Molecular docking, synthesis and in vitro antimalarial evaluation of certain novel curcumin analogues

<div><p>ABSTRACT The receptor protein PfATP6 has been identified as the common target of artemisinin and curcumin. The work was initiated to assess the antimalarial activity of six curcumin derivatives based on their binding affinities and correlating the in silico docking outcome with in vitro antimalarial screening results. A ligand library of thirty two Knoevenagel condensates of curcumin were designed and docked against PfATP6 protein and six compounds with the best binding scores were synthesized and screened for their antimalarial activity against the sensitive 3D7 strain of Plasmodium falciparum. ADME/Tox, pharmacokinetic and pharmacodynamic profiles of the designed compounds were analyzed and reported. 4-FB was found to have similar binding energy to the standard artemisinin (-6.75 and -6.73 respectively) while 4-MB, 3-HB, 2-HB, B, 4-NB displayed better binding energy than curcumin (-5.95, -5.89, -5.68, -5.35, -5.29 and -5.25 respectively). At a dose of 50 µg/mL all the six compounds showed 100% schizont inhibition while at 5µg/ml, five showed more than 75% inhibition and better results than curcumin. 4-FB showed the best activity with 97.8% schizonticidal activity. The in vitro results superimpose the results obtained from the in silico study thereby encouraging development of promising curcumin leads in the battle against malaria.</p></div

Sample size, site and genotyped codon wise.

<p>Sample size, site and genotyped codon wise.</p

Demographic and clinical characteristics of patients and their responses to treatment with SP and CQ.

<p>ACPR = Adequate Clinical and Parasitological Response; TF = Treatment failure, ETF = Early Treatment Failure, LCF = Late Clinical Failure; LPF = Late Parasitological Failure; CF = Clinical failure, TF = Treatment failure.</p><p>Demographic and clinical characteristics of patients and their responses to treatment with SP and CQ.</p

Age and codon wise association of CQ (above) and SP (below) ETF.

<p>Age and codon wise association of CQ (above) and SP (below) ETF.</p

Prevalence of <i>dhps</i> and <i>dhfr</i> mutations in isolates of <i>Plasmodium falciparum</i>.

<p>Values within bracket are the percentage of occurrences.</p><p>Prevalence of <i>dhps</i> and <i>dhfr</i> mutations in isolates of <i>Plasmodium falciparum</i>.</p

Map of the studied areas of north east India.

<p>Map of the studied areas of north east India.</p

Frequency of allelic combinations mostly conferring resistance to SP.

<p>Frequency of allelic combinations mostly conferring resistance to SP.</p

Molecular Evidence of Increased Resistance to Anti-Folate Drugs in <i>Plasmodium falciparum</i> in North-East India: A Signal for Potential Failure of Artemisinin Plus Sulphadoxine-Pyrimethamine Combination Therapy

<div><p>North-east India, being a corridor to South-east Asia, is believed to play an important role in transmitting drug resistant <i>Plasmodium falciparum</i> malaria to India and South Asia. North-east India was the first place in India to record the emergence of drug resistance to chloroquine as well as sulphadoxine/pyrimethamine. Presently chloroquine resistance is widespread all over the North-east India and resistance to other anti-malarials is increasing. In this study both <i>in vivo</i> therapeutic efficacy and molecular assays were used to screen the spectrum of drug resistance to chloroquine and sulphadoxine/pyrimethamine in the circulating <i>P. falciparum</i> strains. A total of 220 <i>P. falciparum</i> positives subjects were enrolled in the study for therapeutic assessment of chloroquine and sulphadoxine/pyrimethamine and assessment of point mutations conferring resistances to these drugs were carried out by genotyping the isolates following standard methods. Overall clinical failures in sulphadoxine/pyrimethamine and chloroquine were found 12.6 and 69.5% respectively, while overall treatment failures recorded were 13.7 and 81.5% in the two arms. Nearly all (99.0%) the isolates had mutant <i>pfcrt</i> genotype (76T), while 68% had mutant <i>pfmdr</i>-1 genotype (86Y). Mutation in <i>dhps</i> 437 codon was the most prevalent one while <i>dhfr</i> codon 108 showed 100% mutation. A total of 23 unique haplotypes at the <i>dhps</i> locus and 7 at <i>dhfr</i> locus were found while <i>dhps</i>-<i>dhfr</i> combined loci revealed 49 unique haplotypes. Prevalence of double, triple and quadruple mutations were common while 1 haplotype was found with all five mutated codons (<b><u>F/AGEGS/T</u></b>) at <i>dhps</i> locus. Detection of quadruple mutants (51I/59R/108N/164L) in the present study, earlier recorded from Car Nicobar Island, India only, indicates the presence of high levels of resistance to sulphadoxine/pyrimethamine in north-east India. Associations between resistant haplotypes and the clinical outcomes and emerging resistance in sulphadoxine/pyrimethamine in relation to the efficacy of the currently used artemisinin combination therapy are discussed.</p></div

The frequency distribution of SNPs combination of <i>dhfr</i> alleles.

<p>Allelic combinations are in order of A16V, C50R N51I, C59R, S108N and I164L where bold and underlined allele denotes mutations. Values within bracket are the percentage of occurrences.</p><p>The frequency distribution of SNPs combination of <i>dhfr</i> alleles.</p

Prevalence of point mutations at <i>pfcrt</i> and <i>pfmdr1</i> locus in the two studied sites.

<p>Prevalence of point mutations at <i>pfcrt</i> and <i>pfmdr1</i> locus in the two studied sites.</p