Synthesis of indole substituted thiosemicarbazones as an aldose reductase inhibitor: an in vitro, selectivity and in silico study

Aim: Indole is an important component of many drug molecules, and its conjugation with thiosemicarbazone moiety would be advantageous in finding lead compounds for the development of diabetic complications. Methodology: We have designed, synthesized and evaluated a series of 17 indole-thiosemicarbazones (3a–q) as aldose reductase (ALR2) and aldehyde reductase (ALR1) inhibitors. Results: After in vitro evaluation, all indole-thiosemicarbazones showed significant inhibition against both enzyme ALR1 and ALR2 with IC50 in range of 0.42–20.7 and 1.02–19.1 μM, respectively. The docking study was also carried out to consider the putative binding of molecules with the target enzymes. Conclusion: Compound 3f was found to be most active and selective for ALR2. The indole-thiosemicarbazones series described here has selective hits for diabetes-mellitus-associated complications.

Fidarestat sensitized Caco-2 cells to Doxorubicin via increasing cell cycle-dependent cytotoxicity

Objectives: Anthracycline drugs such as Doxorubicin are considered one of the most active, wide-spectrum, and cost-effective drugs that have been used as a therapy for many cancers, but not for colorectal cancer. Recent reports indicate that inhibiting Aldose Reductase increases the sensitivity of human colorectal cancer cells to Doxorubicin. In the present study, we have investigated the effect of using an Aldose Reductase inhibitor (Fidarestat) as an adjuvant drug with Doxorubicin on colorectal cell line Caco-2, by studying cell viability, type of death, and cell cycle distribution in order to understand the pathways of this treatment. Results: Our results indicated that Fidarestat significantly increased the sensitivity of Caco-2 cells to Doxorubicin in a concentration-independent manner. In addition, Fidarestat increased Doxorubicin-induced G2/M phase arrest as well as induced cell cycle arrest in the S phase, thus potentiated Doxorubicin cytotoxicity. over all, our results demonstrated that a potent and clinically safe Aldose Reductase inhibitor, Fidarestat, sensitized Caco-2 cells to Doxorubicin via increasing Doxorubicin cell cycle-dependent cytotoxicity.

EMERGENCE OF BENZOTHIAZOLE AND ITS DERIVATIVES AS A POTENTIAL ANTIDIABETIC PROBE

Development of drugs against diabetes has always remained a big challenge among the medicinal chemists around the globe because of its continuously increasing prevalence worldwide. The emergence of benzothiazole as a prominent lead against diabetes is credited to the development of the aldose reductase inhibitor, Zopolrestat. Since then, there has been a continuous effort to develop benzothiazole derivatives as potential antidiabetic probes, especially in the last two decades. Use of computer aided drug designing tools such as molecular docking and pharmacophore modelling have also played a crucial role in the exploration of efficacy of benzothiazole against other targets for diabetes. In this review, possible targets for benzothiazole against diabetes will be discussed with the brief role each target plays in maintaining the normal blood glucose level in the body. A trend analysis of the emergence of different inhibitors over various intervals of time along with the structure-activity relationship (SAR) studies of benzothiazole as antidiabetic probe is incorporated in the end of the study.