4-Aminoquinoline-Triazine-Based Hybrids withImproved In Vitro Antimalarial Activity AgainstCQ-Sensitive and CQ-Resistant Strains ofPlasmodium falciparum

Sunny Manohar1, Shabana I. Khan2 andDiwan S. Rawat1,*

1Department of Chemistry, University of Delhi, Delhi,110007, India2National Centre for Natural Products Research, Universityof Mississippi, Oxford, MS 38677, USA*Corresponding author: Diwan S. Rawat,dsrawat@chemistry.du.ac.in

A systematic chemical modification in the triazinemoiety covalently attached via suitable linkers to4-amino-7-chloroquinolines yielded a series of new7-chloro-4-aminoquinoline-triazine hybrids exhibitinghigh in vitro activity against W2 (chloroquine-resistant)and D6 (chloroquine-sensitive) strains of Plasmodiumfalciparum without any toxicity against mammalian celllines (Vero, LLC-PK11, HepG2). Many of the com-pounds (6, 8, 10, 11, 13, 14, 16, 27, 29 and 33) showedexcellent potency against chloroquine sensitive andresistant strains. In particular, compounds 6, 8, 14, 16and 29 were found to be significantly more active thanchloroquine against the chloroquine-resistant strains(W2 clone) of P. falciparum.

Key words: antimalarial, hybrids, Plasmodium falciparum

Received 11 August 2012, revised 18 December 2012 andaccepted for publication 8 January 2013

The prevalence of malaria has been documented about5000 years back, but still it has remained one of the mostlethal disease causing deaths of over one million peopleevery year (1,2). The drugs once considered to be safeand effective have become useless due to the incidencesof increasing reports of drug resistance and that has putan enormous burden on public health (3,4). Among themost commonly used drugs, chloroquine (CQ) (3) hadbeen a drug of choice for the treatment of malaria fornearly half a century and considered to be a wonder drugdue to the fact that it was effective, easily available, safeand inexpensive (5). The added advantage was that itcould be administered to infants and pregnant women.The problem has been complicated due to the fact that

P. falciparum, the cause of the most lethal variety ofmalaria, has developed resistance against CQ and otherantimalarials. Number of isolates of P. falciparum havedeveloped resistance against not only CQ but against themajority of currently used antimalarials. To address theissue of drug resistance, several approaches that includechloroquine-resistant (CQR) reversal agents (6,7), com-bination therapy (8) and use of endoperoxide-basedantimalarials have been introduced (9–14). Although end-operoxides are considered to be useful against resistantstrains, but these compounds are less affordable, andrecently, resistance against endoperoxide-derived anti-malarials has already been reported (15). Arguably, amino-quinolines such as quinine, CQ, mefloquine andamodiaquine are among the most successful antimalarialdrugs ever used (5,16,17), and structural modification ofthese molecules has resulted many additional leadcompounds with improved activity against CQR strains (18–20). Structure activity relationship studies revealed that4-aminoquinolines carrying an aliphatic side chain with 2–3or 10–12 carbon, and the incorporation of a phenol moietyis well tolerated and afford excellent activity-toxicity profiles(20–24). Many reports revealed that replacement of ethylgroup by isopropyl or tert-butyl groups can furnish meta-bolically more stable antimalarials with enhanced lifetimeand retained activity against drug-resistant strains of P. fal-ciparum (25,26). To develop safe, effective and inexpen-sive antimalarials that are active against resistant strainsand multiple species of Plasmodia, efforts have thereforebeen directed towards the development of new CQ ana-logues. Towards these goals, concept of hybrid moleculeshave been put forward by Meunier and co-workers (27) inmalaria chemotherapy, in which two antimalarial pharma-cophore are attached covalently, and it is anticipated thatthese kinds of molecules may solve the problem of drugresistance. In the past few years, number of 4-aminoquin-oline-based hybrid molecules are synthesised in anattempt to solve the problem of drug resistance (27–36).

The previous studies from our laboratory (32,33) and oth-ers showed that aminoquinoline-triazine hybrids exhibitpotent antimalarial activity (37,38). In continuation to ourefforts towards the development of new antimalarials (39–42), we report herein synthesis and antimalarial activity of

ª 2013 John Wiley & Sons A/S. doi: 10.1111/cbdd.12108 625

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Research Article

series of new 4-aminoquinoline-triazine-based hybrids.Systematic chemical modification in the triazine ring andlinker led to the discovery of many potent antimalarialagents.

Results and Discussion

ChemistrySynthesis of substituted 4-aminoquinolines (2a–c) wasachieved by aromatic nucleophillic substitution (SNAr) of4,7-dichloroquinoline (1) with an excess of different linear-chained aliphatic diamines in neat conditions as reportedin literature (Scheme 1) (43).

Temperature controlled stepwise displacement of chlorineatom from commercially available starting material cyanuricchloride (3) was accomplished in stepwise to achieve thesynthesis of target compounds (6–33) as outlined inScheme 2. In the first step, cyanuric chloride (3) wassubjected to nucleophillic substitution by piperidine ormorpholine in presence of a base at 0 °C to yield

monosbustituted triazines (4a,b). These monosubstitutedtriazines (4a,b) on reaction with various aliphatic and aro-matic amines at room temperature provided disubstitutedtriazines (5a–j) in good yield. Third chlorine of disubstitutedtriazines (5a–j) was then substituted by 4-aminoquinolineshaving varying alkyl chain lengths (2a–c) at elevatedtemperature to yield final trisubstituted triazines (6–33) inmoderate to excellent yields.

Antimalarial activity and cytotoxicity evaluationThe synthesized compounds (6–33) were evaluated fortheir in vitro antimalarial activity against D6 clone (CQ-sen-sitive) and W2 clone (CQ-resistant) of P. falciparum

(Table 1), while the cytotoxicity evaluation was carriedagainst a panel of three mammalian cells (Vero, LLC-PK11

and HepG2) by using doxorubicin as standard drug(Table 2). Selectivity index of antimalarial activity was cal-culated based on the cytotoxicity to Vero cells. Of 28compounds synthesised in the present study, 10 com-pounds (6, 8, 10, 11, 13, 14, 16, 27, 29 and 33) haveshown better antimalarial activity (IC50 ranging from 0.11to 0.42 lM) than CQ, while three compounds (12, 26 and32) have shown comparable activity (IC50 ranging from0.48 to 0.49 lM) to CQ against W2 clone of P. falciparum.Four of these hybrids (17, 26, 29 and 31) have also shownpotent antimalarial activity (IC50 ranging from 0.06 to0.10 lM) with high selective index against D6 clone ofP. falciparum. Structure activity relationship studies ofthese hybrid shows that the spacer which links 4-amino-quinoline to 1,3,5-triazine moiety plays an important role indefining the activity of these molecules. It is evident fromthe Table 1 that increasing the length of the linker from C2to C4, activity of the resulting compounds increases.

Scheme 1: (a) aliphatic diamines, neat, 110–120 °C, 6–8 h, 80–85%.

Scheme 2: (a) morpholine or piperidine, K2CO3, THF, 0–5 °C, 3 h, 75–80% (b) aromatic or aliphatic amines, K2CO3, THF, rt, 3 h, 70–85%; (c) 2a–c, K2CO3, DMF, 100–110 °C, 10–12 h, 65–85%.

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However, some deviations from this trend were alsoobserved with few compounds (7, 13, 19, 25 against D6clone and 7, 16, 19, 31 against W2 clone). Enhanced anti-malarial activity with high selective index against W2 cloneof P. falciparum has been observed for compoundscontaining aromatic substitution on 1,3,5-triazine (seven of

12 compounds are better than CQ) than their aliphaticcounterparts (two of 16 compounds are better than CQ).This may be attributed to greater lipophilic character asso-ciated with aromatic compounds (Table 1), which is ingood agreement to our previous observation (33). It maybe noted that no obvious change in activity pattern was

Table 1: In vitro antimalarial activity of new 4-aminoquinoline-triazine conjugates.

NN

N6-33

N N NX

n

R

HHN

CI

Entry n X R cLogP*

P. falciparum (D6 Clone)P. falciparum (W2Clone)

IC50 (lM) S. I. IC50 (lM) S. I.

6 1 O Aniline 6.36 0.29 >86.2 0.17 >147.07 2 O Aniline 6.77 0.44 >56.8 1.05 >23.88 3 O Aniline 6.88 0.29 >170.6 0.25 >198.09 1 O 4-ethyl aniline 7.39 0.47 >53.1 0.67 >37.3

10 2 O 4-ethyl aniline 7.79 0.40 72.0 0.42 68.511 3 O 4-ethyl aniline 7.91 0.39 >64.1 0.18 >138.812 1 O 4-fluoro aniline 6.52 0.24 >104.1 0.48 >52.013 2 O 4-fluoro aniline 6.92 0.43 >58.1 0.33 >75.714 3 O 4-fluoro aniline 7.04 0.24 >104.1 0.11 >227.215 1 O 4-methoxy aniline 6.29 0.25 >100.0 0.59 >42.316 2 O 4-methoxy aniline 6.69 0.16 >156.2 0.15 >166.617 3 O 4-methoxy aniline 6.81 0.07 >357.1 0.71 >35.218 1 O HN

OH3.54 0.49 >51.0 1.70 >14.7

19 2 O HNOH

4.02 0.50 >50.0 2.06 >12.1

20 3 O HNOH

4.14 0.19 >131.5 0.59 >42.3

21 1 O HN OH 3.99 0.67 >37.3 1.56 >16.0

22 2 O HN OH 4.39 0.63 >39.6 1.52 >16.4

23 3 O HN OH 4.42 0.22 >113.6 0.57 >43.8

24 1 O HNOH

3.88 0.48 >52.0 1.52 >16.4

25 2 O HNOH

4.39 0.51 >49.0 1.12 >22.3

26 3 O HNOH

4.50 0.09 >277.7 0.49 >51.0

27 1 CH2 HNOH

5.52 0.14 >178.5 0.40 >62.5

28 2 CH2 HNOH

5.92 ND ND ND ND

29 3 CH2 HNOH

6.04 0.10 >250.0 0.28 >89.2

30 1 CH2 HN OH 5.44 0.21 >119.0 0.83 >30.1

31 3 CH2 HN OH 6.05 0.06 >858.3 1.17 >44.0

32 1 CH2 HNOH

5.16 0.19 >131.5 0.49 >51.0

33 3 CH2 HNOH

5.60 0.19 >131.5 0.42 >59.5

Chloroquine (CQ) 0.05 >500 0.43 >58.1Artemisinin 0.015 >1666.6 0.014 >1785.7

ND – not determined; Selectivity index (SI) – IC50 for cytotoxicity towards VERO cells/IC50 for antimalarial activity; cLogP – Calculated byCHEMBIODRAW 11 Software, Cambridge, MA, USA.

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observed by changing the substituents (fluoro, ethyl ormethoxy groups) on phenyl ring attached to 1,3,5-triazinemoiety. Most interestingly, the introduction of aminoalcohols with terminal hydroxyl groups in the 1,3,5-triazinenucleus enhances the activity of some of the compounds(26, 27, 29, 32 and 33) towards both the strains (D6 andW2 clone) of P. falciparum with IC50 ranging from 0.10 to0.19 lM against D6 clone and 0.28–0.49 lM againstW2 clone. In this series (18–33), the change of piperidine(27–33) from morpholine group (18–26) improved the anti-malarial activity of these compounds against both thestrains of P. falciparum (IC50 ranging from 0.10 to 0.21 lMagainst D6 clone and 0.28–1.17 lM against W2 clone),while the increase in the carbon chain length of aliphaticaminoalcohols attached to 1,3,5-triazine nucleus generallyincreases the antimalarial activity towards W2 clone for aparticular linker (C2, C3 or C4) present between the ami-noquinoline and triazine moiety. Most of the compoundswere found to be non-cytotoxic up to the highest testedconcentration of 25 lM against all three cell lines (Table 2),indicating their safety in mammalian system. The mecha-nistic studies and structural modification of the lead mole-cules are under progress, and results will be published indue course of time.

Conclusion

In summary, systematic chemical modification of previouslyreported 4-aminoquinoline-triazine-based hybrids led tothe discovery of more potent 4-aminoquinoline-1,3,5-triazine-based hybrids with potent activity against bothCQ-sensitive (D6 clone) and CQ-resistant (W2 clone) ofP. falciparum. Ten compounds (6, 8, 10, 11, 13, 14, 16,27, 29 and 33) of total 28 compounds synthesised havedisplayed better activity than CQ against W2 clone ofP. falciparum. Introduction of aminoalcohol side chain withfree terminal hydroxyl group enhances the activity of com-pounds (26, 27, 29, 32 and 33) towards both the strainsof P. falciparum. The activity profile of these molecules, inparticular of compounds 16 and 29, can be beneficial forthe generation of future drug candidates in malarialchemotherapy.

Acknowledgments

DSR thanks University Grants Commission [F. No. 41-202/2012(SR)], New Delhi, India and University of Delhi, Delhi,India for financial support. SM is thankful to CSIR for theaward of senior research fellowship. Thanks to USIC-CIF,University of Delhi for analytical data. SIK is thankful toUnited States Department of Agriculture (USDA), Agricul-tural Research Service Specific Cooperative AgreementNo. 58-6408-2-0009 for partial support of this work. Theauthors declare no conflict of interest.

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