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  • The use of SP in


    The use of SP in IPTp may not be the only driver of parasite polymorphisms in this population, because Senegal has used sulfadoxine and/or pyrimethamine in the national antimalarial treatment plan for many years, and furthermore these drugs are still being used in antibacterial combination therapy. Nonetheless, this type of general population survey could form part of the monitoring system for IPTp as an alert strategy plan, because the genetic and phenotypic PU-H71 among parasites infecting the general population in very low transmission areas like Thies (EIR<5), likely reflect the parasites circulating among pregnant women. Our study is not without limitations. The small number of patients recruited in 2003 was due to logistical constraints, which were addressed in the following years and allowed for deeper sampling in 2008–2011. The intervening years were also spent developing the DAPI ex vivo drug assay (Ndiaye et al., 2010) and High Resolution Melting genotyping (Daniels et al., 2012). The latter technology is a reliable, adaptable, and accessible tool that provides comparable results to PCR-RFLP. Future studies will strengthen the present data set and will provide valuable information for the Senegalese National Malaria Control Program. In conclusion, our results show an increasing prevalence of dhfr N51I/C59R/S108N triple and dhfr N51I/C59R/S108N and dhps A437G quadruple mutations between 2003 and 2011 in Thies, Senegal. This study suggests that intermittent drug pressure with SP is selecting parasites with mutant alleles. The use of SP is not only implemented in IPTp, but also recently for seasonal malaria chemoprevention in children, thus surveillance of molecular markers of drug resistance and ex vivo drug sensitivity assays should be an integral part of planned malaria control programs, so that resistance dynamics can be assessed and the most effective treatment can be selected or modified.
    Acknowledgements The work was supported by a grant (D43 TW001503) to D.F.W. from the National Institutes of Health. The authors are very grateful to Dan Milner, Ambroise Ahouidi, Younouss Diedhiou, Lamine Ndiaye, Amadou Mactar Mbaye, Moussa Dieng Sarr, Ngayo Sy, SLAP patients, and the SLAP health staff.
    Introduction Dihydrofolate reductase (DHFR) inhibition is an attractive goal for PU-H71 the development of therapeutic agents against bacterial and parasitic infections as well as anticancer drugs [1]. DHFR enzyme catalyzes the reduction of dihydrofolate to tetrahydrofolate and couples with thymidylate synthase (TS) to catalyze the reductive methylation of deoxyuridine to deoxythymidine. Inhibition of DHFR or TS activity leads to “thymineless death” [2], [3], [4], [5]. Previous reported studies allowed the allocation of basic nitrogen atom at N-1, 4-carbonyl function, hydrophobic π-system regions and their relative dimensions as pharmacophoric characteristics for the active quinazoline DHFR inhibitors [6], [7], [8], [9]. Compounds 1–3 represent the active DHFR inhibitors obtained as a result of implementing these pharmacophoric features with IC50 value range of 0.3–1.0μM. In addition, 4-Phenyl-thiazole-1,3,5-triazines (4) approved as effective parasitic and microbial DHFR inhibitors (Fig. 1), [10], [11]. Recently, two new compounds belong to 5-(2-aminothiazol-4-yl)-4-phenyl-4H-1,2,4-triazole-3-thiol skeleton were allocated; 5 with antibacterial potency comparable to gentamicin and ciprofloxacin and 6 with DHFR inhibition activity (IC50 0.03μM), Fig. 1 [12]. In continuation to our previous efforts, a new series of 2-mercapto-quinazolin-4-one analogues is designed to possess electron withdrawing or donating functional groups (Cl or CH3O) at position 6- or 7-, 4-methoxyphenyl function at position 3-. The 2-mercapto function is used to connect to either 1,2,4-triazole or 1,3,4-thiadiazole via a methylene bridge. Thioether [13] and amide [14], [15] functional groups are known to contribute to the enhancement of biological activity. Combining the inherited DHFR inhibition activity of the proposed quinazolines and the activity enhancer functional groups in one structure is anticipated to produce remarkably active compounds. Most of the functional groups designed to be accommodated on the quinazoline ring such as thioether, alkyl, aryl, and arylalkyl are known to increase lipid solubility of polar compounds, a character needed for DHFR inhibition [14]. As an application of the use of DHFR inhibitors, the synthesized compounds were tested for their in vitro antitumor and antimicrobial activities.