Natural H H S 58% 8 4-NO2
Naturalplants: There are many plants whose extracts showanti-dengue property.
Caricapapaya is a very common plant whose leaf extract is used inthis disease. It was used in a mid-age patient where it was found that 5 days treatmentof the extract led to increase in WBC as well as platelet count. Other plantsextrants which have significant role in the treanment of dengue are listed in thetable below. SARof methionine–proline anilides:Two methionine–proline anilides have been found toinhibit NS2B-NS3efficiently. Their Kivalues are found to be 4.
9 and 10.5 respectively. Table 1 Chemical structures of dipeptides and their activitiesagainst DENV 2 NS2B-NS3 protease. Sr. No. R X Z Ki (µM) Remaining activity of DENV 2 NS2B-NS3 1 4-NO2 H S 4.
9 31% 2 4-NO2 Boc S 10.5 45% 3 3-NO2 H S 37% 4 2-NO2 H S 96% 5 H H S 60% 6 4-NO2 H S 36% 7 H H S 58% 8 4-NO2 H S(O) 71% 9 4-NO2 H S(O)2 99% 10 4-NO2 H S 103% 11 4-NO2 CF3CO S 54% 12 4-NO2 No2-Bn S 38% 13 4-NO2 MeO-Bn S 90% As it can be seenclearly from the table that no significant change in activity is found if the Sat Z is replaced by S(O)2 but activity got decreased upto 45% when Xgroup was replaced by Boc but replacement with H gave the most potentcompound which decreased the activity for upto 31%. Further if methionine isreplaced by phenylalanine, the activity remains only upto 25% but it has higherinhibitory concentration (200 µM). 1.
X=H2. X=BocSARof tetrapeptide aldehyde inhibitors:They started with the following aldehyde derivative(Ki =5.8 µM) to determinethe pharmacophoric features of the NS3 active site.Figure 1 A tetrapetide aldehyde derivativeTable 2 Results from different scans (alanine, phenylalanine,lysine, and proline, D- and N-Me amino acids) and varying the inhibitor Sr. No.
Aldehyde inhibitors Ki (µM) 1 Bz-Nle-Lys-Arg-Arg-H 5.8 2 Bz-Nle-Lys-Arg-Ala-H 193.0 3 Bz-Nle-Lys-Ala-Arg-H >500 4 Bz-Nle-Ala-Arg-Arg-H 22.
1 5 Bz-Ala-Lys-Arg-Arg-H 5.3 6 Bz-Nle-Lys-Arg-Phe-H 15.9 7 Bz-Nle-Lys-Phe-Arg-H 40.7 8 Bz-Nle-Phe-Arg-Arg-H 15.8 9 Bz-Phe-Lys-Arg-Arg-H 6.
8 10 Bz-Nle-Lys-Arg-Lys-H 20.5 11 Bz-Nle-Lys-Lys-Arg-H 41.3 12 Bz-Nle-Lys-Pro-Arg-H 109.0 13 Bz-Nle-Pro-Arg-Arg-H 61.4 14 Bz-Nle-Lys-N-Me-Arg-Arg-H 47.
4 15 Bz-Nle-N-Me-Lys-Arg-Arg-H 113.3 16 Bz-N-Me-Nle-Lys-Arg-Arg-H 43.7 17 Bz-Nle-Lys-Arg-D-Arg-H 51.0 18 Bz-Nle-Lys-D-Arg-Arg-H 115.0 19 Bz-Nle-D-Lys-Arg-Arg-H 28.
6 20 Bz-D-Nle-Lys-Arg-Arg-H 9.4 21 Bz-Lys-Arg-Arg-H 1.5 22 Bz-Arg-Arg-H 12.
0 23 Bz-Nle-Lys-Arg-(p-guanidinyl)Phe-H 2.8 When they replaced Arg atP1 with Lys, They found that the activity of the inhibitor was increased fourtimes but the activity increased eight fold when they replaced Arg at P2. Themost potent compound was obtained when P1 was replaced with (p-guanidinyl)Phe with Ki = 2.8 µM. When P2 and P3 were replacedwith proline a huge loss in activity was found which indicated that turngeometry was unfavourable in binding.
Replacement of P1 gave some active compound but the Ki is not that much good. Themost effective replacement at P1 was fount to be Trp which gave compound with Ki=7.5µM.Table 3 Effect of modifications in the P1 position of thetetrapeptide P1 Ki (µM) Phe 15.9 Phg 33.0 homoPhe >500 (p-Cl)Phe 138.0 (p-CN)Phe 18.6 (p-Me)Phe 6.0 (p-Ph)Phe 11.6 Trp 7.5 Phe alone at P1 gave lesserpotent compound as compared to the compound which was obtained by replacing P1with -(p-guanidinyl)Phe.