Welcoming you for any type of article submission for the upcoming issue on/before February 26, 2021.

Research Article
Volume 1 Issue 3 - 2015
Synthesis and Anti-leishmanial Activity Evaluation of Some 2,3-Disubstituted Quinazoline-4(3H)-Ones Bearing Quinoline and Pyrazole Moieties
Roza G Tesfahunegn1*, Adnan A Bekhit1 and Ariaya Hymete2
1 Department of Pharmaceutical Chemistry and Pharmacognosy, School of Pharmacy, Addis Ababa University, Ethiopia
2Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Alexandria University, Egypt
*Corresponding Author: Roza G Tesfahunegn, Medicinal Chemistry stream, Department of Pharmaceutical Chemistry and Pharmacognosy, School of Pharmacy, Addis Ababa University, College of Health Sciences, Addis Ababa, Ethiopia.
Received: June 23, 2015; Published: June 30, 2015
Citation: Roza G Tesfahunegn., et al. “Synthesis and Anti-leishmanial Activity Evaluation of Some 2,3-Disubstituted Quinazoline-4(3H)-Ones Bearing Quinoline and Pyrazole Moieties”. EC Pharmaceutical Science 1.3 (2015): 153-164.
Based on the progress reports of biologically active hetrocycles; 2,3-disubstituted-quinazoline-4(3H)-ones, quinolines and pyrazoles are among important scaffolds with promising anti-leishmanial activity. Despite to those findings, demand of new molecules with clinically applicable biological activity to halt leishmaniasis is still an active research area. This present investigation has attempted the synthesis of new hybrid scaffolds of 2,3-disubstituted-quinazoline-4(3H)-one pharmacophore bearing biologically active quinoline and pyrazole moieties and evaluate their enhanced anti-leishmanial activity. Upon simple condensation and cyclization reactions of the essential intermediates; 3-aryl-2-methyl-quinazolin-4-(3H)-ones with some pyrazolyl-4-carboxaldehydes and quinoline-3-carbaldehyde; new hybrids of 2-pyrazolyl-quinazoline-4(3H)-ones (4a-c) and 3-aryl-2-quinolinyl-quinazoline-4(3H)-ones (5a-c) were synthesized. Structures for the synthesized compounds were determined using elemental microanalysis, IR, 1H NMR and 13C NMR. In vitro anti-leishmanial activities of the synthesized compounds were evaluated using L. donovani strain. All the compounds show superior anti-leishmanial activity (IC50 = 0.0265 - 1.9146 μg/ml) compared to the standard drug miltefosine (IC50 = 3.1911 μg/ml). In particular, compound 4a is a potential lead compound (IC50 = 0.0265 μg/ml) exhibited strongest anti-leishmanial activity; 120 and 2 folds more activity as compared to standard drug miltefosine and amphotericin B phosphate (IC50 = 0.0460 μg/ml) respectively. Moreover, among the quinoline containing hybrids (5a-c), compound 5c (IC50 = 0.1862 μg/ml) shows potent activity next to compound 5a with 17 folds better activity compared to miltefosine. In vivo acute toxicity test of these most active compounds show no sign of toxicity.
Keywords: 2,3-Disubstituted-quinazoline-4(3H)-one; 2-pyrazolyl-quinazoline-4(3H)-one hybrid; 2-quinolinyl-quinazoline-4(3H)-one hybrid; anti leishmanial activity
Being one of the major tropical infections classified under the six most dangerous tropical diseases [1] leishmaniasis is a protozoal disease caused by parasites belonging to at least 20 species of the genus leishmania [2]. Worldwide, burden of this disease is revolving in the atmosphere of over 88 countries [3,4]. Currently, there are around 350 million people considered as victims of leishmaniasis with 2 million new cases annually [4,5]. For more than half a century, pentavalent antimonials such as Pentostam (1) and Glucantime (2), alternative drugs such as Amphotericin B (3), Paromomycin (4), and Miltefosine (5) have been the cornerstone of anti-leishmanial chemotherapy [6-9].
Figure 1:
1. Pentostam
2. Glucantime
3. Amphotericin B
4. Paromomycin
5. Miltefosine
Despite the availability, general use of these drugs has declined due to low efficacy, drug resistance [10] and high toxicity [8,11]. Thus, the lack of generally effective anti-leishmanial drugs ensures the crucial need for developing new, effective, cheap and safe drugs in the field of anti-leishmanial chemotherapy. Recent advances in identifying, designing and developing new chemical derivatives as promising anti-leishmanial agents have become an interesting field. In this pursuit, 2,3-disubstituted-quinazolinones have been continuously presented to have diversified biological activities including anti-leishmanial activities [12,13]. Quinazoline-4(3H)-one is a core scaffold of natural alkaloids with potent anti-leishmanial activity such as vasicinone (6) and tryptanthrin (7) [14]. Substitution of this scaffold at 3-position with aryl groups as in 3-aryl-quinazoline-4(3H)-ones [15], at 2-position as in 3-benzyl-2-phenylquinazolin-4(3H)-one (8) [13] and 3-amino-2-aryl-quinazoline-4(3H)-ones (9) [16] led to series of derivatives with potent anti-leishmanial activity. On the other hand, pyrazole and pyrazole bearing compounds have displayed a broad spectrum of potential pharmacological activities such as analgesic, antipyretic, anti-inflammatory, insecticidal, uricosuric, anticancer, antitumor including anti-leishmanial activity [17,18]. Moreover, one of the privileged moieties for its anti-malarial activity; quinoline has been reported to have anti-malarial, antifungal, antibacterial and anti-leishmanial activities [19,20]. Furthermore, synthesis of new pharmacophore which structurally combines these biologically active moieties has been used as an effective strategy in designing derivatives with enhanced pharmacological activity. For example, Pyrazole bearing 4(3H)-quinazolinones have been found to possess antimicrobial activity [21,22].
Figure 2:
6. Vasicinone
7. Tryptanthrin
8. 3-benzyl-2-phenylquinazolin-4(3H)-one
9. 3-amino-2-aryl-quinazoline-4(3H)-one
10. Quinazoline-4-one-8-hydroxyquinoline
Whereas, quinoline bearing quinazolinone hybrids as in case of quinazoline-4-one-8-hydroxyquinoline (10) [23] and metal (II) complexes with schiff bases of 2,3-disubstituted-quinazoline-4(3H)-ones [24] have been found to have potent antifungal and antibacterial activities. However, anti-leishmanial activity of these hybrid scaffolds has not been investigated yet. This prompted us to synthesize some new pyrazole and quinoline bearing 2,3-disubstituted-quinazoline-4(3H)-ones and evaluate the effect of their hybrid system for enhanced anti-leishmanial activity.
Materials and Methods
Materials and Instruments
All chemicals and reagents used were obtained from department of Chemistry, Faculty of Science, Addis Ababa University (AAU) and some donated from DDC (Drug Discovery Center), Department of pharmaceutical chemistry, Faculty of Pharmacy, Alexandria University.
For all the synthesized compounds, melting points (°C) were determined in open capillaries using Electrothermal (9100) apparatus and values are uncorrected. IR spectra (Nujol, λmax: cm−1) were recorded on a SHIMADZU 8400SP FT-IR spectrophotometer. H NMR spectra reported in δ (ppm) were recorded on Bruker Avance DMX400 FT-NMR spectrometer using tetramethylsilane (TMS) as internal standard and deutero chloroform (CDCI3) as a solvent. Elemental microanalyses were carried out on Perkin Elmer 2400 elemental analyzer. Silica gel TLC plates of 0.25 mm thickness were used for chromatographic analysis and spots were visualized using iodine vapour and UV radiation.
Test animals and strains
Swiss albino mice of both sex weighing 26-23g and age of 6-8 weeks were obtained from School of Pharmacy, AAU and used for acute toxicity test. The mice were acclimatized for a period of 7 days at appropriate environmental condition. The animals were housed in standard cages and maintained on standard pellated diet and water [27,28]. L. donovani isolate (CL/039/09) that causes visceral leishmaniasis in Africa especially in Ethiopia was obtained from Leishmania Diagnosis and Research Laboratory (LDRL) culture bank, School of Medicine, AAU.
Culture medium for anti-leishmanial activity
RPMI-1640 (Gibco, Invitrogen Co., UK), 10% heat- inactivated fetal calf serum (HIFCS), penicillin-streptomycin and 1% L-glutamine all from Sigma Chem. Co., St. Louis, USA were supplied to make complete culture mediums.
Reference drugs
Miltefosine/hexadcylephosphocholine (AG Scientific, San Diego, CA, USA) and amphotericin B deoxycholate (Fungizone®, ER Squibb, UK) were included as reference drugs (positive control) in the in vitro anti-leishmanial activity testing of the synthesized compounds.
Stock solution and working concentration preparation for anti-leishmanial activity assay
All the compounds to be evaluated for their anti-leishmanial activity were dissolved in Dimethyl sulfoxide (DMSO) to a final concentration of 1mg/ml. Both test and standard solutions were serially diluted to appropriate concentrations using complete media. The test compounds were prepared by three fold serial dilutions from 10µg/ml to 0.04 µg/ml. Amphotericin B deoxycholate and miltefosine which were used as a positive control for comparison of the anti-leishmanial activities of the test compounds, were also made in three fold serial dilutions [29,30].
In vitro anti-leishmanial activity test
Promastigote forms of L. donovani and standard drugs of amphotericin B deoxycholate and miltefosine were used for the assay. 3x 106 promastigotes of L. donovani in 100 µl were seeded to each well in a 96 well flat bottom plate. Various dilutions of test compounds (10, 3.33, 1.11, 0.37, 0.12, 0.04 µg/ml) were added to the parasites. The tests were done in duplicates. Some of the wells contained only the parasites and served as a positive control. The media and DMSO alone acted as a negative control. The plates were then kept at room temperature. After 24h, 20 µl of alamar blue (12.5 mg resazurin dissolved in 100 ml of distilled water) [31] was added to each of the wells. Absorbance of the resulting mixture was measured after 48 hr at a wavelength of 540 and 630 nm using Enzyme Linked Immuno Sorbent Assay (ELISA) plate reader [32].
In vivo acute toxicity test
The most active compounds 4a, 5b and 5c were tested for oral acute toxicity in mice. Four groups of mice, each consisting of six male mice (26-32g) were used to test the acute toxicity. All mice were fasted over night and weighed before test. Test compound was prepared in suspension form in aqueous vehicle containing 7% tween 80 and 3% ethanol [33]. Mice in group one, two and three were given 50, 100 and 200 mg/kg/day of test compound and the fourth group was treated with the vehicle (control group) at a maximum dose of 1 ml/100 g of body weight by oral route. After administration of the substance, food was withheld for a further 2 h period (38). The mice were observed closely during the first 30 minutes after dosing, periodically during the first 24 h with special attention to the first 4 hr and once daily thereafter for a total of 7 days. The mice were observed for toxicity signs such as changes in skin, blinking eyes, tremors, convulsion, lacrimation, muscle weakness, sedation, urination, salivation, diarrhea, lethargy, sleep, coma and also death. Twenty-four hours later, the weight of test mice in each group was recorded.
Ethical Statement
The in vivo acute toxicity test which involves live mice was performed in compliance with ethical guidelines and approval from the National Ethics Review Board of Ethiopia. And ethical clearance was obtained from Addis Ababa University, College of Health Sciences, School of Pharmacy, Department of Pharmacology.
Data analysis
The IC50 values for synthesized compounds tested for their in vitro anti-leishmanial activity were evaluated from sigmoidal dose- response curves using non linear regression software (GraphPad Prism®; GraphPad Software, Inc., San Diego, CA.
Results and Discussion
The target compounds (4a-c) and (5a-c) were synthesized following reported methods via condensation reaction of 3-aryl-2-methyl-4(3H)-quinazolinones (3a-c) with 1,3-substituted-1H-pyrazole-4-carboxaldehydes (4 and 4') and 2-chloro-7-methylquinolin-3-carbaldehyde (5) respectively (Scheme 1).
Scheme 1: Synthesis of 3-aryl-2-pyrazolyl-4(3H)-quinazolinones and 3-aryl-2-quinolinyl quinazolin-4(3H)-ones.
The reaction starts with the thermal transformation of anthranilic acid in to intermediate compound 2 (2-methyl-4-keto-3,4-dihydroquinazoline) due to condensation followed by cyclization reactions in the presence of acetic anhydride. This was accompanied by condensation reaction of the intermediate with aromatic amines to form a series of 2-methyl-3-aryl-quinazolin-4(3H)-ones (3a-c). Further condensation reaction of the second intermediates (3a-c) with 1, 3-substituted-1H-pyrazole-4- carboxaldehydes (4,4') and 2-chloro-7-methyl-quinolin-3-carbaldehyde (5) yielded the target compounds 4a-c and intermediates of 5a-c respectively. Upon heating of the intermediates of 5a-c in the presence of 70% ethanol yielded target compounds 5a-c (Scheme 1).
All the synthesized compounds were synthesized in quantitative yield (68-80%). The compounds were elucidated by spectroscopic measurements (IR, 1H NMR and 13C NMR). The IR spectra of all target compounds showed absorption bands of quinazolinones carbonyl group stretching vibration at 1646-1685 cm-1. Characteristic medium strength bands at 1544 cm-1 - 1652 cm-1 were assigned to C=N stretching in both the quinazolinone and pyrazole hybrid ring scaffold system of 4a-c compounds. Whereas bands at 1661 cm-1 - 1665 cm-1 represented carbonyl group formed in unstable tautomeric form of the target compounds 5a-c in which keto-enol tautomerism at the pyridine moiety of quinoline ring system occurs (Scheme 2).
Scheme 2: Tautomerism of compounds 6a-c.
The band appeared at low frequency due to the resonance electron donation effect of the adjacent nitrogen atom of the amidic carbonyl group. Absorption band at 3175 cm-1 - 3214 cm-1 was characteristic to -OH group stretching at the pyridine moiety of 5a-c compounds. Among the significant features of 1H NMR data for compounds 4a-c and 5a-c; the appearance of two doublets peaks at δ 6.17 -8.07 ppm (J = 15.5Hz) was attributed to vinylic protons in (E) configuration. The peaks for the vinylic protons appeared down field due to the presence of electron withdrawing groups surrounding it. In case of compounds 4a-c, the disappearance of singlet peak at up field region for the methyl substituent of quinazolinone moiety at N2- position and a singlet peak at down field region (9-10 ppm) for pyrazole aldehyde proton ensured the formation of the target compounds. In case of compounds 5a-c, the peak at δ 9.5 - 11.2 ppm which appeared as a singlet was correlated to hydroxy group at 2-quinoline position. This proves the nucleophilic aromatic substitution of 2-chloro substituent at the highly electronegative sp2 hybridized quinoline carbon by the highly nucleophilic hydroxy group from the aqueous ethanol which was used as a solvent (Scheme 3). In general, aromatic protons of quinazolinone group appeared as set of multiplet in the region δ 6.24-8.77 ppm, aromatic protons of pyrazole moiety as multiplets in region of δ 7.20-8.10 ppm and phenyl protons of quinoline resonated at δ 6.95 - 7.65 ppm.
Scheme 3: Nucleophilic substitution reaction of 3-aryl-2-quinolinyl-4(3H)-ones at chlorine atom on the 2- quinoline position by hydroxyl group.
In vitro Anti-leishmanial Activity
Promastigote forms of L. donovani and standard drugs of amphotericin B deoxycholate and miltefosine were used for the assay with alamar blue as a reagent. The IC50 values of all tested compounds presented in Table 1 indicate that all the synthesized compounds have by far superior anti-leishmanial activity (0.0265-0.1862 μg/ml) compared to the reference drug miltefosine (IC50 = 3.1911 μg/ml). Comparison of IC50 values of the compounds revealed that compound 5a (IC50 = 0.0265 μg/ml) has the highest activity; having about 120 and 2 folds more activity than the standard drugs miltefosine and amphotericin B deoxycholate (IC50 = 0.0460 μg/ml) respectively.
Test Compounds IC50 (µg/ml)
5a 0.0265
5b 1.4217
5c 1.9146
6a 1.2284
6b 0.2764
6c 0.1862
Miltefosine 3.1911
Amphotericin B 0.0460
Table 1: In vitro antipromastigote activity of the synthesized compounds in IC50 (μg/ml).
These results showed that formation of quinoline and pyrazole bearing quinazoline-4(3H)-one hybrids has definitely positive impact in the enhanced anti-leishmanial activity. This can be justified with previous reports of low anti-leishmanial activity results of 3-alkyl-2-styryl-quinazolone-4(3H)-one derivatives. Particular example is report of Arfan., et al. [] 2010, in which 2-Methyl-3-(4-methylphenyl)-quinazolin-4(3H)-ones (11) was synthesized and evaluated to have no activity against Leishmania major. Whereas, introduction of aryl moiety in place of 2-methyl substitute intended to improve the anti-leishmanial activity as in case of 3-aryl-2-styryl-quinazoline-4(3H)-ones. Among which; 3-benzyl-2-phenyl-4(3H)-quinazolinone) (12) showed the highest potency (IC50 = 48 μg/mL) against Leishmania major promastigotes and considered as a new anti-leishmanial candidate [13]. In addition, 2-aryl-3-styryl-quinazoline-4(3H)-ones synthesized in our laboratory revealed improved anti-leishmanial activity as in case of (E)-2-(4-hydroxystyryl)-3-p-tolylquinazolin-4(3H)-one (13) with IC50 = 1.842 μg/ml which has significantly improved activity compared to 2-Methyl-3-(4-methylphenyl)-quinazolin-4(3H)-ones but still 70 folds less active than compound 5a. These advocate strategies to design quinazolinone-hybrid system with more bulky and lipophilic hetrocyclic scaffolds at 2-postion such as pyrazole and quinoline moieties in order to improve anti-leishmanial activity of 2-aryl-3-alkylaryl-quinazoline-4(3H)-ones.
Figure 6:
11. 2-Methyl-3-(4-methylphenyl)-quinazolin-4(3H)-ones
12. 3-benzyl-2-phenyl-4(3H)-quinazolinone
13. (E)-2-(4-hydroxystyryl)-3-p-tolylquinazolin-4(3H)-one
14. (N,N-dimethylaminomethylene-4-[(3-(4-methylphenyl)-4-(phenyl-hydrazonomethylene))-1H-pyrazol-1-yl] benzene sulfonamide
Furthermore, Para-substitution at phenyl group (ring D) of N1 of pyrazole ring (ring C) of compounds 4a-c (3-aryl-2-pyrazolyl-quinazolin-4(3H)-one) was critical in determination of their anti-leishmanial activity. The highest activity of compound 4a might be attributed to the presence of para substituent of dimethyl aminomethylene substituted sulphonamide group at ring D which is absent in the other analogues. The most possible reason for this may be the good electron withdrawing effect of Sulphonyl moiety which may involve in delocalization of electrons from aminomethylene group and lead to free radical formation to form covalent bond with some amino acid residues in the parasite such as cysteine proteases. Cysteine proteases and protein kinases are among the most active drug targets against leishmaniasis and their catalytic activity is mostly influenced by lysine, cysteine and aspartic acid residues [25]. From previous SAR reports of substituted quinazoline-4(3H)-ones, carbonyl group and hydroxy group substituents are essential for hydrogen bond interaction with active sites of suggested receptors in leishmania parasites. The aryl groups may act as hydrophobic structural features for van der waal force of interaction with the active site where as dimethyl amino nitrogen may act as a site for hydrogen bonding. Furthermore, this dimethyl aminomethylene substituted sulphonamide group have been reported before [26] to be essential for anti-leishmanial activity of pyrazole derivatives as in case of (N,N-dimethylaminomethylene-4-[(3-(4-methylphenyl)-4-(phenyl-hydrazonomethylene))-1H-pyrazol-1-yl] benzene sulfonamide (14) (IC50 = 0.0175 μg/ml) which is about 180 times more active than miltefosine and 2.7 fold more active than amphotericin B deoxycholate. Replacement of this group with electron withdrawing bromine atom at the 1H-pyrazole-phenyl group as in case of 4b (IC50 = 1.4217 μg/ml) and 4c (IC50 =1.9146 μg/ml) showed a decrease in anti-leishmanial activity by more than 50 folds. This ensures that dimethyl aminomethylene substituted sulphonamide group is essential for anti-leishmanial activity and needs further docking study.
On the other hand; the anti-leishmanial activity test of compounds 5a-c (3-aryl-2-quinolinyl-quinazolin-4(3H)-one derivatives) have shown promising activity. Compound 5c (2-((E)-2-(2-hydroxyquinoline-7-methyl-3-yl)vinyl)-3-o-tolylquinolin-4(3H)-one) (IC50 = 0.1862 μg/ml) has shown potent activity second to compound 4a with 17 folds better activity than miltefosine. Interestingly; methyl substitution at ortho and para position of the aryl substituent exhibited better activity probably due to an increase in liphophilicity of the compounds to penetrate through the membrane of the parasites. In detailed comparison; compound 5c which contained methyl substituent at ortho position showed almost doubled activity than 5b with methyl substituent at para position. This may be pronounced as such groups can enhance interactions with functional groups on the active site of the responsible receptor.
Oral acute toxicity
A preliminary acute toxicity of the most active compounds (4a, 5b and 5c) were evaluated to assess the acute lethal, physical and behavioral changes of these three most active synthesized compounds after administering to mice (weighing 26 to 32g) orally at dose levels of 50 mg/kg, 100 mg/kg and 200 mg/kg. The weight of each mouse was recorded and survival was followed up to 7 days. All the experimental mice did not show any toxicity signs after being treated with test compounds. There was no significant difference in the weight of the mice and no death was recorded during the 7 days after administration of the test compounds. This indicates that the median lethal dose (LD50) of the compounds is much greater than 200 mg/kg. From these results, the test compounds have proved to be non-toxic and well tolerated by the experimental animals up to 200 mg/kg.
Synthesis Chemistry
Synthesis of 2,3-disubstituted-3(4H)-quinazolinone derivatives
Synthesis of 2-methyl-4H-1,3-benzoxazin-4-one (2)
A solution of anthranilic acid 1 (Scheme 1) (15g, 0.09316 mole) in acetic anhydride (38 ml) was heated under reflux for 1h [34,35]. The excess acetic anhydride was evaporated under reduced pressure and the resulting solid mass was obtained which, without purification was suitable for the subsequent reaction. Melting point is 81°C [36].
Synthesis of 3-aryl-2-methyl-4(3H)-quinazolinones (3a-c)
To a separate mixtures of acetanthranil 2 (Scheme 1) (0.1 mole); an equimolar amount of the appropriate aromatic amine (aniline, p-toluidine and o-toluidine) was added. The reaction mixture was heated under reflux at 19°C for 5h, cooled to room temperature and finally recrystalized from ethanol [36-37]. The products obtained were then separated out, filtered, washed with ethanol and air dried.
Synthesis of 3-aryl-2-pyrazolyl-quinazolin-4(3H)-ones (4a-c)
To a mixture of an appropriate 3-aryl-2-methyl-4(3H)-quinazolinone (3a and 3b) (1 mmol) in acetic anhydride (5 ml); an equimolar amount of appropriate pyrazolyl aldehyde 4 and 4’ (Scheme 1) obtained by the Vilsmeier–Haack reaction [38,39] was added with 10 mg of anhydrous zinc chloride as catalyst. The reaction mixture was heated under reflux for 16h and set aside at room temperature. The separated yellow product was filtered, dried and recrystalized from ethanol/chloroform in 1:1 mixture.
Synthesis of 3-aryl-2-quinolinyl quinazolin-4(3H)-ones; 5a-c
To a separate mixtures of an appropriate 3-aryl-2-methyl-4(3H)-quinazolinones; 3a-c (1 mmol) in acetic anhydride (5 ml); an equimolar amount of 2-chloro-7-methylquinolin-3-carbaldehyde (5) (scheme 1) synthesized using vilsmeier haack reagent [40,41] was added. Anhydrous zinc chloride (10 mg) was used as a catalyst. The reaction mixture was heated under reflux for 2h. The yellow precipitate formed was filtered, dried and recrystalized from chloroform/ethanol (1:1).
Spectroscopic and elemental analysis data of the synthesized compounds
2-((E)-2-(1-(4-dimethylmethyleneaminosulfonylphenyl)-3-(4-chlorophenyl-1H-pyrazol-4-yl)vinyl)-3-p-tolylquinazolin-4(3H)-one (4a): Yellow solid. Yield: 70%. Mp: 238.0-241.0°C. 1H NMR (CDCl3/CHCl3 δ, ppm): 2.5 (s, 1H, p-tolyl-CH3), 3.1 (s, 3H, -N-CH3), 3.2 (s, 3H, -N-CH3), 6.2 (d, 1H, J = 15.6Hz, vinyl-C2 H), 7.1 (d, 2H, J = 8.2Hz, p-tolyl-C3,5 H), 7.35 (d, 2H, J = 8.1Hz, p-tolyl-C2,6 H), 7.4 (d, 2H, J = 8.5Hz, p-chlorophenyl-C3,5 H), 7.46 (t, 1H, quinazolin-C7 H), 7.53 (d, 2H, J = 8.5Hz, p-chlorophenyl-C2,6 H), 7.73-7.84 (m, 4H, 4-dimethylmethylene aminosulphonylphenyl-C2.6 H and quinazolin-C6,8 H), 7.94-8.02 (m, 3H, dimethyl methylene aminosulphonylphenyl-C3,5 H and vinyl-C1 H), 8.03-8.05 (s, 1H, pyrazolyl-C5 H) , 8.19 (s, 1H, N=CH) and 8.27 (d, 1H, J = 7.8Hz, quinazolin-C5 H). 13C NMR (CDCl3/CHCl3) δ ppm: 21.35, 35.61, 41.57, 118.74, 119.4, 120.56, 120.84, 126.53, 127.2, 127.3, 128.16, 128.2, 128.92, 129.26, 129.89, 130.57, 130.74, 134.09, 134.57, 134.80, 139.31, 140.66, 141.51, 147.71, 151.66, 152.22, 159.15, 162.41. Anal. calcd. for C35H29ClN6O3S: C, 64.76; H, 4.5; Cl, 5.46; N, 12.96; S, 4.94. Found: C, 64.54; H, 4.26; N, 13.21; Cl, 5.14; S, 5.21.
2-((E)-2-(1-(4-bromophenyl)-3-phenyl-1H-pyrazol-4-yl)vinyl)-3-p-tolylquinazolin-4(3H)-one (4b): Yellow solid. Yield: 68%. Mp: 277.0-279.0°C. 1H NMR (CDCl3/CHCl3) ppm: 2.5 (s, 3H, CH3), 6.22 (d, 1H, J = 15.6 Hz, vinyl-C2 H), 7.13 (d, 2H, J = 8.2 Hz, p-tolyl-C3,5 H), 7.35 (t, 3H, phenyl-C3,4,5 H), 7.44-7.52 (m, 5H, pyrazolylphenyl-C2,6 H; Phenyl-C2,6 H and quinazolin-C7 H), 7.57 (d, 2H, J = 8.423Hz, bromophenyl-C2,6 H), 7.68-7.82 (m, 4H, 4-bromophenyl)-C3,5 H; quinazolin-C6 H and vinyl-C1 H), 8.0 (m, 2H, quinazolin-C8 H and Pyrazolyl-C5 H), 8.3 (d, 1H, J = 7.808Hz, quinazolin-C5 H). Anal. Calcd for C32H23BrN4O: C, 68.70; H, 4.14; Br, 14.28; N, 10.01. Found: C, 68.99; H, 3.87; Br, 14.56; N, 9.84.
2-((E)-2-(1-(4-bromophenyl)-3-phenyl)-1H-pyrazol-4-yl)vinyl)-3-phenylquinazolin-4(3H)-one(4c): Yellow solid: Yield:69%. Mp: 217-219°C. 1H NMR (CDCl3/CHCl3) ppm: 6.17 (d, 1H, J = 15.5 Hz, vinyl-C2 H), 7.25-7.28 (m, 2H, pyrazolylphenyl-C4 H and quinazolinylphenyl C4 H), 7.35 (t, 1H, quinazolin-C7 H), 7.45-7.5 (m, 6H, phenyl- C3,5 H, pyrazolylphenyl-C3,5 H and bromophenyl-C2,6 H), 7.54-7.59 (m, 4H, pyrazolylphenyl-C2,6 H and bromophenyl-C3,5 H), 7.7 (d, 2H, J = 8.04 Hz, phenyl-C2,6 H), 7.8 (m, 2H, quinazolin-C6,8 H), 7.96 (s, 1H, pyrazolyl-C5 H), 8.02 (d, 1H, J = 15.5 Hz, vinyl-C2 H), 8.3 (d, 1H, J = 7.3 Hz, quinazolin-C5 H). Anal. Calcd for C31H21BrN4: C, 68.26; H, 3.88; Br, 14.65; N, 10.27. Found: C, 67.92; H, 4.04; Br, 14.32; N, 10.54.
2-[(E)-2-(2-hydroxyquinoline-7-methyl-3-yl)vinyl]-3-p-tolylquinazolin-4(3H)-one(5a): Yellow solid. Yield: 78%. Mp: 311-313°C. 1H NMR (CDCl3/CHCl3) δ ppm: 2.4 (s, 3H, p-tolyl-4-CH3), 2.55 (s, 3H, quinolin-7-CH3), 7.0-7.08 (m, 2H, p-tolyl-C3,5 H), 7.24 (d, 2H, p-tolyl-C2,6 H), 7.35-7.52 (m, 4H, vinyl-C2 H, quinolin-C5,6 H and quinazolin-C7 H), 7.81-7.86 (m, 3H, quinazolin-C6,8 H and quinolin-C8 H), 8.07 (d, 1H, J = 15.2 Hz, Vinyl-C1H), 8.34 (d, 1H, J = 7.8 Hz, quinazolin-C5 H) and 10.9 (s, 1H, quinolin-C2 OH enol form). Anal. Calcd. For C27H20ClN3O, C, 77.31; H, 5.05; N, 10.02: Found C, 77.26; H, 4.82; N, 10.38.
2-[(E)-2-(2-hydroxy-7-methylquinolin-3-yl)vinyl)-3-phenylquinazolin-4(3H)-one(5b): Yellow solid: Yield: 80%. Mp: 321-324°C. 1H NMR (CDCl3/CHCl3) δ ppm: 2.5 (s, 3H, CH3), 7.06 (d, 1H, J = 15.2 Hz, vinyl-C2 H), 6.9 (s, 1H, quinolin-C4 H), 7.35-7.64 (m, 8H, phenyl-C3,4,5 H, quinazolin-C6,7 and quinolin-C5,6,8 H), 7.8-7.85 (m, 3H, quinazolin-C8 H and phenyl-C2,6 H), 8.0 (d, 1H, J = 15.2 Hz, vinyl-C1 H), 8.35 (d, 1H, J = 7.9 Hz, quinazolin-C5 H) and 9.5 (s, 1H, quinolin-C2 OH, D2O exchangeable). Anal. Calcd. For C26H18ClN3O, C, 77.02; H, 4.72; N, 10.36: Found C, 76.85; H, 4.64; N, 10.17.
2-[(E)-2-(2-hydroxy-7-methylquinolin-3-yl)vinyl]-3-o-tolylquinazolin-4(3H)-one(5c); Yellow solid: Yield: 76%. Mp: 276-278°C. 1H NMR (CDCl3/CHCl3) δ ppm: 2.1 (s, 3H, o-tolyl-CH3), 2.4 (s, 3H, quinolin-7- CH3), 6.85 (s, 1H, quinolin-C8 H), 6.95-7.10 (m, 3H, quinolin-C6 H and o-tolyl-C3,5 H), 7.15-7.20 (m, 2H, o-tolyl-C4,6 H), 7.25-7.38 (m, 2H, quinazolin-C7 H and vinyl-C1 H), 7.45-7.60 (m, 2H, quinazolin-C8 H and quinolin-C5 H), 7.78-7.85 (m, 2H, quinazolin-C6 H and quinolin-C4 H), 7.88-7.95 (d, 1H, J = 7.783Hz, vinyl-C2 H), 8.31 (d, 1H, J = 15.078Hz, quinazolin-C5 H ), and 11.2 (s, 1H, -N=C-OH ). Anal. Calcd. For C27H20ClN3O, C, 77.31; H, 5.05; N, 10.02: Found C, 77.81; H, 5.44; N, 10.42.
In this study, six new pyrazolyl and quinolinyl hybrids of 2,3-disubstituted-quinazoline-4(3H)-ones were synthesized and evaluated for their anti-leishmanial activity against Leishmania donovani in vitro. Among the synthesized compounds, compound 4a exhibited strongest anti-leishmanial activity; 120 folds more activity than miltefosine. In addition, from compounds bearing quinoline moiety, compound 5c has shown potent activity second to compound 4a with 17 folds better activity than miltefosine. These properties highlighted that quinazolinone hybrid system with biologically active pyrazole and quinoline moieties have shown promising anti-leishmanial activity and enhance further study depending on this strategy. Detail SAR and molecular docking study of these compounds can lead to important results in identification of molecular targets of these compounds and can be applied to design quinazolinone hybrid system with potent anti-leishmanial activity. Acute toxicity test of these two more active compounds have also shown no sign of toxicity.
The authors would like to praise their gratitude and acknowledgment to Addis Ababa University for granting fund; Egyptian Fund for Technical Cooperation with Africa: Ministry of Foreign Affairs, Egypt, Alexandria University, Faculty of Pharmacy, Department of Pharmaceutical Chemistry for complete funding of supervision and availability of professor Adnan Ahmed Bekhit and donation of some chemicals; Addis Ababa University, Faculty of Science, Department of Chemistry, Biomedical Laboratory, Department of Biology and Ethiopian Health and Nutritional Research Institute (EHNRI) for availability of chemicals, laboratory instruments, equipments and all facilities.
  1. Freason JA., et al. “Target assessment for antiparasitic drug discovery”. Trends in Parasitology 23.12 (2007): 589-595.
  2. Kato H., et al. “Molecular epidemiology for vector research on leishmaniasis”. International Journal of Environmental Research and Public Health 7.3 (2010): 814-826.
  3. Desjeux P. “Leishmaniasis: current situation and new perspectives”. Comparative Immunology, Microbiology & Infectious Diseases 27.5 (2004): 305-318.       
  4. Hotez PJ and A Kamath. “Neglected tropical diseases in Sub-Saharan Africa: Review of their prevalence, distribution and disease burden”. PLOS Neglected Tropical Diseases 3.8 (2009):  
  5. WHO. “Control of the leishmaniases”. Report of a meeting of the WHO Expert Committee on the Control of Leishmaniases. Geneva (2010): 5-88.
  6. Frezard F., et al. “Pentavalent antimonials: new perspectives for old drugs”. Molecules14.7 (2007): 2317-2336.
  7. Ferreira C S., et al. “Characterization of reactions of antimoniate and meglumine antimoniate with a guanine ribonucleoside at different pH”. BioMetals19.5 (2006): 573-581.
  8. Fre´zard F and C Demicheli. “New delivery strategies for the old pentavalent antimonial drugs”. Expert Opinion on Drug Delivery 7.12 (2010): 1343-1358.
  9. Ameen M. “Cutaneous and mucocutaneous leishmaniasis: emerging therapies and progress in disease management”.Expert Opinion on Pharmacotherapy11.4 (2010): 557-569.
  10. Piñero JE., et al. “Advances in leishmaniasis chemotherapy and new relevant patents”. Expert Opinion on Therapeutic Patents 14 (2004): 1113-1123.
  11. Berman J. “Clinical status of agents being developed for leishmaniasis”. Expert Opinion on Investigational Drugs14.11 (2005): 1337-1346
  12. Agarwal K C.,et al. “Design and synthesis of novel substituted quinazoline derivatives as antileishmanial agents”. Bioorganic & Medicinal Chemistry Letters19.18 (2009): 5474-5477
  13. Arfan M., et al. “Synthesis and antileishmanial and antimicrobial activities of some 2,3-disubstituted 3H-quinazolin-4-ones”. Journal of Enzyme Inhibition and Medicinal Chemistry25.4 (2010):451-458
  14. Michael J P. “Quinoline, quinazoline and acridone alkaloids”. Natural Product Reports20.5 (2007): 476-493
  15. Mahato A K., et al. “Chemistry, Structure Activity Relationship and Biological Activity of Quinazoline-4 (3H)-one derivatives”. Inventi Journals Pvt.Ltd2.1(2011)
  16.  Mishra A P and Rajput R. 2012. “A review on biological activities of quinazolinones”. International Journal of Pharmacy and Pharmaceutical Sciences 4.2 (2012)
  17. Mirzaie M., et al. “Antileishmanial activity of Peganum harmalaextract on the in vitro growth of Leishmania major promastigotes in comparison to a trivalent antimony drug”. Veterinarski arhiv 77.4 (2007): 365-375
  18. Khaliq T., et al. “Peganine hydrochloride dihydrate an orally active antileishmanial agent”. Bioorganic & Medicinal Chemistry Letters19.9 (2009): 2585-2586
  19. Tempone G A., et al. “Synthesis and Antileishmanial Activities of Novel 3-Substituted Quinolines”. Antimicrobial Agents and Chemotherapy49.3 (2005): 1076 -1080
  20. Kumar S., et al. “Biological activities of quinoline derivatives”.Mini Reviews in Medicinal Chemistry9.14 (2009):1648-1654.
  21. Nanda A., et al. “Antibacterial Activity of Some 3-(Arylideneamino)-2-phenylquinazoline-4(3H)-ones: Synthesis and Preliminary QSAR Studies”. Molecules 12.10. (2007): 2413-2416.
  22. Patel N B., et al. “Synthesis and Antimicrobial Activity of 2-[2-(2,6-dichloro phenyl)amino]benzyl-3-(5-substituted phenyl-4,5-dihydro-1H-pyrazol-3-yl-amino)-6,8-dibromoquinazolin-4(3H)ones”. Journal of Young Pharmacists2.2 (2010): 173-182.
  23.  Patel N B., et al. “Synthesis and Antimicrobial Activity of 2-[2-(2,6-dichloro phenyl)amino]benzyl-3-(5-substituted phenyl-4,5-dihydro-1H-pyrazol-3-yl-amino)-6,8-dibromoquinazolin-4(3H)ones”. Journal of Young Pharmacists2.2 (2010): 173-182
  24. Siddappa K and Reddy P C. “Synthesis, Spetral and Antimicrobial Studies of Some Transition Metal (II) Complexes with Schiff Base 3-[(2-hydroxy-6-methoxyquinolin-3-sylmethylene)-amino]-2-methyl-3H-quinazoline-4-one”. International Journal of Applied Biology and Pharmaceutical Technology3.3 (2012)
  25. Meslin B., et al. “Are protozoan metacaspases potential parasite killers?” Parasites & Vectors4.26 (2011)
  26. Halefom G., et al. ”Synthesis and biological activity evaluation of some pyrazole derivatives as antimalarial and antileishmanial activity. Msc thesis, Department of Pharmaceutical Chemistry, School of pharmacy, Addis Ababa University, Addis Ababa, Ethiopia (2011).
  27. Peters W and Robinson BL. ”Parasitic infection models: Handbook of animal models of infection”. Academic Press London (1999): 757-773.                
  28. Dikasso D., et al. “In vivo anti-malarial activity of hydoalcoholic extracts from Aspargus Lam. In mice infected with Plasmodium berghei”. Ethiopian Journal of Health Development20.2 (2006): 112-118
  29. Seifert S., et al. “In vitro activity of anti-leishmanial drugs against Leishmania donovani is host cell dependent”. Journal of Antimicrobial Chemotherapy 65.3 (2010): 508-511 
  30. Loiseau PM., et al. “In Vitro Activities of New 2-Substituted quinolines against Leishmania donovani”. AntimicrobialAgents and Chemotherapy55.4 (2011): 1777-1780
  31. Lenta BN., et al. “Leishmanicidal and Cholinesterase Inhibiting Activities of Phenolic Compounds from Allanblackia monticola and Symphonia  globulifera”. Molecules12.8 (2007): 1548-1557
  32. Witschel M., et al. “Agrochemicals against Malaria, Sleeping Sickness, Leishmaniasis and Chagas Disease”. PLOS Neglected Tropical Diseases6.10 (2012)
  33. Dong Y., et al. “Comparative Antimalarial Activities of Six Pairs of 1,2,4,5-Tetraoxanes (Peroxide Dimers) and 1,2,4,5,7,8-Hexaoxonanes (Peroxide Trimers)”. Antimicrobial Agents and Chemotherapy 51.8 (2007): 3033-3035
  34. Musiol R and Sajewicz M. “Optimization of solid phase synthesis of quinazolin-4-ones”. Der Pharma Chemica1.1 (2009): 63-69
  35. Sayyed MA., et al. “Synthesis of 6-iodo /bromo- 3-amino-2-methylquinazolin-4 (3H)-ones by direct halogenation and their Schiff base derivatives”.  ARKIVOC Journal(2006): 221-226
  36. Bogert MT and Seil AH. “Researches on quinazolines (eighteenth paper), on 2, 3 dialkyl-4-quinazolones and the products obtained by alkylating 2-alkyl-4-quinazolones (2-alkyl-4-hydroxy quinazolones)”. Journal of the American Chemical Society 29.4 (1907): 517-536
  37. Tephen H and Staskun B. ”A new mechanism for the beckmann rearrangement of ketoximes”. Journal of the Chemical Society (1956): 980-985
  38. Abdel-Wahab., et al. “Pyrazole-3(4)-carbaldehyde: synthesis, reactions and biological activity”. ARKIVOC 1 (2011): 196-245
  39. Pundeer R., et al. “One-pot synthesis of some new Semicarbazone Thiosemicarbazone, and hydrazone derivatives of 1-Phenyl-3-Arylpyrazole-4- carboxaldehyde from acetophenone Phenylhydrazones using Vilsmeier–Haack Reagent”. Synthetic Communications 39.2(2008): 316-324
  40. Yang M., et al. “Fluorinated Rhodacyanine (SJL-01) Possessing High Efficacy for Visceral Leishmaniasis”. Journal of Medicinal Chemistry 14.53 (2010): 368-373
  41. Al-Nasiry S., et al. “The use of Alamar Blue assay for quantitative analysis of viability, migration and invasion of choriocarcinoma cells”. Human Reproduction 25.5 (2007): 1304-1309
  42. Freason JA., et al.“Target assessment for antiparasitic drug discovery”. Trends in Parasitology 23.12 (2007): 589-595
Copyright: © 2015 Roza G Tesfahunegn., et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

PubMed Indexed Article

EC Pharmacology and Toxicology
LC-UV-MS and MS/MS Characterize Glutathione Reactivity with Different Isomers (2,2' and 2,4' vs. 4,4') of Methylene Diphenyl-Diisocyanate.

PMID: 31143884 [PubMed]

PMCID: PMC6536005

EC Pharmacology and Toxicology
Alzheimer's Pathogenesis, Metal-Mediated Redox Stress, and Potential Nanotheranostics.

PMID: 31565701 [PubMed]

PMCID: PMC6764777

EC Neurology
Differences in Rate of Cognitive Decline and Caregiver Burden between Alzheimer's Disease and Vascular Dementia: a Retrospective Study.

PMID: 27747317 [PubMed]

PMCID: PMC5065347

EC Pharmacology and Toxicology
Will Blockchain Technology Transform Healthcare and Biomedical Sciences?

PMID: 31460519 [PubMed]

PMCID: PMC6711478

EC Pharmacology and Toxicology
Is it a Prime Time for AI-powered Virtual Drug Screening?

PMID: 30215059 [PubMed]

PMCID: PMC6133253

EC Psychology and Psychiatry
Analysis of Evidence for the Combination of Pro-dopamine Regulator (KB220PAM) and Naltrexone to Prevent Opioid Use Disorder Relapse.

PMID: 30417173 [PubMed]

PMCID: PMC6226033

EC Anaesthesia
Arrest Under Anesthesia - What was the Culprit? A Case Report.

PMID: 30264037 [PubMed]

PMCID: PMC6155992

EC Orthopaedics
Distraction Implantation. A New Technique in Total Joint Arthroplasty and Direct Skeletal Attachment.

PMID: 30198026 [PubMed]

PMCID: PMC6124505

EC Pulmonology and Respiratory Medicine
Prevalence and factors associated with self-reported chronic obstructive pulmonary disease among adults aged 40-79: the National Health and Nutrition Examination Survey (NHANES) 2007-2012.

PMID: 30294723 [PubMed]

PMCID: PMC6169793

EC Dental Science
Important Dental Fiber-Reinforced Composite Molding Compound Breakthroughs

PMID: 29285526 [PubMed]

PMCID: PMC5743211

EC Microbiology
Prevalence of Intestinal Parasites Among HIV Infected and HIV Uninfected Patients Treated at the 1o De Maio Health Centre in Maputo, Mozambique

PMID: 29911204 [PubMed]

PMCID: PMC5999047

EC Microbiology
Macrophages and the Viral Dissemination Super Highway

PMID: 26949751 [PubMed]

PMCID: PMC4774560

EC Microbiology
The Microbiome, Antibiotics, and Health of the Pediatric Population.

PMID: 27390782 [PubMed]

PMCID: PMC4933318

EC Microbiology
Reactive Oxygen Species in HIV Infection

PMID: 28580453 [PubMed]

PMCID: PMC5450819

EC Microbiology
A Review of the CD4 T Cell Contribution to Lung Infection, Inflammation and Repair with a Focus on Wheeze and Asthma in the Pediatric Population

PMID: 26280024 [PubMed]

PMCID: PMC4533840

EC Neurology
Identifying Key Symptoms Differentiating Myalgic Encephalomyelitis and Chronic Fatigue Syndrome from Multiple Sclerosis

PMID: 28066845 [PubMed]

PMCID: PMC5214344

EC Pharmacology and Toxicology
Paradigm Shift is the Normal State of Pharmacology

PMID: 28936490 [PubMed]

PMCID: PMC5604476

EC Neurology
Examining those Meeting IOM Criteria Versus IOM Plus Fibromyalgia

PMID: 28713879 [PubMed]

PMCID: PMC5510658

EC Neurology
Unilateral Frontosphenoid Craniosynostosis: Case Report and a Review of the Literature

PMID: 28133641 [PubMed]

PMCID: PMC5267489

EC Ophthalmology
OCT-Angiography for Non-Invasive Monitoring of Neuronal and Vascular Structure in Mouse Retina: Implication for Characterization of Retinal Neurovascular Coupling

PMID: 29333536 [PubMed]

PMCID: PMC5766278

EC Neurology
Longer Duration of Downslope Treadmill Walking Induces Depression of H-Reflexes Measured during Standing and Walking.

PMID: 31032493 [PubMed]

PMCID: PMC6483108

EC Microbiology
Onchocerciasis in Mozambique: An Unknown Condition for Health Professionals.

PMID: 30957099 [PubMed]

PMCID: PMC6448571

EC Nutrition
Food Insecurity among Households with and without Podoconiosis in East and West Gojjam, Ethiopia.

PMID: 30101228 [PubMed]

PMCID: PMC6086333

EC Ophthalmology
REVIEW. +2 to +3 D. Reading Glasses to Prevent Myopia.

PMID: 31080964 [PubMed]

PMCID: PMC6508883

EC Gynaecology
Biomechanical Mapping of the Female Pelvic Floor: Uterine Prolapse Versus Normal Conditions.

PMID: 31093608 [PubMed]

PMCID: PMC6513001

EC Dental Science
Fiber-Reinforced Composites: A Breakthrough in Practical Clinical Applications with Advanced Wear Resistance for Dental Materials.

PMID: 31552397 [PubMed]

PMCID: PMC6758937

EC Microbiology
Neurocysticercosis in Child Bearing Women: An Overlooked Condition in Mozambique and a Potentially Missed Diagnosis in Women Presenting with Eclampsia.

PMID: 31681909 [PubMed]

PMCID: PMC6824723

EC Microbiology
Molecular Detection of Leptospira spp. in Rodents Trapped in the Mozambique Island City, Nampula Province, Mozambique.

PMID: 31681910 [PubMed]

PMCID: PMC6824726

EC Neurology
Endoplasmic Reticulum-Mitochondrial Cross-Talk in Neurodegenerative and Eye Diseases.

PMID: 31528859 [PubMed]

PMCID: PMC6746603

EC Psychology and Psychiatry
Can Chronic Consumption of Caffeine by Increasing D2/D3 Receptors Offer Benefit to Carriers of the DRD2 A1 Allele in Cocaine Abuse?

PMID: 31276119 [PubMed]

PMCID: PMC6604646

EC Anaesthesia
Real Time Locating Systems and sustainability of Perioperative Efficiency of Anesthesiologists.

PMID: 31406965 [PubMed]

PMCID: PMC6690616

EC Pharmacology and Toxicology
A Pilot STEM Curriculum Designed to Teach High School Students Concepts in Biochemical Engineering and Pharmacology.

PMID: 31517314 [PubMed]

PMCID: PMC6741290

EC Pharmacology and Toxicology
Toxic Mechanisms Underlying Motor Activity Changes Induced by a Mixture of Lead, Arsenic and Manganese.

PMID: 31633124 [PubMed]

PMCID: PMC6800226

EC Neurology
Research Volunteers' Attitudes Toward Chronic Fatigue Syndrome and Myalgic Encephalomyelitis.

PMID: 29662969 [PubMed]

PMCID: PMC5898812

EC Pharmacology and Toxicology
Hyperbaric Oxygen Therapy for Alzheimer's Disease.

PMID: 30215058 [PubMed]

PMCID: PMC6133268

News and Events

December Issue Release

We always feel pleasure to share our updates with you all. Here, notifying you that we have successfully released the November issue of respective journals and the latest articles can be viewed on the current issue pages.

Submission Deadline for Upcoming Issue

ECronicon delightfully welcomes all the authors around the globe for effective collaboration with an article submission for the upcoming issue of respective journals. Submissions are accepted on/before December 20, 2022.

Certificate of Publication

ECronicon honors with a "Publication Certificate" to the corresponding author by including the names of co-authors as a token of appreciation for publishing the work with our respective journals.

Best Article of the Issue

Editors of respective journals will always be very much interested in electing one Best Article after each issue release. The authors of the selected article will be honored with a "Best Article of the Issue" certificate.

Certifying for Review

ECronicon certifies the Editors for their first review done towards the assigned article of the respective journals.

Latest Articles

The latest articles will be updated immediately on the articles in press page of the respective journals.