Computer assisted drug repurposing: Anti TB activity in non antibiotics

1295-1303TB drug development is a formidable challenge at all times. As a part of our anti TB drug development program, we recently identified sertraline as a potential anti TB agent with an MIC-1.6µg/mL against MtbH37Rv. Sertraline is a popular marketed anti-depressant drug, hence we have planned to use the pharmacophoric signature of sertraline for virtual screening of drug database.We have performed shape based virtual screening of Drug Bank 5.0 database using vROCS software. Twenty chemically diverse drug molecules have been selected using Tanimoto COMBO score (TC>1.0). This gives chlormidazole, an obsolete anti-fungal drug as a Hit molecule with TC=1.67 (ranked 6th) and shows excellent anti TB activity (MIC 1.6µg/mL). It has been subjected to lead optimization studies and various chlormidazole analogues have been synthesized (1b-9b). They have been further screened for in vitro anti TB activity studies. Our results have successfully identified chlormidazole (5b) with MIC=1.6 µg/mL which can be repurposed as anti TB drug. Compounds 1b and 4b show selective potent anti TB activity. The compound 8b shows selective antibacterial activity against Staphylococcus aureus (gram+ve) bacteria. Compounds 2b, 3b, 5b and 6b show potent anti TB activity along with antifungal activity against Aspergillus niger. In conclusion, our study has successfully identified potent anti-TB activity in Chlormidazole and its analogues

Microwave assisted synthesis and SAR studies of novel hybrid phenothiazine analogs as potential antitubercular agents

556-566The present work has been initiated based on the interest driven by phenothiazine based neuroleptics with a special focus on thioridazine. Their clinically useful spectrum of anti-TB profile is the motivating factor. A hybrid pharmacophore has been designed containing phenothiazine nucleus and the synthetic reaction conditions have been optimized successfully with the help of a microwave synthesizer. Among the 60 synthesized compounds 4b, 4e, 4i and 4n show potent in vitro anti TB activity with an MIC 6.25 µg/mL and selectivity index >10

1,5-Benzothiazepine Derivatives: Green Synthesis, In Silico and In Vitro Evaluation as Anticancer Agents

Considering the importance of benzothiazepine pharmacophore, an attempt was carried out to synthesize novel 1,5-benzothiazepine derivatives using polyethylene glycol-400 (PEG-400)-mediated pathways. Initially, different chalcones were synthesized and then subjected to a cyclization step with benzothiazepine in the presence of bleaching clay and PEG-400. PEG-400-mediated synthesis resulted in a yield of more than 95% in less than an hour of reaction time. Synthesized compounds 2a–2j were investigated for their in vitro cytotoxic activity. Moreover, the same compounds were subjected to systematic in silico screening for the identification of target proteins such as human adenosine kinase, glycogen synthase kinase-3β, and human mitogen-activated protein kinase 1. The compounds showed promising results in cytotoxicity assays; among the tested compounds, 2c showed the most potent cytotoxic activity in the liver cancer cell line Hep G-2, with an IC50 of 3.29 ± 0.15 µM, whereas the standard drug IC50 was 4.68 ± 0.17 µM. In the prostate cancer cell line DU-145, the compounds displayed IC50 ranges of 15.42 ± 0.16 to 41.34 ± 0.12 µM, while the standard drug had an IC50 of 21.96 ± 0.15 µM. In terms of structural insights, the halogenated phenyl substitution on the second position of benzothiazepine was found to significantly improve the biological activity. This characteristic feature is supported by the binding patterns on the selected target proteins in docking simulations. In this study, 1,5-benzothiazepines have been identified as potential anticancer agents which can be further exploited for the development of more potent derivatives

Some Selected Phytoconstituents from Rhus succedanea as SARS CoV-2 Main Protease and Spike protein (COVID-19) Inhibitors: Selective Phytoconstituents from Rhus succedanea against SARS CoV-2: In silico approach

Rhus succedanea (Anacardiaceae) was used to treat multiple human afflictions. Literary works demonstrate that it has many biological activities. Today's research aims to recognize Rhus succedanea Phyto-derived anti-viral compounds against the main protease and spike protein of the viral agent of COVID-19 (SARS-CoV-2) gain insight into the molecular interactions. In the current study, ten molecules taken from R. succedanea are analyzed through docking, derived from the PubChem database. Docking experiments with Autodock vina and PyRx tools were conducted. AdmetSAR and DruLito servers were eventually used for drug-like prediction. Our research shows that the phytoconstituents from R. succedanea, namely, Amentoflavone, Rhoifolin, and Agathisflavone acts against SARS CoV-2 main protease with the binding affinity of -9.3, -8.6 and -8.4 Kcal/mol; Hinokiflavone Robustaflavone and Amentoflavone acts against the SARS-CoV-2 receptor-binding domain of spike protein with a binding affinity of -10.5, -10.4 and -10.1 Kcal/mol respectively. These phyto-compounds can use contemporary strategies to develop effective medicines from natural origins. The substances identified potential anti-viral as likely. However, In-vitro studies are even more necessary to assess their effectiveness versus SARS CoV-2