• 2018-07
  • 2018-10
  • 2018-11
  • 2019-04
  • 2019-05
  • 2019-06
  • 2019-07
  • 2019-08
  • 2019-09
  • 2019-10
  • 2019-11
  • 2019-12
  • 2020-01
  • 2020-02
  • 2020-03
  • 2020-04
  • 2020-05
  • 2020-06
  • 2020-07
  • 2020-08
  • 2020-09
  • 2020-10
  • Toremifene br Conclusion AS SP the first line treatment stil


    Conclusion AS+SP, the first-line treatment, still remains highly effective in Pakistan following its introduction in 2007. However, molecular data indicate that SP resistance is being established in Pakistan, although mutations that confer a high risk of SP treatment failure are rare or non-existent. This underscores the need for close monitoring of both in vivo AS+SP efficacy and dhfr and dhps mutations to inform national treatment policy.
    Competing interests
    Acknowledgements We would like to express our appreciation to all of the patients and to the parents and guardians of the children who participated in the study. We thank the health authorities in the study areas for their collaboration. We also appreciate the work of all of the staff at the sentinel sites. Special thanks goes to Lutfullah Gandapur for the malaria microscopy work. We are grateful to Dr. Hoda Atta, Dr. Pascal Ringwald and Dr. Ghasem Zamani for their collaboration. Financial support for the studies was provided by the WHO through the Bill and Melinda Gates Foundation, as well as by the Global Fund to Fight AIDS, Tuberculosis and Malaria. The funding source(s) had no involvement in the different stages of the reported work.
    Introduction Dihydrofolate reductase (DHFR) catalyzes the transformation of 7,8-dihydrofolate into tetrahydrofolate [1]. The one-carbon transfer reactions involved in the pyrimidine, purine, and amino Toremifene biosynthesis utilize tetrahydrofolate asa cofactor in the production of serine, and thymidine needed for DNA replication [2], [3]. DHFR proved asa drug target in the treatment of bacterial infections and cancers [4], [5], [6]. In addition, it is known that the structure of the classical DHFR inhibitor, Methotrexate (MTX), can be modified without altering its biological potency [7], [8]. 1,3-Thiazole exists in many fused heterocyclic systems responsible for variety of biological activities. This includes the antitumor activity of PRL-3 associated with the affinity to phosphatases as bio-targets for the regeneration of liver cells [9]; the anti-apoptotic bio-complex Bcl-XL-BH3 and integrin-avb3 [10], [11]. 1,3-Thiazole also found in the groove binders tiazofurin, distamycin, bleomycin [11], [12]; and the antineoplastic compounds netropsin, and thia-netropsin [13], [14], [15], [16], [17]. The aforementioned pointed out the importance of the 1,3-thiazole asa bioactive moiety. In view of these facts, and in continuation to our previous efforts [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28], [29], the present study reports an efficient and reproducible synthesis of a new series of 2,4-substituted-1,3-thiazoles and thiazolo[4,5-d]pyridazine bearing the 2-thioureido function, which known to contribute to biological potency [18], [19], [20], [29], with anticipated antitumor and DHFR inhibitory activity. The aim of this study is to identify novel synthetic lead compound(s) through structure modification and the design of new compounds of different structure class and reduced molecular weight to define the structure requirements and features that enhance selectivity and specificity for binding to DHFR receptor sites. The synthesized derivatives were tested for their in vitro DHFR inhibition, and in-vitro antitumor activity using cell-based disease oriented approach [30], [31], [32], [33].
    Results and discussion
    Structure-activity correlation The electronegativity of the substituent on the 3-[4-substituted-phenyl)thioureido]- function of the intermediates 4 and 5 affected the DHFR inhibitory activity. The 4-chlorophenyl-thioureido derivative 4 (IC50 9.5±0.76μM) proved to be eight fold more active than the 4-methoxyphenyl- counterpart 5 (IC50 79.0±3.98μM). The thioureido- analogues 4 and 5 were used to prepare the corresponding thiazolo[4,5-d]pyridazin-4(5H)-one derivatives 20–27. The type of substituent on 20–27 also manipulated the DHFR inhibition activity. Two series of thiazolo[4,5-d]pyridazin-4(5H)-one analogues were synthesized namely: 1-(4-chlorophenyl)- 20, 22, 24, 26 and 1-(4-methoxyphenyl)-3-(4-oxo-7-substituted-4,5-dihydro-thiazolo-[4,5-d]pyridazin-2-yl)-thiourea 21, 23, 25, 27. In the 1-(4-chlorophenyl)-thioureido series: the type of substituent on the phenyl ring at position 7- of the thiazolo[4,5-d]pyridazine nucleus affected the DHFR inhibition activity dramatically. Compound 20 Toremifene with 7-phenyl group showed IC50 value of 14.6±1.32μM. The replacement of the 7-phenyl by 7-(4-methoxyphenyl)- moiety produced 22 (IC50 0.1±0.004μM) with more than one hundred and forty fold increase in potency; while the use of 7-(4-bromophenyl)- group produced 26 (IC50 0.06±0.003μM), the most active member of this study with more than two hundred fold increase in DHFR inhibition activity. The 1-(4-methoxyhenyl)-thioureido series proved to be less active in the magnitude and the effect of various substitution pattern on activity. In general, 3-[4-chlorophenyl)thioureido]- series is more active than the 3-[4-methoxyphenyl)-thioureido]- counterparts. Also the type of substituent at positions 7- of the thiazolo[4,5-d]pyridazine affected the DHFR inhibition potency. In the 3-[4-chloro-phenyl)thioureido]- series, the order of activity was 4-BrPh>4-CH3OPh>pH>4-CH3Ph; while in the 3-[4-methoxy-phenyl)-thioureido]-series, the order of activity was 4-CH3OPh>pH>4-CH3Ph=4-BrPh. The obtained antitumor results added another piece of evidence which emphasize the order of activity concluded in the DHFR inhibition study. Comparing the potency of the active antitumor compounds and their DHFR inhibition revealed that compounds 4, 20, 22, 23 and 26 might exert their antitumor activity through DHFR inhibition.