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  • br Conclusion New series of thiazolo d pyridazine and imidaz


    Conclusion New series of thiazolo[4,5-d]pyridazine and imidazo[2′,1′:2,3]thiazolo[4,5-d]pyridazine were designed and synthesized using thiazole as scaffold based on its previously observed activity as DHFR inhibitor. Compounds 13 and 43 (Fig. 9) proved to be the most active DHFR inhibitors with IC50 0.05 and 0.06 μM, respectively; comparable to MTX. Compounds 13 and 43 proved to be the most active antitumors with growth inhibition potency against most of the tested tumor cell lines. Compound 43 proved lethal to OVCAR-3 Ovarian cancer and MDA-MB-435 Melanoma with a typical apoptotic pattern of DNA content that reflected at G0/G1, S-, G2/M phases of the cell cycle, together with a pre-G1 phase. Structure activity correlation revealed that the electronegativity of the substituent affected the DHFR inhibitory activity. The ciprofloxacin withdrawing functions like phenoxy or chloro favor the potency rather than the electron donating methoxy group. Molecular modeling study proved that rigidity and fixed orientation of the cyclized structure 43 favor the binding mode and hence the biological activity.
    Experimental Melting points (oC) were determined by open capillary tube method using (Bio Cote SMP 10) apparatus and they are uncorrected. Microanalyses were performed using FLASH 2000 CHNS/O analyzer, Thermo Scientific at the Regional Center for Mycology and Biotechnology (RCMB), Al-Azhar University, Nasr City, Cairo. All of the new compounds were analyzed for C, H and N and agreed with the proposed structures within ±0.4% of the theoretical values. 1H and 13C NMR spectra were recorded on Bruker Avance III HD FT‐high resolution‐ NMR 400 MHz, Center for Drug Discovery Research and Development, Faculty of Pharmacy‐Ain Shams University, and Faculty of pharmacy, Cairo University. Chemical shifts are expressed in δ ppm with reference to TMS. Mass spectra were carried out on Direct Inlet part to mass analyzer in Thermo Scientific GCMS model ISQ at the Regional Center for Mycology and Biotechnology (RCMB), Al-Azhar University, Nasr City, Cairo. Thin layer chromatography was performed on precoated (0.25 mm) silica gel GF254 plates (E. Merck, Germany), compounds were detected with 254 nm UV lamp. Silica gel (60–230 mesh) was employed for routine column chromatography separations. Dihydrofolate reductase (DHFR) Inhibition assay was performed at Pharmacology and Biochemsitry department, Faculty of Pharmaceutical Sciences and Pharmaceutical Industries, Future University in Egypt. Bovine liver DHFR enzyme and methotrexate (MTX) were used in the assay (Sigma Chemical Co, USA). Elisa reader SN208125 Bio Tek MQX200 and Software program GEN5 at wave length 340 nm were used to measure the changes in absorbance. In vitro antitumor assay was performed by National Cancer Institute (NCI), Bethesda, Maryland, USA. Cell Cycle analysis was performed at the confirmatory diagnostic unit, VACSERA, Egypt. Molecular modeling study was conducted using Discovery Studio Client version 2.5 software. Enzyme structure and starting coordinate of hDHFR in tertiary complex with NADPH and MTX, code ID 1U70, was obtained from the Protein Data Bank of Brookhaven National Laboratory [36].
    Introduction Malaria is a threat to global public health, with an estimated 214 million cases and 438 000 deaths in 2015 (WHO, 2015a). Malaria is a major health problem in Pakistan, accounting for 19% of all malaria cases in the Eastern Mediterranean Region (WHO, 2015a). Plasmodium vivax is the predominant Plasmodium species, accounting for 88% of cases, and P. falciparum accounts for 12% (WHO, 2015a). Pakistan recommended artesunate+sulfadoxine-pyrimethamine (AS+SP) as the first-line treatment for uncomplicated falciparum malaria in 2005, but Transplantation antigen was deployed only in 2007. Oral quinine was recommended as a second-line treatment in 2005. This was replaced with artemether+lumefantrine (AL) in 2013, although quinine remained the drug of choice for pregnant women in their first trimester, as ACTs are contraindicated for this group (WHO, 2015b). For malaria-endemic countries to be vigilant regarding the emergence of resistance to recommended antimalarial medicines and to generate evidence to inform treatment policy, the WHO recommends routine monitoring of these drugs at least every two years (WHO, 2010).