dc.description.abstract |
Leishmaniasis, a worldwide prevalent disease, is still enjoying the ruling with no proper medication; and
to add to this current gloomy scenario the disease causing parasite Leishmania is becoming resistant to
the ongoing medication that is being practiced now a days. Hence, the need is to search for reasonable,
safe and targeted drugs; the present research is one such effort in this direction. To begin with,
Leishmanolysin (GP63), zinc metalloprotease, expressed over the surface of Leishmania species was
selected as drug target due to its virulence and reason for parasite resistance. A library of benzimidazole
derivatives (1-37) was synthesized and screened for its antileishmanial potential against L. major. All the
compounds were found potent antileishmanial with IC50 values in the range of 0.62-0.92 μg/mL as
compared to amphotericin B (standard drug) IC50 value 0.56 μg/mL. 2-(Thiophen-2-yl)-1H-
benzimidazole (19) and 2-(1H-indol-3-yl)-5-nitro-1H-benzimidazole (34) were identified as the lead
compounds of the library with IC50 value of 0.62 μg/mL. ADMET properties of the entire library were
also predicted by using ADMET PredictorTM and were observed to be safe. Molecular docking studies
carried out on all the members of library and amphotericin B by using MOE software, indicated that the
most active compounds fitted at the centre of binding pocket of GP63 built by amino acid residue His264,
His268, His334 and Zn578. On the basis of molecular docking results, receptor based pharmacophore
model was built containing three Aro|Hyd features and one Acc&ML feature. This pharmacophore model
was used to design new scaffolds for antileishmanial compounds. Four libraries, 2-(2-
aryl/heteroarylbenzimidazol-1-sulfonyl)anthraquinones
(38-69),
N-(heteroaryl)-anthraquinon-2-
sulfonamides (70-95), aryl anthraquinon-2-sulfonates (96-111) and N-(anthraquinon-2-sulfonyl)-amino
acid methylesters (112-123) were designed and all the cmpounds were found as hit by pharamocophoric
search. Their antleishmanial activities were predicted by QSAR model; built by MOE software by
selection of 94 descriptors and partial least square (PLS) method on experimental antileishmanial activity
of 37-mebered library and amphotericin B, validated by internal and exernal test sets with correlation
coefficient (R2) 0.7762. All the compounds belonging to four libraries (38-69, 70-95, 96-111 and 112-
123) were found potent antileihmanial with predicted activity in the range of 0.5435-0.9940. All the
compouds were observed safe according to predicted ADMET properties and Lipinski’s rule of five
(Ro5). Later, these four designed libraries were synthesized and characterized by physical constants and
spectroscopic techniques for onward screening for their antileishmanial potential against L. major by
using amphotericin B as standard control which confirmed that all the compounds were potent
antileishmanial. Compliance of the predicted activity by QSAR model with observed activity from in
vitro antileishmanial activity resulted in identification of the same lead compounds in each library 38-69,
70-95, 96-111 and 112-123 i.e. 2-(5-Nitro-4-methoxyphenyl-1H-benzimidazol-1-sulfonyl)anthraquinone
(61) (predicted activity 0.6794, IC50 0.67 μg/mL), 2-(1H-benzo-1,2,3-triazol-1-sulfonyl)anthraquinone
(91) (predicted activity 0.5579, IC50 0.57 μg/mL), 2-(1H-pyrazol-1-sulfonyl)anthraquinone (90)
(predicted activity 0.5435, IC50 0.58 μg/mL), benzyl anthraquinon-2-sulfonate (100) (predicted activity
0.7615, IC50 0.76 μg/mL) and N-(anthraquinon-2-sulfonyl)-2-phenylglycine methylester (123) (predicted
activity 0.7305, IC50 0.75 μg/mL). Pharmacophore based molecular docking studies carried out on all the
eighty six compounds on GP63 by MOE software showed hydrophobic interactions, hydrogen bonding
and metal ligation interactions with His268, His264, His334 and Zn578, respectively. This entire set of
experiments in both dry and wet labs led to a successful designing of a variety of anthraquinon-2-
sulfonamides as a novel scaffold having strong antileishmanial effect. |
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