Designing, synthesis of selective and high-affinity chalcone-
benzothiazole hybrids as Brugia malayi thymidylate kinase
inhibitors: in vitro validation and docking studies
Koneni V. Sashidhara‡, *, Srinivasa Rao Avula‡, Pawan Kumar Doharey§, L. Ravithej Singh‡,
Vishal M. Balaramnavarψ,‡, Jyoti Gupta#, Shailja Misra-Bhattacharya#, Sushma Rathaur▲,
Anil K. Saxena‡, Jitendra Kumar Saxena§ *
‡Medicinal and Process Chemistry Division, §Biochemistry Division, #Parasitology Divion, CSIR-Central Drug
Research Institute, BS-10/1, Sector 10, Jankipuram extension, Sitapur Road, Lucknow 226031, India.
▲Department of Biochemistry, Banaras Hindu University, Varanasi 221005, India. ψPresent Address- Dept. of
Pharmaceutical Chemistry, Global Institute of Pharmaceutical Education and Research, Kashipur,
Uttarakhand, 244713, India.
*Corresponding author. Tel.: +91 9919317940; Fax: +91-522-2628493.
Email: [email protected], [email protected] (Dr. K. V. Sashidhara)
All reagents were commercial and were used without further purification.
Chromatography was carried on silica gel (60-120 and 100-200 mesh). All
reactions were monitored by thin-layer chromatography (TLC), silica gel plates
with fluorescence F254 were used. Melting points were taken in open capillaries
on Complab melting point apparatus and are presented uncorrected. Infrared
spectra were recorded on a Perkin-Elmer FT-IR RXI spectrophotometer. 1H
NMR and 13C NMR spectra were recorded using Bruker Supercon Magnet
DRX-300 spectrometer (operating at 400 MHz, 300 MHz for 1H and 75 MHz
for 13C) using CDCl3 and DMSO-d6 as solvent and tetramethylsilane (TMS) as
internal standard. Chemical shifts are reported in parts per million and
multiplicity(s = singlet, brs = broad singlet, d = doublet, brd = broad doublet, dd
1
= double doublet, t = triplet, q = quartet, m = multiplet). Electro spray ionization
mass spectra (ESIMS) were recorded on Thermo Lcq Advantage Max-IT. High
resolution mass spectra (HRMS) were recorded on 6520 Agilent Q Tof LC
MS/MS (Accurate mass).
1H NMR of compound 33 at 400 MHz (DMSO-d6)
2
1H NMR of compound 47 at 400 MHz (DMSO-d6)
Figure 1. A linear regression graph between docking scores and ki values.
16
c) d)
Figure 3. The molecular interactions of compounds 34 and 42 with BmTMK binding site are shown in a and b respectively, whereas the comparative binding site interactions of molecule 34 and 42 with human thymidylate kinase enzyme (PDB 1E2D) are shown in c and d respectively.
Table 1: The predicted physicochemical & toxicity of the most active compounds.
S.
No.
ADME
T_BBB
_Level
ADMET_Hepatotox
icity_Probability
ADMET_CYP2
D6_Probability
ADMET_P
PB_Level
ADMET_
AlogP98
34 4 0.576 0.257 2 5.667
42 4 0.913 0.178 2 6.976
18