تصميم, تحضير وفحص النشاط السمي لمشتقات البيرازين ثنائية التفرع
Date
2017-12-06
Authors
آلاء محمود ربيع فرعون
Ala Mahmoud Rabie Faroun
Journal Title
Journal ISSN
Volume Title
Publisher
AL-Quds University
جامعة القدس
جامعة القدس
Abstract
Pyrazine derivatives possess numerous pharmacological effects including but not limited to
antiviral, antibiotic, antifungal, diuretic, anticonvulsant, antidiabetic, analgesic and anti
proliferative effect. Consequently, interest has been shown by researchers in the field of
pyrazine-based drug synthesis and many of the synthesized derivatives succeeded to reach the
clinical field. A promising research discipline was concerned in utilizing the antiproliferative and
cytotoxic activity of pyrazine derivatives -that is attributed to various mechanisms one of which
is protein kinase inhibition- in designing new anti-cancer agents.
In this study a set of disubstituted pyrazine derivatives has been designed and synthesized
through a sequential nucleophilic substitution of chlorine atoms of 2,3-dichloropyrazine with
amines or other nucleophiles. The synthesized derivatives were purified using several
chromatographic techniques, and characterized by (1H-NMR, 13C-NMR, FT-IR, and MS (ESI))
spectroscopy.
The mono-substituted pyrazine derivative A-7 (7) and three of its disubstituted analogues (YAN1(18),
YAN-2 (19), and YAN-3(20)) were in vitro screened for their biological activity against
two forms of acute myeloid leukemia cells (Molm-13). The viability of the cells was determined
using WST-1 assay. Initial results of the tested derivatives showed that A-7 (7) was more potent
than its analogues with IC50 of 18 and 39 µM against Molm-13 (sh-p53) and Molm-13 (empty
vector) respectivelyThe biological activity of mono and disubstituted pyrazine derivatives was predicted using PASS
software. Initial results demonstrated that A13 (13), A14 (14), YAN-7 (24), and YAN-8 (25)
exhibited predicted activities as antineoplastic agents and signal transduction pathway inhibitors
with relatively high Pa values. The previously mentioned compounds shared also the same
mechanism of action “protein kinase inhibitor” with Pa values larger than 0.8SAR derived from PASS and initial biological activity screening results proved that the activity
of the synthesized derivative is highly affected by the site and type of the substituent on the
pyrazine ring. 2,3-disubstituted derivatives showed better Pa values when compared to the
corresponding 2,5-disubstituted ones. In addition, amine substituents at positions 2 and 3 of
pyrazine ring were preferred over alkoxide substituents in terms of antineoplastic activity. It was
noticed that 1-(5-trifluoromethylpyridin-2-yl)-piperazine and 2-aminopyridine pharmacophores
were the most active amine substituents.
In order to gain an insight into the binding mode of pyrazine derivatives with CDK-2, a series of
sixteen derivatives were docked with inactive monomeric cyclin dependent kinase-2 using
SwissDock software. Results were compared with ‘Aloisine B‟, a well-known CDK-2 inhibitor.
In terms of binding mode, pyrazine derivatives occupied the CDK-2 ATP binding site and made
hydrogen bonds to the kinase backbone within the hinge sequence that links the two lobes of the
kinase. The docked derivatives exhibited different binding affinities to the target, YAN-8 (25)
showed the highest full fitness value (-1422.14 kcal/mol) among the synthesized derivatives.
Moreover, both the full fitness and energy values indicated that YAN-8 (25) has higher affinity
to the target in comparison to the known inhibitor Aloisine B (-1406.92 kcal/mol).
Finally, the concept of drug likeness of the synthesized derivatives was investigated using the
rule of five. Results revealed that all of the tested derivatives successfully met the rule of 5requirements except YAN-9 (26) and YAN-10 (27) which possessed molecular weights larger
than 500 Daltons..
Description
Keywords
العلوم الصيدلانية , Pharmaceutical Sciences