STUDY OF POTENTIAL TO INHIBIT HEMOZOIN FORMATION OF SOME NOVEL AMINOPROPANOLS

STUDY OF POTENTIAL TO INHIBIT HEMOZOIN FORMATION OF SOME NOVEL AMINOPROPANOLS

Priya Jain ^*1 and Dheeraj S. Bele ²

Pacific Academy of Higher Education and Research Society ¹, Udaipur, Rajasthan, India.

Charak Institute of Pharmacy ², Mandleshwar, Madhya Pradesh, India.

ABSTRACT: One of the factors responsible for malaria pathogenesis is the suppression of host immune responses. This suppression enhances parasitemia and diminishes the host immune response to malaria-expressed proteins and other pathogens. Hemozoin is a key metabolite associated with severe malaria anemia (SMA), immunosuppression, and cytokine dysfunction. Targeting of this pigment may be necessary in the design of new therapeutic products against malaria. In the present research, some novel compounds are synthesized and targeted against hemozoin growth. The consideration of new chemotherapeutic targets in malaria research is most likely to identify new classes of drugs. The present work deals with the synthesis of a small library of 2-alkoxy/phenoxy-3-amino-3-arylpropan-1-ols by reductive ring opening of the corresponding azetidine-2-ones. After characterization of synthesized compounds, these were evaluated for hemozoin formation inhibition assay. The results showed that all compounds are inhibiting hemozoin formation comparable to Clotrimazole. This may be concluded that the synthesized compounds exhibit antimalarial activity via inhibition of hemozoin formation.

Antimalarials, Aminopropanols, Hemozoin, Clotrimazole

INTRODUCTION: Malaria has plagued humankind since ancient times and is still a significant threat to half of the world’s population. Malaria is the fifth most common cause of death from infectious diseases worldwide ¹. The World Malaria Report 2015 written by the World Health Organization (WHO) summarizes advances that have taken place in each WHO region over the 2000–2015 period. Malaria is endemic in 95 countries mainly in Africa (88%). This report shows that this goal was achieved with an almost 37% and 60% drop in malaria incidence and in death rates, respectively, over this period.

In 2015, 214 million cases of malaria were recorded including 438 000 that have led to the death of the patients, reflecting a decline of 18% and 48% in cases and deaths, respectively, over the 2000–2015 period. ². Malaria parasites reside in erythrocytes throughout their life cycle in human beings. P. falciparum invades red cells of all ages and digest hemoglobin into small fragments consisting of about 20 different amino acids and free ferrous [Fe(II)protoporphyrin IX], which is rapidly oxidized to heme ³. Free toxic heme is rapidly oxidized to hematin and sequestered into inert, nontoxic crystalline Hemozoin, Hz, which is present in the pRBC ⁴.

The presence of Hz in RBC results in appearance of antigenic molecules on membranes of these cells ⁵. Recognition of Hz-containing RBC results in phagocytosis by circulating macrophages and removal from circulation.

A study of the antigens exposed on the surface of pRBCs with different isolates of P. falciparum showed that the surface antigens could induce isolate-specific immunity ⁶. Over 25-75% of the erythrocyte hemoglobin is digested during growth of the parasite in erythrocytes ⁷. Heme then undergoes auto-oxidation to liberate toxic hematin [aqua Fe(III) protoporphyrin IX]. The parasite detoxifies hematin and converts it   to an insoluble material known as hemozoin (malaria pigment) ⁸. For hemozoin formation histidine rich proteins like Pf-hrp-2 play key role. It may serve as precursors for hematin binding prior to formation as hemozoin ⁹. The hemoglobin degradation mechanism was studied in detail, and it was shown that it implies enzymes (proteases) present in the food vacuole of the parasite such as two aspartic (plasmepsins I and II) and cysteine (falcipain) proteases ¹⁰. In the food vacuole, hemoglobin is degraded into heme, which is polymerized into insoluble hemozoin pigment and globin, which is hydrolyzed to individual amino acids. Antimalarial drugs appear to act by preventing hemozoin formation, producing free radicals in the food vacuole or by preventing globin hydrolysis ¹¹.

The formation of hemozoin is apparently the primary mechanism of heme detoxification in malaria parasites ¹². Free heme is oxidatively active and toxic to both the host cells and the malarial parasites, and it causes parasite death. Heme could cause extensive damage to membranes and inhibit a variety of enzymes resulting in the death of the parasite. Due to the absence of heme oxygenase, the parasite is unable to cleave heme into an open-chain tetra pyrrole, which is necessary for cellular excretion ¹³. The heme neutralization process is one of the main targets of the antimalarial drugs, with different researchers expressing different views on whether the drugs affect catalytic enzymes or direct crystallization of hemozoin, or both, or alternatively affect the direct oxidation of heme ¹⁴.

The heme detoxification by P. falciparum results in the formation of β-haematin (BH) also known as hemozoin (HZ), which is a water-insoluble malarial pigment produced in the food vacuole by template mediated crystallization (“biocrystallization”), and a number of studies have been conducted in order to understand the hemozoin formation ¹⁵. Free heme is oxidatively active and toxic to both the host cells and the malarial parasites, and it causes parasite death. Heme could cause extensive damage to membranes and inhibit a variety of enzymes resulting in the death of the parasite ¹².

The sequestration of heme into hemozoin is a suitable target for new antimalarials. Hence, an understanding of the mechanisms of hematin crystallization and its inhibition by antimalarials may prove to be influential for drug development ¹⁶. The fundamentals regarding the mechanism of hematin crystallization and its inhibition remain elusive. The nature of the environment within the parasite where hemozoin crystals recruit hematin and grow is still unkown. The two likely candidates are the aqueous phase in the parasite digestive vacuole (DV) ^{17, 18} and the lipid subphase that has been reported to reside either in the DV bulk ^{19, 20} or along the DV membrane ^{17, 21}. The mechanism of hematin crystallization may be classical, i.e., addition of molecules to growth sites ²², or non-classical, i.e., association of precursors ^23–25. The mechanism of action of the inhibitor species, it is possible that the inhibitors either reduce the concentration and activity of hematin in the growth medium through complexation ^{26, 27}, or interfere with crystallization by binding to the crystal surface(s) and restricting solute addition.

Clotrimazole, an imidazole containing antifungal drug, has also shown promising antimalarial activity in vitro ²⁸. Clotrimazole also enhances heme induced membrane damage and inhibits β-hematin formation ²⁹. However, a significant correlation was noticed between inhibition of in vitro β-hematin formation and antimalarial activity of the antifugal azoles ³⁰. So, Clotrimazole is employed as standard drug for assay of hemozoin formation inhibition.

The present work deals with the synthesis of 2-alkoxy-3-amino-3-(3/4 substituted aryl) propan-1-ols 3, followed by study of their potential to inhibit hemozoin formation. The synthesis of these compounds involve reaction between the appropriate imines and ketenes. The substituted aldehydes and appropriate amine is condensed in dichloromethane in the presence of magnesium sulfate as drying agent which results in corresponding imines. The treatment of these 3/4-substituted phenylmethanimine 1 with methoxy-, phenoxy-, or benzyloxyacetyl chloride in dichloromethane in the presence of triethylamine results in corresponding novel azetidin-2-ones 2. Then 4-arylazetidin-2-ones 2 were subjected to a reductive ring-opening by means of lithium aluminum hydride in diethyl ether, results in corresponding 2-alkoxy/phenoxy substituted 2-alkoxy-3-amino-3-(3/4 substituted aryl) propan-1-ols, 3 ^{31, 32}. The combination of a γ-amino alcohol moiety and an aryl group in these propanes might result in novel and easily accessible classes of antimalarial agents.

To obtain molecular diversity within γ-aminoalcohols, a variety of different representatives of this class of compounds was prepared by altering the amino group (R₂= Me, Bu, iPr, nPr), the aryl moiety (R₁= m-NO₂, p-NO₂, p-Cl) and the alkoxy or phenoxy substituent (R_3­= Ph, Bn). This small library of novel γ-aminoalcohols was then screened for antimalarial activity by their hemozoin formation inhibition ability ²⁰. Clotrimazole and compounds with different molar equivalents (0.12-5.0) to haemin was prepared by dissolving compounds separately in DMSO.

FIG. 1: SCHEME OF SYNTHESIS

TABLE 1: DETAILS OF SUBSTITUTIONS

MATERIALS AND METHODS: All the reagents and solvents were used as purchased without further purification. Melting points were determined are uncorrected. The qualities of all the synthesized compounds were tested by TLC using a mixture of non-aqueous solvents. IR spectra were obtained on a IR Affinity 1 Spectrophotometer, Shimadzu, Kyoto, Japan. NMR spectra were recorded on a Brucker Spectrospin DPX 300 Spectrophotometer, Bruker AG, Switzerland with DMSO as solvent. Purity of the synthesized compound was checked by TLC using Silica gel-G plates.

Experimental Procedure: A mixture of 10 mmol of the appropriate aromatic aldehyde in 100 ml of dichloromethane was treated with 10 mmol of the appropriate amine and 15 mmol of magnesium sulfate. The mixture was refluxed for 1.5-3 h and then filtered. After evaporation of the solvent, N-(arylmethylidene)-amine 1 was obtained, and the solvent was further evaporated under high vacuum (to remove the last traces of solvent, if required). To an ice-cooled solution of N-(arylmethylidene)-amine 1 (10 mmol) and triethylamine (30 mmol) in dichloromethane (25ml) were added dropwise a solution of alkoxyacetyl chloride (11 mmol) in CH₂Cl₂ (10 ml). After stirring for 15-18 h at room temperature, the reaction mixture was poured into water (30 ml) and extracted with CH₂Cl₂ (twice using 25ml each time). Drying (MgSO₄), filtration of the drying agent, and removal of the solvent afforded azetidin-2-ones, 2, this was purified by recrystallization from ethanol. To an ice-cooled solution of azetidin-2-ones 2 (10 mmol) in dry diethyl ether (50 ml) was added lithium aluminum hydride (20 mmol) in small portions. After reflux for 3-5 h, the reaction mixture was cooled to 0⁰C and water (10 ml) was added in order to quench the excess of LiAlH₄.

The resulting suspension was filtered and washed with diethyl ether (40 ml), and the filtrate was poured into water (50 ml) and extracted with diethyl ether (3×30 ml). Drying (MgSO₄), filtration of the drying agent and removal of the solvent in vacuum afforded 2-alkoxy-3-amino-3-(3/4 substituted aryl) propan-1-ols, 3, which was purified by means of column chromatography on silica gel or recrystallization from absolute EtOH.

Procedure for Assay of hemozoin formation inhibition: 50 μl of an 8 mM solution of hemin chloride was dissolved in DMSO and compounds dissolved in DMSO, in doses ranging from 0.5 to 10 molar equivalents to haemin chloride. In control 50 μl distilled water was added. By adding 100 μl of 8 M acetate buffer (pH 5) the hemozoin formation was initiated and the plates were incubated at 37 ºC for 18 h. After centrifugation, the soluble fraction was collected. 200μl of DMSO was added to resuspend the remaining pellet in order to remove unreacted haematin. The plates were centrifuged again, the DMSO soluble fraction was collected and the residual pellet, consisting of pure precipitate of β-haematin, was dissolved in 200 μl of 0.1 M NaOH. 75 μl of it was transferred to new tubes and diluted four times by adding 0.1 M NaOH. The amount of haematin was determined by measuring the absorbance at 414 nm using UV spectophotometer (Shimadzu UV 1800). Clotrimazole was used as positive control.

The percentage inhibition of hemozoin formation was calculated using the formula given below:

The percentage inhibition of hemozoin by the standard drug clotrimazole was compared with the control. Method was standardized and validated.

RESULTS AND DISCUSSION: The target compounds were synthesized according to the synthetic pathway outlined in Scheme 1. Generally, the structures of the products were characterized by the presence of appropriate signals in NMR spectra and the characteristic peak in FTIR. The hemozoin inhibition assay of the synthesized compounds was studied using reported procedure ^{19, 20}. All of the compounds were found to inhibit hemozoin formation to a certain extent comparable to Clotrimazole (Table 1).

TABLE 2: HEMOZOIN FORMATION INHIBITION ASSAY

These findings could provide rational for the hypothesis that haem could be the drug receptor, at least in part, for aminopropanols as antimalarial agent.

3-(methylamino)-3-(4-nitrophenyl) – 2 - phenoxy propan-1-ol  (3b): White crystals; Yield (48%); melting range (115-116 ⁰C); λ_max: 309nm, IR (ATR, ν max, cm^-1): 3356 (OH str), 2877, 2841, 2183 (2⁰ NH₂), 1658 (N=O str), 1641 (C=C str, Ar), 1525 (asy NO₂ str, Ar), 1469 (asy C-H bend, Ali), 1350 (sym Ar NO₂ str), 1132 (C-O-C str), 1022 (C-N str, NH₂), 794, 682 (C-H bend, Ar) cm^-1; 1H NMR (CDCl₃, δ ppm): δ 1.96 (1H, d, J =6.5 Hz for (–OH)(C1)), 2.85 (1H, septet, J =5.9 Hz, (-CH)), 3.16-4.10 (1H, m, to (-CH(NO₂)(C7)), 3.29 and 4.77 (2H, 2 × (d×d), J =12.2, 3.6, 1.9 Hz, (-C-O)(C4)), 4.35 and 4.60 (2H, 2 × d, J=10.1 Hz, to (-NHR1)), 7.11-7.98 and 7.00-7.68 (10H, 2 × m (-Aryl) (C3)).

3-(butylamino) - 3 - (3-nitrophenyl)- 2 - phenoxy propan-1-ol (3c): White crystals; Yield (32%); melting range (125-126 ⁰C); λmax: 339nm, IR (ATR, ν max, cm^-1): 3350 (OH str), 2960, 2187, 2019 (2⁰ NH₂), 1641 (C=C Ar str) , 1552 (asy Ar NO₂ str), 1350 (sym Ar NO₂ str),1072 (C-O-C str), 1028 (C-N str NH₂), 758, 694 (C-H bend) cm^-1; 1H NMR (CDCl₃, δ ppm): 1.41 (1H, d, J =6.3 Hz, of (-OH)(C1)), 1.33 (1H, septet, J =5.9 Hz, of (-CH)), 3.79 (1H, m of (-CH(NO₂)(C6)), 2.55 (2H, 2 × (d×d), J =10.9, 2.3, 2.0 Hz, of (-C-O)(C4)), 4.40 (2H, d, J=19.8 Hz, (-NC₄H₉)(C3)), 7.15 and 8.01-8.05 (10H, 2 × m (-Aryl)(C3)).

3-(butylamino)- 3 - (4-nitrophenyl) – 2 - phenoxy propan-1-ol (3d): White crystals; Yield (56%); Melting Range (131-132 ⁰C); λ_max: 340nm, IR (ATR, ν max, cm^-1): 3321 (OH str), 2958, 2873, 2160 (2⁰ NH₂), 1631 (C=C str, Ar), 1529 (asy NO₂ str, Ar), 1462 (asy C-H bend, Ali), 1348 (sym Ar NO₂ str), 1112 (C-O-C str), 1028 (C-N str, NH₂), 846, 705 (C-H bend) cm^-1; 1H NMR (CDCl₃, δ ppm): 2.11 (1H, d, J =6.1 Hz, of (-OH) (C1)), 2.15 (1H, septet, J =9.9 Hz of (-CH)), 3.26-4.85 (1H, m(-CH(NO₂))(C7)), 3.29 and 4.77 (2H, 2 × (d×d), J =13.9, 4.6, 2.9 Hz, of (-C-O)(C4)), 4.39 (2H, d, J=17.6 Hz (-NC₄H₉) (C3)), 7.01-7.34 and 8.02-8.68(10H, 2 × m(-Aryl) (C3)).

2-(benzyloxy) - 3-(isopropylamino) – 3 - (4-nitro phenyl)propan-1-ol (3f): White crystals; Yield (30%); Melting Range (127-128 ⁰C); λ_max- 395nm, IR (ATR, ν max, cm^-1): 3315 (OH str), 2972, 2881, 2160 (2⁰ NH₂), 1641 (C=C str, Ar), 1527 (asy NO₂ str, Ar), 1467 (asy C-H bend, Ali), 1348 (sym Ar-NO₂ str), 1163 (C-O-C str), 1128, 1026 (C-N str, NH₂), 948, 815 (C-H bend, Ar) cm^-1; 1H NMR (CDCl₃, δ ppm): 1.05 (3H, d, J =5.7 Hz(-OH)(C1)), 3.86-5.95 (1H, m (-CH(NO₂))(C7)), 4.63 (2H, t, J = 6.5, 6.9Hz(-CH)), 7.85 (2H, d, J = 10.6 Hz(-NHR1)(C3), 7.02-7.41 and 7.14–7.78 (10H, 2 × m(-Aryl)(C3)), 8.15 (3H, t, J = 9.7 , 12.5 Hz(-NH)).

3-(4-nitrophenyl) - 2 - phenoxy -3-(propylamino) propan-1-ol (3h): White crystals; Yield (35%); Melting Range (135-136 ⁰C); λ_max: 303nm, IR (ATR, ν max, cm^-1): 3358 (OH str), 2962, 2877, 2187 (2⁰ NH₂), 1705 (C=C str, Ar), 1527 (asy NO₂ str, Ar), 1456 (asy C-H bend, Ali), 1348 (sym NO₂ str, Ar), 1230 (C-O-C str), 1068 (C-N str, NH₂), 968, 709 (C-H bend, Ar) cm^-1; 1H NMR (CDCl₃, δ ppm): 1.45 (d, J =2.9  Hz(-OH)(C1)), 3.86-5.95 (1H, m (-CH(NO₂))(C7)), 4.27 (2H, t, J = 6.9, 7.3 Hz, (-CH)), 7.85 (2H, d, J = 10.6 Hz, (-NHR1)(C3)), 7.02-7.41 and 7.18–7.56  (10H, 2 × m(-Aryl)(C3)).

3-(butylamino)-3-(4-chlorophenyl) - 2 - phenoxy propan-1-ol (3q): White crystals; Yield (42%); Melting Range (148-149 ⁰C); λ_max: 323nm, IR (ATR, ν max, cm^-1): 3370 (OH str), 2958, 2935 (2⁰ NH₂), 1701 (C=C str, Ar), 1467 (asy C-H bend, Ali), 1294 (C-O-C str), 1031 (C-N str, NH₂), 844, 750 (C-H bend, Ar) cm^-1; 1H NMR (CDCl₃, δ ppm) 1.02 2H, s, (-OH)(C1)), 1.97-2.6 (2H, t, J = 15.5, 12.5 Hz, (-CH)), 4.63 1H, m, (-C-O)(C4)), 7.51 (1H, d, J = 12.8, 6.7 Hz (-Cl (p-Aryl))(C7)), 7.95-8.56 (3H, t, J = 15.3, 12.5 Hz, (-NHR1)(C3)), 8.81–9.39 (6H, septet, J =23.5 Hz, (-Ph)(C4)).

CONCLUSION: The mechanism of action of aminopropanols is still not clear. The action of synthesized compounds on hemozoin formation found to be considerable. The results help in concluding that aminopropanol derivatives are having antimalarial action because of hemozoin formation inhibition. A rich library will help in studying the exact mechanism of these compunds. On the basis of above conclusions, the parent nucleus could be explored further to obtain more potent derivatives.

ACKNOWLEDGEMENT: Authors are grateful to Dr. P. K. Dubey, Principal, Swami Vivekanand College of Pharmacy, Indore for providing facilities to carry out research work.

CONFLICT OF INTEREST: The authors report no conflict of interest.

REFERENCES:

1. Lal S, Sonal JS, Phukan PK. Status of malaria in India. Journal Indian Academy of Clinical Medicine. 2008; 5: 19-23.
2. World Malaria Report. 2015. Available from: http://www.who.int/malaria/publications/world-malaria-report-2015/report/en/
3. Huy NT, Shima Y, Maeda Al. Phospholipid membrane mediated hemozoin formation: the effects of physical properties and evidence of membrane surrounding hemozoin. PLoS One. 2013; 8:7-12.
4. Tripathi AK, Garg SK, Tekwani BL. A physiochemical mechanism of hemozoin (?-hematin) synthesis bymalaria parasite. Biochemical and Biophysical Research Communications. 2002; 290(1): 595–601.
5. Giusti P, Urban BC, Frascaroli G. Plasmodium falciparum-Infected erythrocytes and ?-hematin induce partial maturation of human dendritic cells and increase their migratory ability in response to lymphoid chemokines. Infection and Immunity. 2011; 79(7): 2727–2736.
6. Kalantari N, Ghaffari S. Identification and characterization of the antigens expressed on the surface of human erythrocytes infected with Plasmodium falciparum. Iranian Journal of Parasitology. 2013; 8(2): 197–206.
7. McKerrow JH, Sun E, Rosenthal PJ, Bouvier J. The proteases and pathogenicity of parasitic protozoa. Annual Review of Microbiology. 1993; 47: 821-53.
8. Bohle DS, Dinnebier RE, Madsen SK, Stephens PW. Characterization of the products of the heme detoxification pathway in malarial late trophozoites by X-ray diffraction. Journal of Biological Chemistry. 1997; 2: 713-716.
9. Pandey AV, Bisht H, Babbarwal VK, Srivastava J, Pandey KC, Chauhan VS. Mechanism of malarial haem detoxification inhibition by chloroquine. Biochemistry Journal. 2001; 355: 333-338.
10. Coronado LM, Nadovich CT, Spadafora C. Malarial hemozoin: from target to tool. Biochim Biophys Acta. 2014; 1840: 2032–2041.
11. Fichera ME, Roos DS. A plastid organelle as a drug target in apicomplexan parasites. Nature. 1997; 390: 407–409.
12. Olafson KN, Ketchum MA, Rimer JD, Vekilov PG. Mechanisms of hematin crystallization and inhibition by the antimalarial drug chloroquine. Proc Natl Acad Sci USA. 2015; 112: 4946–4951.
13. Eckman JR, Modler S, Eaton JW, Berger E, Engel RR. Host heme catabolism in drug-sensitive and drug-resistant malaria. Journal of Laboratory and Clinical Medicine. 1997; 90: 767–770.
14. Vega-Rodríguez J, Pastrana-Mena R, Crespo-Lladó KN, Ortiz JG, Ferrer-Rodríguez I, Serrano AE. Implications of Glutathione Levels in the Plasmodium berghei Response to Chloroquine and Artemisinin. PLoS One. 2015; 10: e0128212–13.

15. Vanderesse R, Colombeau L, Frochot C, Acherar S. Inactivation of Malaria Parasites in Blood: PDT vs Inhibition of Hemozoin Formation, Current Topics in Malaria, Dr. Alfonso Rodriguez-Morales (Ed.), InTech Open. 2016; pp. 205-233.
16. Pisciotta JM, Coppens I, Tripathi AK, Scholl PF, Shuman J, Bajad S, Shulaev V, Sullivan DJ. The role of neutral lipid nanospheres in Plasmodium falciparum haem crystallization. Biochemistry Journal. 2007; 402(1): 197–204.
17. Kapishnikov S. Oriented nucleation of hemozoin at the digestive vacuole membrane in Plasmodium falciparum. Proc Natl Acad Sci USA. 2012; 109(28): 11188–11193.
18. Kapishnikov S, Berthing T, Hviid L, Dierolf M, Menzel A, Pfeiffer F, Als-Nielsen J, Leiserowitz L. Aligned hemozoin crystals in curved clusters in malarial red blood cells revealed by nanoprobe X-ray Fe fluorescence and diffraction. Proc Natl Acad Sci USA. 2012; 109(28): 11184–11187.
19. Egan TJ. Haemozoin formation. Mol Biochem Parasitol. 2012; 157(2): 127–136.
20. Pisciotta JM,  Coppens I, Tripathi AK, Scholl PF, Shuman J, Bajad S, Shulaev V, Sullivan DJ Jr. The role of neutral lipid nanospheres in Plasmodium falciparum haem crystallization. Biochem J. 2007; 402(1): 197–204.
21. Kapishnikov S, Weiner A, Shimoni E, Schneider G, Elbaum M, Leiserowitz L. Digestive vacuole membrane in Plasmodium falciparum infected erythrocytes: Relevance to templated nucleation of hemozoin. Langmuir. 2013; 29(47): 14595–14602.
22. Burton WK, Cabrera N, Frank FC. The growth of crystals and equilibrium structure of their surfaces. Phil Trans R Soc London Ser A. 1951; 243: 299–360.
23. Banfield JF, Welch SA, Zhang H, Ebert TT, Penn RL. Aggregation-based crystal growth and microstructure development in natural iron oxyhydroxide biomineralization products. Science. 2000; 289(5480): 751–754.
24. Li D,  Nielsen MH, Lee JR, Frandsen C, Banfield JF, De Yoreo JJ. Direction-specific interactions control crystal growth by oriented attachment. Science. 2012; 336(6084): 1014–1018.
25. Van Driessche AE, Benning LG, Rodriguez-Blanco JD, Ossorio M, Bots P, García-Ruiz JM. The role and implications of bassanite as a stable precursor phase to gypsum precipitation. Science. 2012; 336(6077): 69–72.
26. Dinio T, Gorka AP, McGinniss A, Roepe PD, Morgan JB. Investigating the activity of quinine analogues versus chloroquine resistant Plasmodium falciparum. Bioorg Med Chem. 2012; 20(10): 3292–3297.
27. Gorka AP, Alumasa JN, Sherlach KS, Jacobs LM, Nickley KB, Brower JP, de Dios AC, Roepe PD. Cytostatic versus cytocidal activities of chloroquine analogues and inhibition of hemozoin crystal growth. Antimicrob Agents Chemother. 2013; 57(1): 356–364.
28. Tiffert T, Ginsburg H, Krugliak M, Elford B, Lew VL. Potent antimalarial activity of clotrimazole in in vitro cultures of Plasmodium falciparum. Proceedings of the National Academy of Science of the United States of America, PNAS. 2000; 97: 331.
29. Huy NT, Takano R, Hara S, Kamei K. Enhancement of Heme-Induced Membrane Damage by the Anti-malarial Clotrimazole: the Role of Colloid-Osmotic Forces. Biological and Pharmaceutical Bulletin. 2004; 27: 361.
30. Parapini S, Basilico N, Pasini E, Egan TJ, Olliaro P, Taramelli D, Monti D. Standardization of the physicochemical parameters to assess in vitro the beta-hematin inhibitory activity of antimalarial drugs. Experimental Parasitology. 2000; 96: 249.
31. Dejaegher Y, Mangelinckx S, De Kimpe N. Rearrangement of 2-Aryl-3,3-dichloroazetidines: Intermediacy of 2-Azetines. Journal of Organic Chemistry. 2002; 67: 2075–2081.
32. D’ hooghe M, Dekeukeleire S, Mollet K, Lategan C, Smith PJ, Chibale K and De Kimpe N. Synthesis of Novel 2-Alkoxy-3-amino-3-arylpropan-1-ols and 5-Alkoxy-4-aryl-1,3-oxazinanes with Antimalarial Activity. Journal of Medicinal Chemistry. 2009; 52:
    

    ---

    How to cite this article:

    Jain P, Bele DS: Study of potential to inhibit hemozoin formation of some novel aminopropanols. Int J Pharm Sci Res 2017; 8(6): 2567-72.doi: 10.13040/IJPSR.0975-8232.8(6).2567-72.

    ---

    All © 2013 are reserved by International Journal of Pharmaceutical Sciences and Research. This Journal licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License.

    ---