In continuation of our previous studies to optimise potent carbonic anhydrase inhibitors, two new series of isatin N- phenylacetamide based sulphonamides were synthesised and screened for their human (h) carbonic anhydrase (EC 4.2.1.1) inhibitory activities against four isoforms h CA I, h CA II, h CA IX and h CA XII. The indole-2,3-dione derivative 2h showed the most effective inhibition profile against h CAI and h CA II (K I = 45.10, 5.87 nM) compared to acetazolamide ( AAZ) as standard inhibitor. Moreover, 2h showed appreciable inhibition activity against the tumour-associated h CA XII, similar to AAZ showing K I of 7.91 and 5.70 nM, respectively. The analogs 3c and 3d showed good cytotoxicity effects, and 3c revealed promising selectivity towards lung cell line A549. Molecular docking was carried out for 2h and 3c to predict their binding conformations and affinities towards the h CA I, II, IX and XII isoforms.

A novel series of coumarin-thiadiazole heterocycle derivatives was synthesized by the nucleophilic substitution reaction. The synthesized compounds were structurally verified by IR, 1 H NMR, 13 C NMR, mass spectra, and elemental analyses. to 42%, 45%, and 43% methyl green displacement, respectively. Out of the 60-cell line panel, the leukemia HL-60 cell line was the most susceptible to growth inhibition when treated with 14a, resulting in 61% growth, followed by the lung carcinoma cell line NCI-H522 showing 67% growth when treated with 9. Moreover, compound 10c had an IC 50 value of 24.9 μg/mL against the HepG-2 cell line. K E Y W O R D Santitumor, coumarin, DNA binding, DNA cleavage, thiadiazole

Compounds I–X were designed to inhibit SARS-CoV-2 Mpro based on pharmacophore modeling of SARS-CoV Mpro inhibitors. Compounds V and VI showed promising molecular docking and molecular dynamic simulation results that surpassed baicalein.

Major protease enzyme of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS‐CoV‐2 Mpro) is one of the key enzymes of viral replication which amuses many scientists as a promising drug target. Nonetheless, few studies reported new synthetic small molecule inhibitors of the Mpro but many were repurposing drugs such as chloroquine or predicting the activity based on in silico results. This study had the privilege of synthesizing new coumarin‐based derivatives with possible Mpro inhibition based on the previously reported ligand‐based pharmacophore model. Compound 3 showed comparable Mpro inhibitory activity to chloroquine with IC50 15.0 and 13.1 μg/mL, respectively. Moreover, compounds 4 b, 4 d, 5 b, 5 c, 5 e and 5 g managed to inhibit the Mpro enzymatic activity by more than 50.0 % at 100 μM among which 5 g showed 63.9 % inhibition and IC50 25.8 μg/mL. The binding conformations of the promising compounds were illustrated using molecular docking as well as their drug‐likeness and ADMET properties. A pharmacophore model was generated using the compounds with more than 50.0 % Mpro inhibition to annotate the essential moieties for enzyme binding. All compounds were fully characterized using the conventional spectroscopic and microanalyses methods.

A novel series of 2,4,5- and 2,3,4-trisubstituted thiazole hybrids with 1,3,4-thiadiazolylbenzenesulfonamide was designed following the tail approach as possible hCAIX inhibitors.