Synthesis and biological evaluation of 1,2,3-triazole linked aminocombretastatin conjugates as mitochondrial mediated apoptosis inducers.

A series of 1,2,3-triazole linked aminocombretastatin conjugates were synthesized and evaluated for cytotoxicity, inhibition of tubulin polymerization and apoptosis inducing ability. Most of the conjugates exhibited significant anticancer activity against some representative human cancer cell lines and two of the conjugates 6d and 7c displayed potent cytotoxicity with IC50 values of 53 nM and 44 nM against A549 human lung cancer respectively, and were comparable to combretastatin A-4 (CA-4). SAR studies revealed that 1-benzyl substituted triazole moiety with an amide linkage at 3-position of B-ring of the combretastatin subunit are more active compared to 2-position. G2/M cell cycle arrest was induced by these conjugates 6d and 7c and the tubulin polymerization assay (IC50 of 1.16 µM and 0.95 µM for 6d and 7c, respectively) as well as immunofluorescence analysis showed that these conjugates effectively inhibit microtubule assembly at both molecular and cellular levels in A549 cells. Colchicine competitive binding assay suggested that these conjugates bind at the colchicine binding site of tubulin as also observed from the docking studies. Further, mitochondrial membrane potential, ROS generation, caspase-3 activation assay, Hoechst staining and DNA fragmentation analysis revealed that these conjugates induce cell death by apoptosis.

TAT-peptide conjugated repurposing drug against SARS-CoV-2 main protease (3CLpro): Potential therapeutic intervention to combat COVID-19.

The Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that originated in Chinese city of Wuhan has caused around 906,092 deaths and 28,040,853 confirmed cases worldwide (https://covid19.who.int/, 11 September 2020). In a life-threatening situation, where there is no specific and licensed anti-COVID-19 vaccine or medicine available; the repurposed drug might act as a silver bullet. Currently, more than 211 vaccines, 80 antibodies, 31 antiviral drugs, 35 cell-based, 6 RNA-based and 131 other drugs are in clinical trials. It is therefore utter need of the hour to develop an effective drug that can be used for the treatment of COVID-19 before a vaccine can be developed. One of the best-characterized and attractive drug targets among coronaviruses is the main protease (3CLpro). Therefore, the current study focuses on the molecular docking analysis of TAT-peptide47-57 (GRKKRRQRRRP)-conjugated repurposed drugs (i.e., lopinavir, ritonavir, favipiravir, and hydroxychloroquine) with SARS-CoV-2 main protease (3CLpro) to discover potential efficacy of TAT-peptide (TP) - conjugated repurposing drugs against SARS-CoV-2. The molecular docking results validated that TP-conjugated ritonavir, lopinavir, favipiravir, and hydroxychloroquine have superior and significantly enhanced interactions with the target SARS-CoV-2 main protease. In-silico approach employed in this study suggests that the combination of the drug with TP is an excelling alternative to develop a novel drug for the treatment of SARS-CoV-2 infected patients. The development of TP based delivery of repurposing drugs might be an excellent approach to enhance the efficacy of the existing drugs for the treatment of COVID-19. The predictions from the results obtained provide invaluable information that can be utilized for the choice of candidate drugs for in vitro, in vivo and clinical trials. The outcome from this work prove crucial for exploring and developing novel cost-effective and biocompatible TP conjugated anti-SARS-CoV-2 therapeutic agents in immediate future.

Synthesis and biological evaluation of conformationally flexible as well as restricted dimers of monastrol and related dihydropyrimidones.

A series of conformationally flexible and restricted dimers of monastrol as well as related dihydropyrimidones have been synthesized by employing one-pot Biginelli multicomponent reaction. These dimers have been evaluated for cytotoxic potency against selected human cancer cell lines and some of the compounds have exhibited more cytotoxic potency than the parent monastrol. Further, the DNA binding ability by thermal denaturation studies and antimicrobial activities of these compounds are also discussed.