatic amines moiety and to evaluate their

antioxidant potency. This study is aimed to investigate the Invitro anti inflammatory by using

bovine serum albumin (BSA), antioxidant and radical scavenging properties of quinazolinone

with different analytical methodology.

The antioxidant potential of synthesised compound was explained on the basis of total

antioxidant activity by, ferrous ions chelating activity, scavenging activity of free radicals

such as DPPH, Hydrogen peroxide radical scavenging activity and Nitric oxide scavenging



1467

activity assay[33-38]

Furthermore, an important goal of this investigation is to show the in vitro

antioxidative effects of quinazolinone as compared with standard antioxidants such as

ascorbic acid, BHA, BHT, commonly used by the pharmaceutical industry.

E. Manivannan and S. C. Chaturvedi have synthesized a series of methyl sulfanyl/methyl

sulfonyl substituted 2,3-diaryl quinazolinone derivatives. These compounds were evaluated

for both non-ulcerogenic and anti-inflammatory activities. The compound 19 emerged as the

most active compound in this series. Halogen atoms or methoxy groups at R1 and R3 position

of 2,3-diaryl-3H-quinazolin-4-ones appears to have a positive effect on the non-ulcerogenic

and anti-inflammatory potency.

Rakesh etal, designed and synthesized a series of quinazolinone derived Schiff‘s bases and

screnned for their antioxidant activity. Compounds 1 and 2 with OH and OCH3 groups in

benzene ring (electron donating) exhibited stronger radical scavenging activities than the

standards.

Quinazolinone As Anticonvulsant Acitivity

Novel 3-substituted-6-fluro-2-methyl-quinazolin-4(3H)-one derivatives were synthesized and

tested for anticonvulsant activity. All the newly synthesized compounds had significant

1 2



1468

anticonvulsant activity. Three compounds showed promising activity, while the other five

compounds had moderate activity. All compounds tested for neurotoxicity showed a good

safety margin. In silico design, synthesis and pharmacological screening of novel mono

bromo quinazolinone derivatives as NMDA receptor antagonists for anticonvulsant activity

was reported. Compounds (49) gave good results.[39]

Ponnilavarasan ilangovan et al. synthesized a series of 3-N'(benzylidene semicarbazone)-2-

phenyl 3H-quinazolin-4-one and evaluated for anticonvulsant and neurotoxicity. Compound

displayed potent activity.[41]

Schiff bases of 3-amino-6, 8-dibromo-2-phenyl quinazolin-4-

(3H)-ones with various substituted aldehydes were synthesized and evaluated for their

anticonvulsant activity on albino mice by maximal electroshock method using phenytoin as a

standard. The compound (51) bearing a cinnamoyl functionality displayed a very high

activity.[40]



1469

Quinazolinone As Anti-Malerial Activity

Effective antimalarial drugs with a simpler structure and with a low cost synthetic

methodology, few 2,3-substituted quinazolin-4(3H)-one derivatives were designed and

synthesized according to the structural features of febrifugine [a] which is obtained from

Chinese plant roots of Dichroa febrifuga Lour. (Chinese name: Cha΄ng Shan), a

saxifragaceous plant that has been employed against malaria fevers, and no parasite resistant

to D. febrifuga has been reported. Two alkaloids, i) febrifugine [a] and ii) isofebrifugine [b],

were isolated from D. febrifuga as active principles against malaria.

New derivatives with incorporation of an indole and a fluorinated aromatic ring at 2 and 3

positions of quinazolinone, respectively, were prepared by Dave and colleagues. All the

newly synthesized compounds were screened for antibacterial activity. Three derivatives

including a, (2-fluoro benzylideneamino) b, (benzylideneamino) and c, (2-nitro

benzylideneamino) were found to be active against S. aureus.

Quinazolinone As Anti-Tubular Activity

Meenu chaudhary etal[42]

A series of novel substituted (1, 2, 4) triazolo (1,5c) quinazolinone

derivatives were synthesized by mannich reaction using foramide and different secondary

amines. Structures of compounds were confirmed by IR, H-NMR and mass spectroscopic

analysis. The anti tubercular activity of synthesized compounds was performed against

M.tuberculosis H37Rv at concentration 30μg/ml using streptomycin and pyrazinamide



1470

7.5μg/ml as standard drug. All the synthesized compounds have shown antitubercular activity

as compared to standard drug. compounds shown very good anti tubercular activity.

Kalpnana Devi etal[43]

Synthesis and anti tubercular activity of some new 2-3-disubstituted

quinazolinone were reported. Nicotinic acid and thionyl chloride were refluxed for 2hrs to

form the nicotinyl acid chloride which was added drop wise into the solution of anthranillic

acid in dry pyridine to form 2-(pyridine-2-yl)-4H-benzo(d)(1,3)oxazin-4-one). this compound

react with hydrazine hydrate to form the 3-amino-2-(pyridine-2-yl) quinazolin-4(3H)one.

This compound react with2-(secondary amino (morpholine))-acid chloride in the presence of

dry pyridine to form the 2-(substituted)-N-(4-oxo-2-pyridin-2-yl-4H-quinazolin-3-yl)-

acetamide derivatives.

All the synthesized compounds were screened for in vitro anti tubercular activity by MABA

method against mycobacterium tuberculosis and it was found that almost all the compounds

have exhibited moderate activity (MIC at 50μg/ml) as compared to standard drugs which

have shown activity at 3.125μg/ml. the structure of all the synthesized compounds was

confirmed by IR, NMR, and mass, CHN spectral data.

1



1471

Quinazolinone As A Anti-cancer Acivity

AAF. Wasfy etal[44]

Synthesis and anti-cancer properties of novel quinazoline derivatives

were reported. The results revealed that some of the synthesized compounds have a signicant

biological activity as anti cancer agents. a novel quinazoline were synthesized by reaction of

5-chloroanthranilic acid with isonicotinyl chloride in dry pyridine to form 5-chloro-2-

(isonicotinamido) benzoic acid. Cylocodensation of 5-chloro-2-(isonicotinamido) benzoic

acid with acetic anhydride to form 6-chloro-2-(pyridine-4-yl)-4H-benzo(d)(1,3)oxacin-4-one.

Interaction of 5-chloro-2-(isonicotinamido) benzoic acid with ammonium acetatein the

presence of ammonium hydroxide in sand bath to produce 6-chloro-2-(pyridine-4-

yl)quinazolin-4(3H)-one. the reaction of 6-chloro-2-(pyridine-4-yl)-4H-benzo(d)(1,3)oxacin-

4-one with phosphorous pentachloride to form 6-chloro-4-chloro-2-(pyridine-4-

yl)quinazoline. Interaction of 6-chloro-4-chloro-2-(pyridine-4-yl) quinazoline with p-amino

acetophenone in pyridine to form 1-(4-(6-choloro-2-(pyridine-4-yl) quinazolin-4-

ylamino)phenyl) ethanone.1-(4-(6-choloro-2-(pyridine-4-yl) quinazolin-4-ylamino) phenyl)

ethanonereacted with different aldehydes. certain new quinazoline

derivatives(3,4,5,6b,6d,8b,8d) were synthesized, characterized and subjected to a screening

system for evaluation of anti tumor activity against liver cancer (HEPG2) tumor cell line. The

anti tumor activity results indicated that the selected quinazoline derivatives showed anti

tumor activity against liver cancer tumor cell line tested but with varying intensities in

comparison to the known anti cancer drug:doxorubicin. compounds (6b,8d) exhibited a

strong growth inhibition activity against liver cancer (HEPG2) on the tested tumor panel cell

line in comparison to the standard drug. The newly synthesized compounds were

characterized by IR, NMR analysis.

All newly synthesized compounds were screened for their anti cancer studies.



1472

Zahoor et al[45]

Anticancer activity of a novel quinazolinone-chalcone derivative were

reported. The condensation of anthranillic acid with acetic anhydride to form the

benzoxazinone. benzoxazinone was coupled with 3-amino acetophenone to produce the

quinazolinone. this quinazolinone was made to undergo condensation reaction with

substituted benzaldehydes in presence of a base to afford the desired quinazolinone –halcone

derivatives.anti cancer activity determined through MTTassay, colony formation assay,

wound healing assay, cell cycle and western blot analysis in mia paca-2 cells treated with

quinazolinone –chalcone derivatives.

The findings are indicative of synthesized compounds exerting anti cancer activity through

cell cycle arrest at G2/M phase and not through apoptosis. Reduction in the motility of mia

paca -2 cells indicates anti-metastatic potential of quinazolinone-chalcone derivatives.

Quinazolinone Derivatives As A Potential Class Of Compounds In Malaria Drug

Discovery

INTRODUCTION

Malaria is symptoms are described in ancient Chinese and Sanskrit medical texts and

Hippocrates referred to the disease in the 4th

Century BC.[46]

It was associated to ‗bad air‘ by

the 18th century Italians meaning mala ria from where the name malaria is derived.[47-48]

In

children under age five malaria accounts for almost 1 in 10 deaths worldwide and 1 in 5

deaths in Sub- Saharan Africa (SSA), which makes it one among the leading killers.[49]

More

than 80% of deaths due to malaria occurs in SSA where 90% accounts for children under

five. Malaria causes over a million deaths each year (2 per cent of the global total of deaths),

with hundreds of millions of clinical episodes per annum.[48]

Malaria also places a

tremendous burden on national health systems and individual families.[50]

In the

governmental budget proportions allocated to health system ranges from 5% in Africa, Asia



1473

and the Who Easten Mediterranean Region, to well over 20% in some countries in

Americans.[51]

The economic impact of malaria is disproportionately felt by the poor.

A study in Tanzania indicated that the death due to acute fever among children of the poorest

families was 39% higher than among the wealthiest children.[52]

The Plasmodium parasite,

responsible for causing malaria, is a protozoan with four identified species which causes

human malaria via a female Anophelous mosquito as a vector, namely: P.falciparum,

P.vivax, P. malariae and P. ovale. Even though these four species of plasmodium parasite

can infect human and cause malaria, P. falciparum is the most risky and potentially

threatening.[53]

However, Plasmodium vivax also creates significant human morbidity, suffering and

economic loss, being responsible for 70 million to 80 million cases of the global malaria

burden each year.[54]

Life Cycle of Maleria

Malaria parasites live in mosquito and human hosts and go through several developmental

and transmission phases on the way to causing disease in humans.[55]

Malaria is a mosquito-

borne infectious disease transmitted by a parasitic protozoan in the Plasmodium genus.[56]

The malaria parasite is a single-cell protozoan (plasmodium). Members of the genus

Plasmodium have a complex life cycle, A sexual stage occurs within the Anopheles mosquito,

while asexual stages take place in the host. Malaria is actually transmitted from one human to

another through the insect vector, the female Anopheles mosquito.[58-59]

Only the female

mosquito bites because it needs blood to produce eggs. Mosquitoes bite a variety of hosts -

birds, dogs, horses, cattle and people.[57]

The infection of human erythrocytes is ultimately

responsible for all the clinical pathologies associated with the disease.[55]

Initially, when female Anopheles mosquito bites an infected human, it gets infected and

intakes gametocytes. The sexual transformation of gametocytes into ookinetes and ookinetes

into oocyst takes place inside the midgut of mosquito. Finally, sporozoites are developed

from oocysts, which eventually burst, releasing sporozoites into the salivary gland. At the

mosquito‘s next feeding, the sporozoites are injected into the blood stream of another human

to begin the asexual stages. Once the mosquito inoculates the parasites (sporozoites) into the

blood stream, the parasites invade the liver within 30 min and start replicating there



1474

(schizonts). In addition, P. vivax and P. ovale can remain dormant in the liver and cause

relapses years after the initial infection.[60]

After a relatively brief residence (less than an hour) in the systemic circulation, the

sporozoites invade liver parenchymal cells, where they divide and develop asexually into

multinucleated schizonts. These are the primary exoerythrocytic tissue forms of the parasite.

When this primary stage of development is completed (6–12 days), the schizonts will rupture,

releasing merozoites into the blood. These latter forms invade host erythrocytes, where they

again grow and divide asexually (erythrocytic schizogony) and become red cell schizonts.

Some of the parasites differentiate into sexual (male and female) forms, or gametocytes. If

the diseased human is bitten by a mosquito at this time, the gametes will be taken up into the

organism‘s gut to repeat the sexual cycle.[58]

Prevention & Control of Maleria

Since the launch of the Roll Back Malaria initiative by WHO in 1998 and particularly in the

past few years, malaria control has intensified in endemic countries, supported by a greatly

increased investment of financial resources and technical assistance from the international

community. Three main strategies are presently attempting to control the disease:

vaccination, vector control and parasiticidal drugs. Of these, parasiticidal drugs are currently

the main line of disease control until vaccination or mosquito control can be implemented

more successfully.[61]

To eradicate malaria, achievable milestones must be set. The publication of the Global

Malaria Action Plan (GMAP) by the WHO set some of those milestones; for example, a

tenfold reduction in malaria incidence and deaths by 2030 (compared with 2015). The first

GMAP was published in 2008 and covered the period until 2015. More recently, input and

consultations are being sought from experts and regions for GMAP2. Both GMAP2 and the

Global Technical Strategy for Malaria(co-ordinated by the WHO) will cover the 10 years

between 2016 and 2025 24. On Oct 17, 2007, Bill and Melinda Gates called for complete

eradication to be adopted as the new goal for the ageold fight against malaria, with the

Director General of WHO, Margaret Chan, promptly echoing their conviction. Two crucial

questions stand out for those organisations that will now begin striving towards malaria

eradication. When and how can it be achieved?[62-63]

During the past decade, a range of

organizations have led a global movement to combat malaria.



1475

Accurate assessments of the levels and time trends in malaria burden are crucial for the

assessment of progress towards goals and the focusing of future efforts. A report released by

WHO finds that the global burden of malaria remains enormous, but that access to malaria

control interventions, especially bed nets in Africa, increased sharply between 2004 and

2006.[64]

As a result of malaria control efforts across the world, 80 countries are now in the

phase of malaria control; 12 countries are making the program transition to elimination; 11

countries are operating malaria elimination programs; and 6 countries are actively engaged in

preventing reintroduction of malaria. Despite extensive control efforts, the incidence of the

disease is not decreasing in most malaria-endemic areas of the world and in some it is clearly

increasing.[65]

Drugs for Treatment of Maleria

Currently available antimalarial agents comprises classes of drugs classified based on their

chemical structures and mechanism of action.[66]

The number of antimalarial drugs in use

today is limited due to the wide spread of resistance. Those in use to date are the quinine

derivatives, the artemisinines and antifolate combination drugs.

Quinoline Derivatives

The quinoline derivatives have long been used for the treatment of malaria, the first one being

quinine which is isolated from the bark extract of Cinchona trees. In 17th century the

pulverized bark was widely used in Europe. As the quest for new compounds for treating

malaria was on rise the first 4(8)-aminoquinolines derivatives were developed.[67]

The success

of the antimalarial aminoquinoline drugs has been based on excellent clinical efficacy,

limited host toxicity, ease of use and simple, cost-effective synthesis.[68]

The 4-

aminoquinoline derivatives of quinine. chloroquine, amodiaquine and mefloquine whereas

primaquine is an 8-aminoquinoline derivative of quinine.[69]

The mode of action and

mechanism of resistance of these derivatives is not fully understood since much of the focus

is directed to identification of novel chemotherapeutic agents.[70]

The quinolines are known to

inhibit the polymerization of heme and prevent disposal of polymers from the food vacuole to

the cytoplasm where hemozoin is formed. This leads to intraparasitic accumulation of free-

heme, which is highly toxic to the parasite.[71]

Antifolate Combination Drugs

Antifolates are various combinations of dihydrofolate-reductase inhibitors (proguanil,

pyrimethamine, chlorproguanil and trimethoprim) and sulfa drugs (sulfadoxine,



1476

sulfamethoxazole, dapsone and others), Most commonly used combinations include

sulfadoxine-pyrimethamin and sulfamethoxazole-trimethoprim. Currently an antifolate

combination drug, dapsone andchlorproguanil, was tested and has a more potent synergistic

antimalarial action than other drugs such as sulfadoxine-pyrimethamine.[69]

Antibiotics

Tetracyclines usually in conjunction with quinine, have been reported to be suppressive in

human malaria and proved to be of value as an additional drug for the radical cure of

chloroquine-resistant falciparum infections. Clindamycin alone or in combination with

quinine, has also been used for the treatment of CQR falciparum malaria in Thiland with

good results, despite the side effects. In non-immune individuals its efficacy has not been

fully established.[72]

Artemisinin Compounds

Artemisinin (qinghaosu) artesunate, artemether and arteether have all been used alone or

incombination therapy as antimalarial agents.[73]

Artemisinin which is present in the extracts

of the aerial parts of the plant Artemissia annua, has been utilized for more than a millennia

for fever and rediscovered as antimalarial agent.[74]

Emergence of multidrug–resistant strains

in P. falciparum and chloroquine –resistant strains of P. vivax in 6 malaria endemic areas

emphasize on preparing new, effective and affordable antimalarial medications.

Thus, artemisinin combination therapy (ACT) was recommended by WHO for successful

treatment of uncomplicated malaria.[75]

Others Compound With Antimalerial Activity

Halofantrine which consists phenanthrene-methanol and is a active against the erythrocytic

stage of malaria. In areas of multi drug resistant falciparum malaria, halofantrine is mainly

recommended. Atovaquone which is a hydroxynaphtoquinone, is most widely used for

treating opportunistic infections in immune-compromised patients. It is also effective against

CQR P.falciparum. however its usually given in combination with proguanil to avoid the

development of resistance. Lumefantrine a fluoromethanol compound, is being produced as a

fixed combination tablet with artemether.[69]



1477

Recent Advances In Anti Malerial Drug Development

Mefloquine is the only synthetic antimalrial agent discovered over the past 30 years.

Whereas, artimisisin, which is discovered in this period is a natural product, whose medicinal

actions have been known for over 2 millennia.[76]

However the sudden resurgence of malaria

and emergence of malarial drug resistancein many countries of the world have made the

synthetic efforts toward new antimalarial drugs very important. Recently some synthetic

compounds are reported to have potent antimalarial activity against different Plasmodium

species.

Clinical trials conducted with fosmidomycin in combination with clindamycin or artesunate

have shown high efficiency in the treatment of acute, uncomplicated malaria. Recently

synthetic chalcone analogue, 2,4-dimethoxy-4′butoxychalcone was reported to have

outstanding antimalarial activity.[77-78]

In addition to this, the antimalarial activity of

naphthoquinone derivatives has been widely reported. Acylation of the hydroxyl moiety of

atovaquone led to a compound exhibiting similar activity as atovaquone and more active than

chloroquine and quinine against P. falciparum.[79]

Arylsulfonyl acridinyl derivatives having

acridinic ring and arylsulfone moiety together, are also reported to have an antimalarial

activity on P. falciparum.[80]

Structure-based drug design resulted in P218 a DHFR inhibitor active against all clinically

relevant mutations. P218 combines the pyrimidine ring of pyrimethamine which brings

potency, and the linker of the DHFR inhibitor WR99210 which tolerates mutations due to its

flexibility. P218 is more potent than pyrimeth amine against DHFR in the wild-type strain

TM4 (IC50= 4.6 and 58 nM, respectively) as well as in the quadruple mutant strain V1/S

(IC50= 56 and >100,000 nM, respectively).[60]

Recently, a series of bisquinolines where the 4-aminoquinoline part of chloroquine was

retained and the two units were joined by bisamide links, have been synthesized and screened

against CQS and CQR strains of P. falciparum in vitro. The resistant indices for all the

compounds were found to be lower than that of CQ. The position of attachment and length of

the linker chain had marked effect on the activity.[71]

CONCLUSION

Globally the importance fighting malaria is recognized, however the burden of malaria is still

high in developing countries especially in the Sub-Saharan African region. Although decades



1478

long efforts and accadamic engagements has been there malaria continues to pose challenge

in view of its resurgence and problem of drug resistance. Most of the existing antimalarial

drugs including chloroquine are brought to the side line by the emergence of resistance.

Currently a combination therapy is recommended by WHO to reduce the risk of drug

resistance. However, there are still reports indicating drug resistance even to those used in

combination recommended by WHO such as artimisinin.

Thus, malaria drug discovery is unquestionably urgent to battle against the disease. To

minimize the likely hood of cross resistance the focus of the drug discovery must be on newer

drug targets, such as plasmepsin. In finding a novel antimalarial agent various library of

chemicals has been investigated and hetrocyclic compounds such as chalcones,

thienopyrimidinone, quinolones, quinazolins, quinazolinones, enaminones, and acridines

have been reported to posses antimalarial activity. Further, assessment on quinazolinones has

showed fruitful results and their activity as antimalarial agent is appealing. In this regard,

febrifugine and its derivatives have been reported to have excellent activity.

Therefore, quinazolinones can be considered potential compounds in seeking for novel drugs

that act against the malarial pathogen.

REFERENCES

1. Mahesh Chand, archana gupta and Subash C Jain, Antimicrobial activity of quinazolinone

derivatives: A Review, Heterocyclic letters, 2017; (1): 201-214.

2. Dan He, Menglei Wang, Siju Zhao, Yisong Shu, Honglian Zeng, Cheng Xiao, Cheng Lu,

Yuanyan Liu, pharmaceutical prospects of naturally occurring quinazolinone and its

derivatives, fitoterapia, 2017; 119: 136-149.

3. Griess, P.Ber. Dtsch. Chem. Ges., 1903; 36: 800.

4. Oriefs, Ber. Dtsch. Chem. Ges., 1869; 2: 416.

5. Oriefs, Ber. Dtsch. Chem. Ges., 1869; 2: 415.

6. Dewick, P.M., Medical natural products John Wiley & Sons ltd, U.K, 2009; 395-397.

7. Wilklund, P.Bergman, and J. Curr. org. synth, 2006; 3: 379.

8. Weber, C: Demeter, A:Szenndrei, G:Greiner, I. Tetrahedron let, 2003; 44: 7533.

9. Bogert, M.T: Seil, H. A. J. Am. Chem. Soc., 1907; 29: 517.

10. Bogert, M.T: May, C.E.J. Am. Chem. Soc., 1909; 31: 517.

11. Horton, D. A.: Bourne, G.T: Smythe, M.L. Chem. Rev., 2003; 103(3): 893.



1479

12. Hour, M. J: Hung, L. J: Kuo, S.C: Xia, Y.: Bastow, K.: Nakanishi, Y.: Hamel, E.: Lee,

K.H. J. Med. chem, 2000; 43: 4479.

13. Ghorab, M. M.: Abdel-Hamide, S.G.: El-Hakim A.E.: Indian j. Heterocycl. chem, 1995;

5: 115.

14. Chen K, Wang K, Kirichian AM, et al., In siligo design, synthesis, and biological

evaluation of radio iodinated quinazolinone derivatives for alkaline phosphate-mediated

cancer diagnosis and therapy. mol cancer ther, 2006; 5: 3001-3013.

15. Blagden SP, Molife LR, Seebaran A, Payne M, Reid AM, et al., A phase 1 trial of

ispinesib, a kinesin spindle protein inhibitor, with docetaxel in patients with advanced

solid tumours. Br J Cancer, 2008; 98: 894-899.

16. Jodrell Dl, Bowman A, Rye R, Byrne B, Boddy A, A phase1 study of the lipophilic

thymidylate synthase inhibitor thymitaq given by 10-day oral administration. Br J Cancer:

1999; 79: 915-920.

17. McLaughlin, Noel, p., and evans, P.Dihydroxylation of vinyl sulfones: stereoselsctive

synthesis of (+)- and (-)-Febrifugine and Halofugine, Journal of organic chemistry, 2010;

75(2): 518.

18. Sundrud MS, Koralov SB, Feuerer M, Calado DP, Kozhaya AE et al., Halofuginone

inhibits TH17 cell differentiation by activating the amino acid starvation response,

Science, 2009; 324: 1334-1338.

19. Armarego WLF, A Text book of quinazoline.

20. Mohammad asif, Chemical Characteristics, Syntheticmethods, and Biological potential of

quinazoline and quinazolinone derivatives, International Journal of Medicinal Chemistry,

2014; 395637: 27.

21. Achaial G, Reddy V M, Reddy V Malla. Synthesis and biological activities of 3-[n-(4-

oxo-2-substituted-3-quinazolinyl) formimidoyl] chromones. Indian J Pharm. Sci., 1991;

53: 253-255.

22. Anjani K. Tiwari, Vinay Kumar Singh, Aruna Bajpai, Gauri Shukla, Sweta Singh, Anil K.

Mishra. Synthesis and biological properties of 4-(3H)-quinazolone derivatives European

Journal of Medicinal Chemistry, 2007; 42(9): 1234-1238.

23. Bekhit, A.A. Synthesis and Antimicrobial Evaluation of Some Quinazolinone Derivatives

Bull. Pharm. Sci. Assiut Univ., 1995; 18: 107-114.

24. Bekhit AA, Habib NS, El-Din A, Bekhit A. Synthesis and antimicrobial evaluation of

chalcone and syndrome derivatives of 4- (3H)-quinazolinone. Boll Chim Farm., 2001;

140(5): 297-301.



1480

25. Bhusare, S.R., Shinde, A.B., Pawar, R.P., and Vibhute, Y.B. Synthesis And Antimicrobial

Activity Of Heterocyclic Schiff Bases, 4-Thiazolidinones And 2-Azetidinones. Indian J.

Pharm. Sci., 2004; 66: 228-231.

26. Connolly DJ, Cusack D, Sullivan T PO and Guiry PJ. Synthesis of quinazolinones and

quinazolines. Tetr ahedron, 2005; 61: 10153–10202.

27. Mhaske SB and Argade NP. The chemistry of recently isolated natur ally occurring

quinazolinone alkaloids. Tetr ahedron, 2006; 62: 9787–9826.

28. Mandhane PG, Joshi RS, Mahajan PS, Nikam MD, Nagargoje DR and Gill CH.

Synthesis, char acterization and antimicrobial screening of substituted quiazolinones der

ivatives. Arabian Journal of Chemistry, 2011; 1878-5352.

29. Kadi AA. Synthesis and antimicrobial activity of some new quinazolin -4(3H)-one

derivatives. Journal of Saudi Chemical Society, 2011; 15: 95–100.

30. G.W Schmid-Schonbein, Annu Rev Biomed Eng., 2006; 8: 93.

31. S.M Lucas, N.J Rothwell and R.M Gibson, J. Pharmacol., 2006; 147: 232.

32. K.Z Guyton, M. Gorospe and N.J Holbrook, Cold spring Harbor laboratory press, New

York., 1997; 247.

33. I.Gulicin, Toxicology., 2006; 217: 213.

34. D.L.Trepanier, and S.Sundar, J.Heterocycl. Chem, 1975; 12: 231.

35. V.Alagarsamy, V.Rajasalomon and K.Dhanabal, Bioorg. Med. Chem., 2007; 15: 235.

36. J.N.Sharma, A.M.Samud and M.Z.Asmawi, Inflammopharmacolog, 12, 2004; 4(2):

(2011), 418-424.

37. IIhami Gülçin, Zubeyr Huyut, Mahfuz Elmastas and Y.Hassan, Toxicology., 2009; 3: 43.

38. Yerra Rajeshwar, G.P. Senthil Kumar, Malaya Gupta and Upal Kanti Mazumder,

European Bulletinof Drug Research, 2005; 13: 1.

39. Amit Nerkar G, Poorvashree Joshi P, Sarika Singh M, Satyendra More A, Mahesh A,

Hemanth Chikhale U, et al. In silico design, synthesis and pharmacological screening of

novel mono and di-bromo quinazolinone derivatives as nmda receptor antagonists for

anticonvulsant activity. Int J Pharm Pharm Sci., 2013; 5: 331.

40. Ponnilavarasan I, Swastika G, Vijay P, James Stables P. Design and synthesis of novel

quinazolinone derivatives as broad spectrum anticonvulsants. Pharm Lett., 2010; 2:

13-21.

41. Paneersalvam P, Raj T, Ishar MPS, Singh B, Sharma V, Rather BA. Anticonvulsant

activity of schiff bases of 3-amino-6, 8-dibromo-2-phenyl-quinazolin-4(3H)-ones. Indian

J Pharm Sci., 2010; 72: 375-8.



1481

42. Meenu Chaudhary, S.Bhattacharya, Yusra Ahmad, design and synthesis of quinazolinone

derivatives as a novel anti tubercular agents, Der Pharmacia letter, 2012; 4(3): 954-960.

43. Kalpana Devi and Monica Kachroo, synthesis and anti tubercular activity of some new 2,

3-disubstituted quinazolinones, Der pharma chemical, 2014; 6(5): 353-359.

44. AAF.Wasfy, NA.Mohmed and AA.Salman, synthesis and anti-cancer properties of novel

quinazoline derivatives, international journal of research in pharmacy and chemistry,

2015; 5(1): 34-40.

45. Zahoor A. Wani, Anup S. Pathania, Girish Mahajan, Akanksha Behl, et al., anticancer

activity of a novel quinazolinone-chalcone derivative through cell cycle arrestin

pancreatic cancer cell line, Journal of solid tumors., /www.sciedu.ca, 2015; 5(2): 73-85.

46. 1. de Oliveira RB., de Souza-Fagundes EM., Soares RPP., Andrade AA., Krettli AU.,

Zani CL, 2008. Synthesis and antimalarial activity of semicarbazone and

thiosemicarbazone derivatives. Eur J Med Chem., 43: 1983–8.

https://doi.org/10.1016/j.ejmech.2007.11.012.

47. Kalra BS., Chawla S., Gupta P., Valecha N, 2006. Screening of antimalarial drugs: An

overview. Indian J Pharmacol., 38: 5. https://doi.org/10.4103/0253-7613.19846.

48. World Economic Forum. Global Health Initiative, Harvard School of Public Health

Business and malaria: a neglected threat? Geneva, Switzerland: World Economic Forum,

Global Health Initiative in cooperation with Harvard School of Public Health, 2006.

Available from:

http://allafrica.com/download/resource/main/main/idatcs/00011012:690add3c64834fd5e

266b865e6784c52.pdf. [Accessed 26 February 2017].

49. Bule MH., Haymete A., Kefale B, 2015. Synthesis and In-Vivo Pharmacological

Evaluation of Some Novel 4(3H)- Quinazolinone Derivatives as Potential Anti-malarial

Agents. Drug Des Open Access. https://doi.org/10.4172/2169-0138.1000121.

50. pmi_annual_report09.pdf. n.d. Available from: https://www.pmi.gov/docs/defaultsource/

default-document-library/pmi-reports/pmi_annual_report09.pdf?sfvrsn=13. [Accessed 27

February 2017].

51. Diagana TT, 2015. Supporting malaria elimination with 21st century antimalarial agent

drug discovery. Drug Discov Today, 20: 1265–70.

https://doi.org/10.1016/j.drudis.2015.06.009.13

52. WHO | World Health Statistics 2006. WHO. Available from:

http://www.who.int/whosis/whostat2006/en/. [Accessed 28 February 2017].



1482

53. Dikasso D., Makonnen E., Debella A., Abebe D., Urga K., Makonnen W., 2006. In vivo

antimalarial activity of hydroalcoholic extracts from Asparagus africanus Lam. in mice

infected with Plasmodium berghei. Ethiop J Health Dev, 20: 112–8.

54. Mbatchi SF., Mbatchi B., Banzouzi JT., Bansimba T., Nsonde Ntandou GF., Ouamba J-

M., et al, 2006. In vitro antiplasmodial activity of 18 plants used in Congo Brazzaville

traditional medicine. J Ethnopharmacol., 104: 168–74.

https://doi.org/10.1016/j.jep.2005.08.068.

55. Haldar K., Murphy SC., Milner DA., Taylor TE, 2007. Malaria: mechanisms of

erythrocytic infection and pathological correlates of severe disease. Annu. Rev. Pathol., 2:

217–49. https://doi.org/10.1146/annurev.pathol.2.010506.091913.

56. Muanda FT., Chaabane S., Boukhris T., Santos F., Sheehy O., Perreault S., et al, 2015.

Antimalarial drugs for preventing malaria during pregnancy and the risk of low birth 14

weight: a systematic review and meta-analysis of randomized and quasi-randomized

trials. BMC Med., 13: 193. https://doi.org/10.1186/s12916-015-0429-x.

57. Charles R. C., Robert E. S, 2003. Modern Pharmacology With Clinical Applications,

Sixth Edition. Philadelphia: LWW.

58. Pérez-Tris J., Hasselquist D., Hellgren O., Krizanauskiene A., Waldenström J., Bensch S,

2005. What are malaria parasites? Trends Parasitol., 21: 209–11.

https://doi.org/10.1016/j.pt.2005.03.001.

59. Sharma C. and Kumar A., 2015. Recent Advances in Antimalarial Drug Discovery —

Challenges and Opportunities, An Overview of Tropical Diseases, Amidou S. (Ed.),

INTECH Open Acsess Publisher, pp: 2829-2843.

60. Biamonte MA., Wanner J., Le Roch KG, 2013. Recent advances in malaria drug

discovery. Bioorg Med. Chem. Lett., 23: 2829–43.

61. Ralph SA., D‘Ombrain MC., McFadden GI, 2001. The apicoplast as an antimalarial drug

target. Drug Resist Update Rev. Comment. Antimicrob. Anticancer Chemother., 4: 145–

https://doi.org/10.1054/drup.2001.0205.

62. Wells TNC., van Huijsduijnen RH., Van Voorhis WC, 2015. Malaria medicines: a glass

half full? Nat Rev Drug Discov, 14: 424–42. https://doi.org/10.1038/nrd4573.

63. Feachem R., Sabot O, 2008. A new global malaria eradication strategy. The Lancet. 371:

1633–5. https://doi.org/10.1016/S0140-6736(08)60424-9.

64. WHO | World Malaria Report. WHO. Available from:

http://www.who.int/malaria/publications/world_malaria_report/en/. [Accessed 28

February 2017].



1483

65. WHO | World Health Statistics 2008. WHO. Available from:

http://www.who.int/whosis/whostat/2008/en/. [Accessed 28 February 2017].

66. Ballou WR., Arevalo-Herrera M., Carucci D., Richie TL., Corradin G., Diggs C., et al,

2004. Update on the clinical development of candidate malaria vaccines. Am J Trop Med

Hyg, 71: 239–47.

67. Rosenthal PJ, 1998. Proteases of malaria parasites: new targets for chemotherapy. Emerg

Infect Dis, 4: 49–57. https://doi.org/10.3201/eid0401.980107.15

68. Vangapandu S., Jain M., Kaur K., Patil P., Patel SR., Jain R, 2007. Recent advances

inantimalarial drug development. Med Res Rev, 27: 65–107.

https://doi.org/10.1002/med.20062.

69. S D-C., E P., L M., E M., C S., P G., et al, 2008. Synthesis and antimalarial activity of

new analogues of amodiaquine. Eur J Med Chem, 43: 252–60

https://doi.org/10.1016/j.ejmech.2007.03.008.

70. Smith RD., Coast J, 2002. Antimicrobial resistance: a global response. Bull World Health

Organ, 80: 126–33. https://doi.org/10.1590/S0042-96862002000200008.

71. Kaur K., Jain M., Reddy RP., Jain R, 2010. Quinolines and structurally related

heterocycles as antimalarials. Eur J Med Chem, 45: 3245–64. 34.

72. Vv K., A G-B, 2009. Recent developments in the design and synthesis of hybrid

molecules based on aminoquinoline ring and their antiplasmodial evaluation. Eur J Med

Chem, 44: 3091–113. https://doi.org/10.1016/j.ejmech.2009.02.024.

73. WHO Expert Committee on Malaria (1998 : Geneva S., Organization WH. WHO Expert

Committee on Malaria : twentieth report. Comité OMS d‘ experts du paludisme :

vingtième rapport. 2000. Available from: http://apps.who.int/iris/handle/10665/42247.

[Accessed 14 February 2017].

74. Malaria GP to RB. Antimalarial drug combination therapy : report of a WHO technical

consultation, 4-5 April 2001. 2001. Available from:

http://apps.who.int/iris/handle/10665/66952. [Accessed 28 February 2017].

75. Khodadad M., Nateghpour M., Sourie., Farivar L., Motevallihaghi A., Rahimi-Froushani

A., et al, 2013. Evaluation of Effectiveness of Ethanolic Extract of Artemisia aucheri,

Individually and in Combination with Chloroquine, on Chloroquine - Sensitive Strain of

Plasmodium berghei in Sourian Mice. Iran J Public Health, 42: 883–8.

76. Loiseau PM., Nguyen DX, 1996. Plasmodium berghei mouse model: antimalarial activity

of new alkaloid salts and of thiosemicarbazone and acridine derivatives. Trop Med Int

Health TM IH, 1: 379–84.

https://doi.org/10.3201/eid0401.980107.15



1484

77. Schlüter K., Walter RD., Bergmann B., Kurz T, 2006. Arylmethyl substituted derivatives

of Fosmidomycin: synthesis and antimalarial activity. Eur J Med Chem, 41: 1385–97.

https://doi.org/10.1016/j.ejmech.2006.06.015.17

78. Xue CX., Cui SY., Liu MC., Hu ZD., Fan BT, 2004. 3D QSAR studies on antimalarial

alkoxylated and hydroxylated chalcones by CoMFA and CoMSIA. Eur J Med Chem, 39:

745–53. https://doi.org/10.1016/j.ejmech.2004.05.009.

79. Valla A., Valla B., Cartier D., Le Guillou R., Labia R., Florent L., et al, 2006. New

syntheses and potential antimalarial activities of new ―retinoid-like chalcones.‖ Eur J Med


80. El Hage S., Ane M., Stigliani J-L., Marjorie M., Vial H., Baziard-Mouysset G., et al,

2009. Synthesis and antimalarial activity of new atovaquone derivatives. Eur J Med


QUINAZOLINONE, IMPORTANCE & MALARIA DRUG DISCOVERY

Documents

Transcript of QUINAZOLINONE, IMPORTANCE & MALARIA DRUG DISCOVERY