122228-39-1Relevant articles and documents
Computational and synthetic approaches for developing Lavendustin B derivatives as allosteric inhibitors of HIV-1 integrase
Agharbaoui, Fatima E.,Hoyte, Ashley C.,Ferro, Stefania,Gitto, Rosaria,Buemi, Maria Rosa,Fuchs, James R.,Kvaratskhelia, Mamuka,De Luca, Laura
, p. 673 - 683 (2016/08/12)
Through structure-based virtual screening and subsequent activity assays of selected natural products, Lavendustin B was previously identified as an inhibitor of HIV-1 integrase (IN) interaction with its cognate cellular cofactor, lens epithelium-derived growth factor (LEDGF/p75). In order to improve the inhibitory potency we have employed in silico-based approaches. Particularly, a series of new analogues was designed and docked into the LEDGF/p75 binding pocket of HIV-1 IN. To identify promising leads we used the Molecular Mechanics energies combined with the Generalized Born and Surface Area continuum solvation (MM-GBSA) method, molecular dynamics simulations and analysis of hydrogen bond occupancies. On the basis of these studies, six analogues of Lavendustine B, containing the benzylamino-hydroxybenzoic scaffold, were selected for synthesis and structure activity-relationship (SAR) studies. Our results demonstrated a good correlation between computational and experimental data, and all six analogues displayed an improved potency for inhibiting IN binding to LEDGF/p75 in?vitro to respect to the parent compound Lavendustin B. Additionally, these analogs show to inhibit weakly LEDGF/p75-independent IN catalytic activity suggesting a multimodal allosteric mechanism of action. Nevertheless, for the synthesized compounds similar profiles for HIV-1 inhibition and cytoxicity were highlighted. Taken together, our studies elucidated the mode of action of Lavendustin B analogs and provided a path for their further development as a new promising class of HIV-1 integrase inhibitors.
Benzoic acid derivatives and use thereof
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, (2008/06/13)
A pharmaceutical composition for use in the treatment of psoriasis comprises 4-aminosalicylic acid (4-ASA) or 5-aminosalicylic acid (5-ASA) or a functional derivative thereof, said pharmaceutical composition being in a form suitable for topical administration. Furthermore, 4- or 5-ASA or a functional derivative thereof are used for the manufacture of pharmaceutical compositions for treating psoriasis, atopic dermatitis, allergic dermatitis, contact dermatitis, seborrhoic dermatitis, or acne diseases. The derivatives have the formulae: STR1 where W is COOX, wherein X is H, Li, Na, K, Mg0.5, Ca0.5, Zn0.5, Al0.33, Fe(II)0.5, Fe(III)0.33, NH4, NH3 R1, NH2 R12, NHR13, NR14, or R1, where R1 is substituted or unsubstituted C1-6 -alkyl, aryl-C1-4 -alkyl, or heteroaryl-C1-4 -alkyl; or COX, where X is NR1 R1', where R1' has the same meaning as R1 defined above and R1 and R1' may be identical or different; Y is H or R1 CO, where R1 is defined as above; Z1 and Z2, which may be identical or non-identical are H, R1 or R1 CO, where R1 is defined as above, or Z1 and Z2 represent R2, where R2 is substituted or unsubstituted C1-6 -alkylidene or aryl-C1-6 -alkylidene, or heteroaryl-C1-6 -alkylidene, or Z1, Z2 together with the nitrogen atom to which they are attached may represent a 3 to 7 membered saturated or unsaturated heterocyclic ring, or may represent a group of the formula --N=N--R3 where R3 is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.
