Prakruti Trivedi

Discovery of Novel 2-Amino-5-(Substituted)-1,3,4-Thiadiazole Derivatives: New Utilities for Colon Cancer Treatment

BACKGROUND Colon cancer is one of the most widespread disease, the mortality rate is high due to cancer metastasis and the development of drug resistance. In this regards, new chemotherapeutic agents with specific mechanisms of action and significant effect on patients survival are the new era for the colon cancer drug development. OBJECTIVE The main objective of present study was to design, synthesize of a novel series of 1,3,4-thiadiazole derivatives (VR1 to VR35) and screen them against HT-29 human colon cancer cell line. METHOD Newly 1,3,4-thiadiazole scaffold were designed, synthesized and further, characterized by FTIR, NMR (1H and 13C), MS and elemental analyses. Before the synthesis, molecular dynamic simulation and ADME studies were performed to find out the most potent lead compounds. Later, SRB assay using HT-29 cells and ELISA assays were performed to explore activity and molecular targets of VR24 and VR27 and find out whether in silico data had a similar pattern in the molecular level. RESULTS The results of docking study revealed that both VR24 and VR27 had interaction energy >-5 kcal/mol with various assigned molecular targets and the ligand-protein complexes were found to be stable with IL-6. The computational analysis of molecules showed good ADMET profiling. Later, the in vitro anticancer study was conducted where VR24 and VR27 were found to be active against HT-29 cells (GI50<10 µM). Finally, ELISA assays revealed that both the compounds had higher inhibition properties to various biomarker of colon cancer like IL-6 and COX-2. CONCLUSION Collectively, these result suggested that VR24 and VR27 inhibited the assigned molecular targets, imparting their ameliorative effects against colon cancer. Due to these encouraging results, we concluded that both VR24 and VR27 may be effective against colon cancer therapy in future.

Design, synthesis and biological screening of 2-aminobenzamides as selective HDAC3 inhibitors with promising anticancer effects

ABSTRACT Histone deacetylases (HDACs) have been found as a potential target for anticancer therapy. A number of HDAC inhibitors have been used pre‐clinically and clinically as anticancer agents. In the current study, we have designed and synthesized compound 12a by combining the scaffolds of CI‐994 and BG45. Moreover, the structure of compound 12a was optimized and a series of 2‐aminobenzamide derivatives were synthesized further. These compounds were tested for their HDAC inhibitory activity and found to be efficient HDAC inhibitors. Compound 26c showed 11.68‐fold HDAC3 selectivity over pan HDACs, better than the prototype HDAC3 inhibitor BG45. Most of these compounds exhibited antiproliferative activity in both B16F10 and HeLa cell lines. Particularly, compound 26c exhibited better antitumor efficacy in the cell lines compared to the prototype inhibitors CI‐994 and BG45. It was also found to promote apoptosis as well as induced significant cell growth arrest in the G2/M phase of cell cycle in B16F10 melanoma cells. This work may provide significant insight regarding structural information to design newer small molecule HDAC3 inhibitors to fight against the target specific malignancies in future.

HDAC3 is a potential validated target for cancer: An overview on the benzamide-based selective HDAC3 inhibitors through comparative SAR/QSAR/QAAR approaches

Deacetylation of histones by histone deacetylase 3 (HDAC3) is involved in apoptosis, cellular progression and DNA damage. Due to the overexpression of HDAC3 in a variety of cancers, it is implicated to be a crucial validated target for cancer. Therefore, HDAC3 selective inhibitors have roles to play in combating these cancers. Nowadays, compounds comprising benzamide functionality as zinc binding group (ZBG) have been emerged out to be highly effective and selective HDAC3 inhibitors. In this article, QSAR and QAAR studies have been conducted on diverse benzamide-derived HDAC3 inhibitors as the first initiative to explore the designing strategies of higher active and selective HDAC3 inhibitors over HDAC1 and HDAC2. QSAR models reveal that molecular size and shape along with the steric effect should have to be optimized to achieve higher HDAC3 inhibition. QAAR models reflect that modification/substitution at the benzamide scaffold should be optimized in such a way so that these molecules possess lower steric bulk along with nonpolar features for achieving higher HDAC3 selectivity over HDAC1 and HDAC2. However, the importance of spiro hydrophobic cap group, as well as electron withdrawing fluorine group at the benzamide scaffold, should be well-accounted for retaining higher HDAC3 selectivity over HDAC1. Moreover, less polar and less hydrophobic benzamides are preferred for HDAC3 selectivity over HDAC2. This detailed structural exploration will surely unveil a new vista of designing highly potent and selective benzamide-based HDAC3 inhibitors that may be a crucial weapon to battle against a variety of cancers.

p -TSA-promoted syntheses of 5H-benzo[h]thiazolo[2,3-b]quinazoline and indeno[1,2-d]thiazolo[3,2-a]pyrimidine analogs: molecular modeling and in vitro antitumor activity against hepatocellular carcinoma

In our efforts to address the rising incidence of hepatocellular carcinoma (HCC), we have made a commitment to the synthesis of novel molecules to combat Hep-G2 cells. A facile and highly efficient one-pot, multicomponent reaction has been successfully devised utilizing a p-toluenesulfonic acid (p-TSA)-catalyzed domino Knoevenagel/Michael/intramolecular cyclization approach for the synthesis of novel 5H-benzo[h]thiazolo[2,3-b]quinazoline and indeno[1,2-d] thiazolo[3,2-a]pyrimidine analogs bearing a bridgehead nitrogen atom. This domino protocol constructed one new ring by the concomitant formation of multiple bonds (C–C, C–N, and C=N) involving multiple steps without the use of any metal catalysts in one-pot, with all reactants effi-ciently exploited. All the newly synthesized compounds were authenticated by means of Fourier transform infrared spectroscopy, liquid chromatography–mass spectrometry, proton nuclear magnetic resonance spectroscopy, and carbon-13 nuclear magnetic resonance spectroscopy, together with elemental analysis, and their antitumor activity was evaluated in vitro on a Hep-G2 human cancer cell line by sulforhodamine B assay. Computational molecular modeling studies were carried out on cancer-related targets, including interleukin-2, interleukin-6, Caspase-3, and Caspase-8. Two compounds (4A and 6A) showed growth inhibitory activity comparable to the positive control Adriamycin, with growth inhibition of 50% <10 μg/mL. The results of the comprehensive structure–activity relationship study confirmed the assumption that two or more electronegative groups on the phenyl ring attached to the thiazolo[2,3-b]quinazoline system showed the optimum effect. The in silico simulations suggested crucial hydrogen bond and π–π stacking interactions, with a good ADMET (absorption, distribution, metabolism, excretion, and toxicity) profile and molecular dynamics, in order to explore the molecular targets of HCC which were in complete agreement with the in vitro findings. Considering their significant anticancer activity, 4A and 6A are potential drug candidates for the management of HCC.