substitution was found to form favorable interactions with Leu531. Also, His185
and Arg265 were observed to form stronger hydrogen bonding interactions with
compound DSM1 indicating that CF 3 substitution increased the polarity of the
compound and thus favored electrostatic interactions. Both the above studies
highlighted the factors responsible for good activity shown by triazolopyrimidine
class of compounds and further modifications which can be possible in this class.
Desai et al. designed a library of N-phenylbenzamide (Fig. 10, V) derivatives
with various substituents consisting of eighty molecules [91]. These were docked in
PfDHODH (PDBID 1TV5) using GOLD program. Out of these eighty designed
molecules, fifteen final molecules were selected (based on their docking scores and
interactions) for further synthesis and biological evaluation using cell-based in vitro
assay (3H-hypoxanthine uptake method on P. falciparum NF54 (sensitive strain)
and K1 (chloroquine and pyrimethamine resistance strain). This was followed by
3D-QSAR studies using CoMFA and CoMSIA models. One CoMFA and four
CoMSIA models were generated from 89 models. The CoMFA model predicted
that the o-position of the N-phenyl ring (Fig. 10, V(Ar 2 )) of the N-phenylbenzamide
and m-/p-positions of the carbonyl phenyl ring (Fig. 10, V(Ar 1 )) can be substituted
with electronegative atoms for improved activity. Similarly, the o- of carbonyl
phenyl ring (Ar 1 ) and p-position of N-phenyl ring (Ar 2 ) show electropositive
substitution. Bulky substituents are well tolerated at the m-/o-positions and not at
the p-position of the carbonyl phenyl ring (Ar 1 ). The m-position of the N-phenyl
ring (Ar 2 ) can only bear bulky substituents to a smaller extent and not at the
p-position. The CoMSIA studies were depicted by hydrophobic contours based on
model 3, i.e., SHE fields (steric, hydrophobic, and H-bond donor) and model 5,
EDH fields (electrostatic, H-bond donor and hydrophobic) along with hydrogen
bond donor and acceptor contours based on model 2, SDA fields (steric, H-bond
donor, and H-bond acceptor). It was observed that the entire carbonyl phenyl ring
(Ar 1 ) is surrounded by the hydrophobic contour except the m-position. In the
N-phenyl ring (Ar 2 ), the hydrophobic contour is situated near the m- and p-position.
H-bond acceptor contour is present at the m-position of the carbonyl phenyl ring
(Ar 1 ), and H-bond donor contour is present at the o-region of the N-phenyl ring
(Ar 2 ) of the N-phenylbenzamide. Out of the five models, r pred
2
for the CoMSIA
model was more satisfactory than the CoMFA model. Two compounds, KMC-3
and KMC-15, were found to be active with IC 50 value of 8.7 and 5.7 µM,
respectively, against P. falciparum.
Vyas et al. in 2013 [92] performed 3D-QSAR on 5-(2-methylbenzimidazol1-yl)-N-alkylthiophene-2-carboxamide derivatives reported by Brooker et al. [65].
A total of thirty-eight molecules were studied with thirty-five molecules in training
set and five molecules in test set. The q
2 for the best CoMFA and CoMSIA models
was determined to be 0.669 and 0.727, respectively. The prediction value (r pred
2 )
obtained after validation by external test set was observed to be 0.799 and 0.815 for
CoMFA and CoMSIA models, respectively. The CoMSIA model was observed to
be better than the CoMFA model. In CoMSIA contour maps, a large favorable
hydrophobic contour was observed near the C 2 position and nitrogen atom of the
benzimidazole ring (Fig. 16). This was correlated with the presence of lipophilic
212
S. Bhagat et al.
and Arg265 were observed to form stronger hydrogen bonding interactions with
compound DSM1 indicating that CF 3 substitution increased the polarity of the
compound and thus favored electrostatic interactions. Both the above studies
highlighted the factors responsible for good activity shown by triazolopyrimidine
class of compounds and further modifications which can be possible in this class.
Desai et al. designed a library of N-phenylbenzamide (Fig. 10, V) derivatives
with various substituents consisting of eighty molecules [91]. These were docked in
PfDHODH (PDBID 1TV5) using GOLD program. Out of these eighty designed
molecules, fifteen final molecules were selected (based on their docking scores and
interactions) for further synthesis and biological evaluation using cell-based in vitro
assay (3H-hypoxanthine uptake method on P. falciparum NF54 (sensitive strain)
and K1 (chloroquine and pyrimethamine resistance strain). This was followed by
3D-QSAR studies using CoMFA and CoMSIA models. One CoMFA and four
CoMSIA models were generated from 89 models. The CoMFA model predicted
that the o-position of the N-phenyl ring (Fig. 10, V(Ar 2 )) of the N-phenylbenzamide
and m-/p-positions of the carbonyl phenyl ring (Fig. 10, V(Ar 1 )) can be substituted
with electronegative atoms for improved activity. Similarly, the o- of carbonyl
phenyl ring (Ar 1 ) and p-position of N-phenyl ring (Ar 2 ) show electropositive
substitution. Bulky substituents are well tolerated at the m-/o-positions and not at
the p-position of the carbonyl phenyl ring (Ar 1 ). The m-position of the N-phenyl
ring (Ar 2 ) can only bear bulky substituents to a smaller extent and not at the
p-position. The CoMSIA studies were depicted by hydrophobic contours based on
model 3, i.e., SHE fields (steric, hydrophobic, and H-bond donor) and model 5,
EDH fields (electrostatic, H-bond donor and hydrophobic) along with hydrogen
bond donor and acceptor contours based on model 2, SDA fields (steric, H-bond
donor, and H-bond acceptor). It was observed that the entire carbonyl phenyl ring
(Ar 1 ) is surrounded by the hydrophobic contour except the m-position. In the
N-phenyl ring (Ar 2 ), the hydrophobic contour is situated near the m- and p-position.
H-bond acceptor contour is present at the m-position of the carbonyl phenyl ring
(Ar 1 ), and H-bond donor contour is present at the o-region of the N-phenyl ring
(Ar 2 ) of the N-phenylbenzamide. Out of the five models, r pred
2
for the CoMSIA
model was more satisfactory than the CoMFA model. Two compounds, KMC-3
and KMC-15, were found to be active with IC 50 value of 8.7 and 5.7 µM,
respectively, against P. falciparum.
Vyas et al. in 2013 [92] performed 3D-QSAR on 5-(2-methylbenzimidazol1-yl)-N-alkylthiophene-2-carboxamide derivatives reported by Brooker et al. [65].
A total of thirty-eight molecules were studied with thirty-five molecules in training
set and five molecules in test set. The q
2 for the best CoMFA and CoMSIA models
was determined to be 0.669 and 0.727, respectively. The prediction value (r pred
2 )
obtained after validation by external test set was observed to be 0.799 and 0.815 for
CoMFA and CoMSIA models, respectively. The CoMSIA model was observed to
be better than the CoMFA model. In CoMSIA contour maps, a large favorable
hydrophobic contour was observed near the C 2 position and nitrogen atom of the
benzimidazole ring (Fig. 16). This was correlated with the presence of lipophilic
212
S. Bhagat et al.