317323-77-6Relevant articles and documents
Pharmacophore modeling, docking and the integrated use of a ligand- And structure-based virtual screening approach for novel DNA gyrase inhibitors: Synthetic and biological evaluation studies
Ahmad, Irfan,Balaramnavar, Vishal M.,Gupta, Madan M.,Jawaid, Talha,Kamal, Mehnaz,Kumar, Santosh,Masand, Mukesh,Mathpal, Deepti,Saeed, Mohd,Sharma, Pramod K.,Srivastava, Swayam Prakash,Thomas, Anisha,Zaman, Gaffar Sarwar
, p. 34462 - 34478 (2021/12/01)
Fluoroquinolones, a class of compound, act via inhibiting DNA gyrase and topoisomerase IV enzymes. This is an important class of drugs with high success rates for the treatment of tuberculosis and other bacterial infections. An indirect drug design approach was used to develop a meaningful pharmacophore model using the HypoGen module of Discovery Studio 2.0 on a set of 27 structurally diverse compounds with a wide range of biological activity (5 log units). The best hypothesis had three hydrogen bond acceptors (HBA) and one hydrophobic (Hy) moiety, showing r = 0.95, and it predicts the test set of 44 compounds well, with r2 = 0.823. The same features (acceptor and hydrophobic functionality) were validated at the binding site of the DNA gyrase active site using GOLD version 3.0.1 and Molegro Virtual Docker, which showed corresponding hydrogen bond interactions and also π-π stacking interactions that correlated well with the PIC50 values (r2 = 0.6142). The thoroughly validated model was used to screen an extensive database of 0.25 million compounds to identify potential leads. The validated model was implemented for the identification, design, synthesis, and biological evaluation of leads. Ten new chemical entities were synthesized based on our scaffold hopping techniques from the identified virtual screening and tested against the tuberculosis bacterium to obtain preliminary MIC values. The results showed that 3 out of 10 synthesized compounds exhibited good MICs, from 1.25 to 50 μM. This proves the robustness and applicability of the developed model, which is a promising tool for identifying new topoisomerase II inhibitors for the treatment of tuberculosis.
Synthesis of the major metabolites of Paroxetine
Segura, Mireia,Roura, Lidia,De La Torre, Rafael,Joglar, Jesus
, p. 248 - 258 (2007/10/03)
Paroxetine is a well-known antidepressant, used worldwide in therapeutics. In comparison with other selective serotonin reuptake inhibitors, it exhibits the highest activity in serotonin reuptake inhibition. Paroxetine metabolism initially involves its demethylenation to the catechol intermediate, which is then O-methylated at positions C3 or C4. Herein, the chemistry resulting in the syntheses of these metabolites (3S,4R)-4-(4-fluorophenyl)-3-(hydroxymethyl)piperidine and (3S,4R)-4-(4-fluorophenyl)-3-(4-hydroxy-3-methoxyphenoxymethyl)piperidine is described starting from the common intermediate (3S,4R)-4-(4-fluorophenyl)-3-hydroxymethyl-1-methylpiperidine. Additionally, the common intermediate was used to synthesize paroxetine, which had the same structure and stereochemistry as commercial paroxetine, thereby confirming our synthetic route.
