Coumarins have received a considerable attention in the last three decades as a lead structures for the discovery of orally bioavailable non-peptidic antiviral agents. A lot of structurally diverse coumarins analogues were found to display remarkable array of affinity with the different molecular targets for antiviral agents and slight modifications around the central motif result in pronounced changes in its antiviral spectrum. This manuscript thoroughly reviews the design, discovery and structure-activity relationship studies of the coumarin analogues as antiviral agents focusing mainly on lead optimization and its development into clinical candidates.
We report herein, the synthesis of two new series of oxadiazole analogues, and their cytotoxicity evaluation. The oxadiazole analogues (5a-h and 12a-h) were structurally related to the heterocyclic (1,3,4- oxadiazole) linked aryl core of IMC-038525 (tubulin polymerization inhibitor), NSC 776715, and NSC 776716, with further modification by incorporating methylene linker. The title compounds (5a-h and 12a-h) were synthesized in good yields, and were characterized by IR, NMR, and mass spectral data. The cytotoxicity evaluation was carried out according to the National Cancer Institute (NCI US) Protocol against NCI-60 human cell lines derived from nine different panels. 2-(5-{[(4-Chlorophenyl)amino]methyl}-1,3,4-oxadiazol-2- yl)phenol (5f) showed maximum cytotoxicity among the first series oxadiazoles (5a-h), while 2-[(2,4- dichlorophenoxy)methyl]-5-(3,4-dimethoxyphenyl)-1,3,4-oxadiazole (12c) showed maximum cytotoxicity among the second series oxadiazoles (12a-h), with the mean percen growth inhibitions (GIs) of 71.56 and 72.68 respectively at 10 μM drug concentrations. Both the compounds (5f and 12c) showed superior cytotoxicity than clinically prevalent anticancer drugs, Imatinib and Gefitinib in one dose assay. The compound 12c was further screened in five dose assay (0.01, 0.1, 1, 10 and 100 μM), and the results was found to be promising, with GI50 values varies between 1.61 and >100 μM, with comparatively higher selectivity towards the renal cancer cell lines. Furthermore, the compounds, 5f and 12c inhibited the polymerization of tubulin with, an IC50 of 2.8 and 2.2 μM, respectively.
Inotropic agents are generally recommended to use in patients with acute decompensated heart failure (HF) with reduced ejection fraction (HFrEF) concurrent to end-organ dysfunction. However, due to certain pharmacological limitations like developing life threatening arrhythmia and tolerance, cannot be employed as much as needed. Meanwhile, Calcium ion (Ca2+) sensitisers exhibits their inotropic action by increasing the sensitivity of the cardiomyocyte to intracellular Ca2+ ion and have been reported as emerging therapeutic alternative in HF cases. Levosimendan (LEVO) is an inodilator and with its unique pharmacology justifying its use in a wide range of cardiac alterations in HF particularly in undergoing cardiac surgery. It is also reported to be better than classical inotropes in maintaining cardiac mechanical efficacy and reducing congestion in acute HF with hypotension. This review paper was designed to compile various evidence about basic pharmacology and potential clinical aspects of LEVO in cardiac surgery and other HF associated alterations. This will benefit directly to the researcher in initiating research and to fill the gaps in the area of thrust.