Synthesis, biological evaluation and molecular docking studies of novel 1,3,4-thiadiazoles as potential anticancer agents and human carbonic anhydrase inhibitors.

Thiosemicarbazide and also 1,3,4-thiadiazole derivatives have been garnering substantial attention from researchers worldwide due to their expansive range of biological activities, encompassing antimicrobial, anti-inflammatory, and anticancer properties. Herein, we embarked on a comprehensive investigation in this study, introducing a novel series of thiosemicarbazides (3a-3i) and their corresponding 1,3,4-thiadiazole (4a-4i) derivatives. The compounds were meticulously designed, synthesized, and subjected to meticulous characterization using various spectroscopic methods such as FT-IR, 1H-NMR, 13C-NMR, and elemental analysis. Afterward, their potential anti-proliferative effectiveness was assessed using MTT assay against two cancer cell lines (U87 and HeLa) and normal fibroblast cells (L929). Among the compounds, 4d showed the highest cytotoxic activity against U87 and 4i against HeLa. Compound 3b exhibited selective cytotoxic activity against both cancer cells. Among the molecules with selective activity against the U87 cell line; 3a, 3b, 4d and 4e were further evaluated by caspase-3 activity levels, Bax and Bcl-2 protein expression, and total oxidant status assay. Besides, carbonic anhydrase IX activity studies were also performed in order to understand the underlying mechanism of action. The results indicated that compound 4e showed higher efficacy than standard acetazolamide (IC50 = 0.58 ± 0.02 µM) with an IC50 value of 0.03 ± 0.01 µM. Furthermore, molecular docking studies were carried out using carbonic anhydrase IX crystals to determine the compound's interactions with the enzyme's active sites. This comprehensive investigation sheds light on the intricate interplay between molecular structure and biological activity, providing valuable insights into the therapeutic potential of these compounds.

Synthesis and Biological Evaluation of Some Hydrazide-Hydrazone Derivatives as Anticancer Agents.

In this study, a series of hydrazide-hydrazone derivatives (3a-3u) were synthesized and evaluated for their anticancer activities against prostate cancer cell line (PC-3), breast cancer cell line (MCF-7), colon cancer cell line (HT-29) and human umbilical vein endothelial cells (HUVEC) using MTT assay. In particular, compound 3h having a pyrrole ring was found to be the most potent derivative with IC50 = 1.32, 2.99, 1.71 µM against PC-3, MCF-7, HT-29 cancer cell lines respectively using paclitaxel as a standard compound. Furthermore, compound 3h was subjected to further biological studies such as caspase-3 activity and Annexin-V assay to evaluate their inhibitory potentials. The activity results displayed that compound 3h increased caspase-3 activation and the number of cells to early apoptosis. The additional studies like pharmacokinetics, bioavailability scores and drug-likeness properties were also evaluated. The in silico pharmacokinetics predictions displayed that the bioavailability of these compounds may be high.

Design, Synthesis, and Molecular Docking Studies of a Conjugated Thiadiazole-Thiourea Scaffold as Antituberculosis Agents.

In view of the emergence and frequency of multidrug-resistant and extensively drug-resistant tuberculosis and consequences of acquired resistance to clinically used drugs, we undertook the design and synthesis of novel prototypes that possess the advantage of the two pharmacophores of thiourea and 1,3,4-thiadiazole in a single molecular backbone. Three compounds from our series were distinguished from the others by their promising activity profiles against Mycobacterium tuberculosis strain H37Rv. Compounds 11 and 19 were the most active representatives with minimum inhibitory concentration (MIC) values of 10.96 and 11.48 µM, respectively. Compound 15 was shown to inhibit M. tuberculosis strain H37Rv with an MIC value of 17.81 µM. Cytotoxicity results in the Vero cell line showed that these three derivatives had selectivity indices between 1.8 and 8.7. In order to rationalize the biological results of our compounds, molecular docking studies with the enoyl acyl carrier protein reductase (InhA) of M. tuberculosis were performed and compounds 11, 15, and 19 were found to have good docking scores in the range of -7.12 to -7.83 kcal/mol.

Synthesis, antiviral and anticancer activity of some novel thioureas derived from N-(4-nitro-2-phenoxyphenyl)-methanesulfonamide.

Due to a continuing effort to develop new antiviral agents, a series of 1-[4-(methanesulfonamido)-3-phenoxyphenyl]-3-alkyl/aryl thioureas 3a-i have been synthesized by the reaction of alkyl/aryl isothiocyanates with 4-amino-2-phenoxymethanesulfonanilide. These derivatives were structurally characterized by the use of spectral techniques and evaluated for their anticancer and antiviral activities. None of the tested compounds showed significant anticancer properties on A549 and L929 cell lines. All synthesized compounds 3a-i were evaluated in vitro against HIV-1 (IIIB) and HIV-2 (ROD) strains in MT-4 cells, as well as other selected viruses such as HSV-1, HSV-2, Coxsackie virus B4, Sindbis virus and varicella-zoster virus using HEL, HeLa and Vero cell cultures. Compound 3b was able to block HIV replication with almost 100% maximum protection at 125 microg/ml, and IC(50) values of 54.9 microg/ml and 65.9 microg/ml against HIV-1 and HIV-2, respectively.

Synthesis and anticonvulsant activity of new N-(alkyl/sub-stituted aryl)-N'-[4-(5-cyclohexylamino)-1,3,4-thiadiazole-2-yl)phenyl]thioureas.

A series of novel thiourea derivatives carrying the 5-cylohexylamino-1,3,4-thiadiazole moiety was synthesized and their anticonvulsant activity was evaluated. Structures of the synthesized compounds have been confirmed by IR, 1H-NMR, and elemental analysis. All of the compounds were administered at a dose of 50 mg/kg. Some of the active compounds have different effects in pentylenetetrazole (PTZ) and maximal electroshock (MES) tests, indicating the therapeutical potential in petit mal seizures, but not in grand mal seizures. Compounds 10, 11, 13, and 14 carrying 2-methylphenyl, 4-chlorophenyl, allyl, and 4-methylphenyl on the thiourea pharmacophore, increased the survival rate in the PTZ model. The ED50 values of the active compounds 10, 11, 13, and 14 were found 68.42, 43.75, 18.75 and 25 mg/kg, respectively.

Development and validation of a rapid RP-HPLC method for the determination of cetirizine or fexofenadine with pseudoephedrine in binary pharmaceutical dosage forms.

The objective of the current study was to develop a simple, accurate, precise and rapid reversed-phase HPLC method and subsequent validation using ICH suggested approach for the determination of antihistaminic-decongestant pharmaceutical dosage forms containing binary mixtures of pseudoephedrine hydrochloride (PSE) with fexofenadine hydrochloride (FEX) or cetirizine dihydrochloride (CET). The chromatographic separation of PSE, FEX and CET was achieved on a Zorbax C8 (150 mm x 4.6mm; 5 microm particle size) column using UV detection at 218 and 222 nm. The optimized mobile phase was consisted of TEA solution (0.5%, pH 4.5)-methanol-acetonitrile (50:20:30, v/v/v). The retention times were 1.099, 2.714 and 3.808 min for PSE, FEX and CET, respectively. The proposed method provided linear responses within the concentration ranges 30-240 and 1.25-10 microg ml(-1) with LOD values of 1.75 and 0.10 microg ml(-1) for PSE and CET, respectively. Linearity range for PSE-FEX binary mixtures were 10-80 and 5-40 microg ml(-1) with LOD values of 0.75 and 0.27 microg ml(-1) for PSE and FEX, respectively. Correlation coefficients (r) of the regression equations were greater than 0.999 in all cases. The precision of the method was demonstrated using intra- and inter-day assay R.S.D. values which were less than 1% in all instances. No interference from any components of pharmaceutical dosage forms or degradation products was observed. According to the validation results, the proposed method was found to be specific, accurate, precise and could be applied to the quantitative analysis of these drugs in capsules containing PSE-CET or extended-release tablets containing PSE-FEX binary mixtures.