Tailored Tetrasubstituted Imidazole Carrying the Benzenesulfonamide Fragments as Selective Human Carbonic Anhydrase IX/XII Inhibitors.

A new series of tetrasubstituted imidazole carrying sulfonamide as zinc-anchoring group has been designed. The structures of the synthesized derivatives 5 a-l have been confirmed by spectroscopic analysis. These compounds incorporate an ethylenic spacer between the benzenesulfonamide and the rest of the trisubstituted imidazole moiety and were tested as inhibitors of carbonic anhydrases and for in-vitro cytotoxicity. Most of them act as effective inhibitors of the tumor-linked CA isoforms IX and XII, in nanomolar range. Also, different compounds have shown selectivity in comparable with the standard acetazolamide. Our IBS 5 d, 5 g, and 5 l (with Ki: 10.1, 19.4, 19.8 nM against hCA IX and 47, 45, 20 nM against hCA IX) showed the best inhibitory profile. In-vitro screening of all derivatives against a full sixty-cell-lined from NCI at a single dose of 10 µM offered growth inhibition of up to 45 %. Compound 5 b has been identified with the most potent cytotoxic activity and broad spectrum. Docking studies have also been implemented and were also in accordance with the biological outcomes. Our SAR analysis has interestingly proposed efficient tumor-related hCAs IX/XII suppression.

Anticonvulsant Classes and Possible Mechanism of Actions.

Epilepsy is considered one of the most common neurological disorders worldwide; it needs long-term or life-long treatment. Despite the presence of several novel antiepileptic drugs, approximately 30% patients still suffer from drug-resistant epilepsy. Subsequently, searching for new anticonvulsants with lower toxicity and better efficacy is still in paramount demand. Using target-based studies in the discovery of novel antiepileptics is uncommon owing to the insufficient information on the molecular pathway of epilepsy and complex mode of action for most of known antiepileptic drugs. In this review, we investigated the properties of anticonvulsants, types of epileptic seizures, and mechanism of action for anticonvulsants.

Design and synthesis of novel rigid dibenzo[b,f]azepines through ring closure technique as promising anticancer candidates against leukaemia and acting as selective topoisomerase II inhibitors and DNA intercalators.

In this research, two novel series of dibenzo[b,f]azepines (14 candidates) were designed and synthesised based on the rigidification principle and following the reported doxorubicin's pharmacophoric features. The anti-proliferative activity was evaluated at the NCI against a panel of 60 cancer cell lines. Further, the promising candidates (5a-g) were evaluated for their ability to inhibit topoisomerase II, where 5e was noticed to be the most active congener. Moreover, its cytotoxicity was evaluated against leukaemia SR cells. Also, 5e arrested the cell cycle at the G1 phase and increased the apoptosis ratio by 37.34%. Furthermore, in vivo studies of 5e showed the inhibition of tumour proliferation and the decrease in its volume. Histopathology and liver enzymes were examined as well. Besides, molecular docking, physicochemical, and pharmacokinetic properties were carried out. Finally, a SAR study was discussed to open the gate for further optimisation of the most promising candidate (5e).HighlightsTwo novel series of dibenzo[b,f]azepines were designed and synthesised based on the rigidification principle in drug design.The anti-proliferative activity was evaluated at the NCI against a panel of 60 cancer cell lines.5e was the most active anti-topo II congener (IC50 = 6.36 ± 0.36 µM).5e was evaluated against leukaemia SR cells and its cytotoxic effect was confirmed (IC50 = 13.05 ± 0.62 µM).In vivo studies of 5e significantly inhibited tumour proliferation by 62.7% and decreased tumour volume to 30.1 mm3 compared to doxorubicin treatment.

New frontier radioiodinated probe based on in silico resveratrol repositioning for microtubules dynamic targeting.

PURPOSE: As the 'de novo' drug discovery faces a highly attrition rates, drug repositioning procures a heighten concern in identifying novel uses for existing medications. This study aimed to fabricate radioiodinated resveratrol as a potent microtubules interfering agent for cancer theragnosis. METHODS: Resveratrol was radiolabeled with radioactive iodine where the radioiodination efficiency was enlightened and the computational approaches were employed to investigate the affinity and specificity with tubulins. Furthermore, the in-vivo distribution and pharmacokinetic studies in normal and tumor induced mice were investigated. RESULTS: The maximum radioiodination yield (94.6 ± 1.66) was achieved at optimum preparation parameters stated as 100 µg/mL of oxidizing agent, 100 µg/ml of resveratrol, reaction time of 30 min and reaction pH 5. The in silico studies showed that di-iodinated resveratrol (compound 6) exhibited the best binding score (-34.46) and interaction with the ß-tubulin binding site. The in vivo distribution in tumor models revealed a significant accumulation (4.02% ID/g) in tumor lesion at 60 min p.i. The rate of drug elimination demonstrated a mono-exponential decline of radioactivity versus time in the blood. CONCLUSION: Radioiodinated resveratrol revealed good microtubules targeting which render it as a novel theranostic probe for cancer management.

Design, Synthesis, Biological Evaluation, and Computational Studies of Novel Fluorinated Candidates as PI3K Inhibitors: Targeting Fluorophilic Binding Sites.

Highly fluorinated candidates containing anticancer pharmacophores like thiosemicarbazone (5a-e) and its cyclic analogues hydrazineylidenethiazolidine (6a-e), 2-aminothiadiazole (7a-e), and 2-hydrazineylidenethiazolidin-4-one (8a-e) were synthesized, and their cytotoxic activity was assayed against 60 tumor cell lines. Compounds 6c, 7b, and 8b displayed the most potent activity with lower toxic effects on MCF-10a. In vitro phosphatidylinositol 3-kinase (PI3K) enzyme inhibition was performed. Compound 6c displayed half-maximal inhibitory concentration (IC50, µM) values of 5.8, 2.3, and 7.9; compound 7b displayed IC50 values of 19.4, 30.7, and 73.7; and compound 8b displayed IC50 values of 77.5, 53.5, and 121.3 for PI3Kα, ß, and δ, respectively. Moreover, cell cycle progression caused cell cycle arrest at the S phase for compounds 6c and 8b and at G1/S for compound 7b, while apoptosis was induced. In silico studies; molecular docking; physicochemical parameters; and absorption, distribution, metabolism, excretion, and toxicity (ADMET) analysis were performed. The results showed that compound 6c is the most potent one with a selectivity index (SI) of 39 and is considered as a latent lead for further optimization of anticancer agents.

Design, synthesis, biological evaluation, and computational studies of novel thiazolo-pyrazole hybrids as promising selective COX-2 inhibitors: Implementation of apoptotic genes expression for ulcerogenic liability assessment.

A novel series of thiazolo-pyrazole hybrids has been prepared and assessed for their in vitro COX-1/COX-2 inhibitory activity. Compound 6c exhibited the most selective COX-2 inhibition profile (SI of 264) not far of Celecoxib (294). In-vivo anti-inflammatory activity revealed that compound 6d exhibited the highest activity (97.30% inhibition of edema) exceeding reference standard Indomethacin (84.62% inhibition of edema). The ulcerogenic liability tested, using gross, microscopic, biochemical analysis and apoptotic genes expression, showed that compound 6b matched the optimal candidate activity (ulcer index = 120, selectivity index of ~ 162 and 77% in-vivo inhibition of edema). Meanwhile, compound 6 m (ulcer index = 0) showcased the highest safety profile. Molecular modeling analysis and drug likeness studies presented appreciated agreement with the biological evaluation.

Design, synthesis and docking studies of novel benzopyrone derivatives as anticonvulsants.

A series of coumarin derivatives 6-8, 9a-h, 11 and 13a, b -16a, b was synthesized and screened for their anticonvulsant profile. Screening of these analogues using the 'gold standard methods' revealed variable anticonvulsant potential with remarkable effects observed particularly in chemically-induced seizure test. Compounds 6, 7, 13b disclosed the highest potency among the series with 100% protection against scPTZ. Quantification study confirmed that compound 6 (ED50 0.238 mmol/kg) was the most active congener in the scPTZ model and was approximately 1.5 folds more potent than ethosuximide as reference drug Meanwhile, in the MES test, candidate drugs exhibited mild to moderate anticonvulsant efficacy, the highest of which was compound 14a, imparting 50% protection at 2.1 mmol/kg, followed by other compounds with activity ranging from 14 to 33%, as compared to diphenylhydantoin. Additionally, all candidate compounds were screened for acute neurotoxicity using the rotarod method to identify motor impairment, where almost all compounds passed the test. Further neurochemical investigation was performed to unravel the effect of the most active compound (6) on GABA level in mouse brain, where a significant elevation was evident by 4 and 1.4 folds with respect to that of the control and reference groups at p < 0.05. Molecular modeling study using Discovery Studio program was performed, where compound 6 exhibited good binding interaction with γ-aminobutyric acid aminotransferase (GABA-AT) enzyme and this was consistent with the attained experimental results.

Design and synthesis of novel parabanic acid derivatives as anticonvulsants.

In this work a set of novel derivatives of parabanic acid 9a-d, 12a-d and 13a-d was synthesized and their anticonvulsant potential was evaluated. All the compounds under investigation exhibited anticonvulsant activity in both scPTZ and MES tests. In phase II anticonvulsant study, the trimethoxy phenyl derivative 9a evoked the highest potency among the tested compounds in scPTZ test. It displayed 1.72- and 17.05-folds activity more than the standard drugs phenobarbital and ethosuximide, respectively. In addition, the margin of safety for compound 9a is better than that of the reference antiepileptic drug ethosuximide. Also, compound 9a was devoid of hepatotoxicity indicated by measurements of serum level of ALT, AST, ALP, albumin and total protein. Furthermore, treatment with compound 9a significantly increased the GABA brain level by 2.56-folds compared to the control value. Additionally, molecular docking was performed on the active site of GABA-AT to clarify the interactions of the most potent compound 9a with the enzyme. In MES test, compound 12a exhibited the most potent activity against electric stimuli-induced seizures with the lowest ED50 = 13.7 mg/kg and protective index >36.5. Both candidates 9a and 12a could be a good starting point to develop new molecules as novel antiepileptic drugs.

Design, synthesis and anticancer evaluation of novel 1,3-benzodioxoles and 1,4-benzodioxines.

A new set of 1,3-benzodioxoles and 1,4-benzodioxines was designed and synthesized starting from gallic acid as anticancer agents. The antiproliferative effect of the target compounds was evaluated against a panel of cancer cell lines (HepG2, PC-3, MCF-7 and A549) using MTT assay. The 1,4-benzodioxine derivative 11a manifested broad spectrum effect towards the four tested cancer cell lines (IC50 < 10 µM) with lower toxic effect on normal human cell line BJ1. Cell cycle progression of MCF-7 after treatment with compound 11a was studied where it induced cells accumulation at G2/M phase as well as increasing in the percentage of cells at pre-G1. Compound 11a is found to be a tubulin polymerization inhibitor with IC50 = 6.37 µM. Also, flow cytometeric analysis revealed that compound 11a could induce both early and late stage apoptosis in MCF-7 cell line. Moreover, the ability of this compound to stimulate apoptosis in the latter cell line was further confirmed by: increment of Bax/Bcl-2 ratio, increase the expression of tumor suppressor gene p53, boosting the levels of initiator and executioner caspases as well as raise in the amount of cytochrome C. In addition molecular docking study was accomplished on the colchicine binding site of tubulin (pdb: 1SA0) to illustrate the interactions of the most potent compound 11a to the receptor.

Anticancer activity of newly synthesized 1,1-disubstituted cyclohexane-1-carboxamides: in vitro caspases mediated apoptosis activators in human cancer cell lines and their molecular modeling.

Novel 1,1-disubstituted cyclohexane-1-carboxamides 6a-h, 7a-e, and 8a-b were designed and synthesized as apoptotic inducers. Cytotoxicity test revealed that some compounds have strong to moderate effect, while others displayed weak action against different cancer cell lines including, MCF-7, HepG2, A549, and HTC-116. A549 carcinoma cell line exhibited higher sensitivity toward all synthesized candidates especially compounds 6a and 8a which offered the lowest IC50 values 3.03 and 5.21 µM, respectively, relative to the positive control doxorubicin with IC50 value of 3.01 µM. Compared to doxorubicin treatment, compounds 6a and 8a induced caspases-3, -8, and -9 activities and G2/M growth arrest in A549 carcinoma cell line. The expression levels of p53 (tumor suppressor protein that in humans is encoded by the TP53 gene), Bax (apoptosis regulator protein in humans that is encoded by bax gene), and the Bax/Bcl-2 ratio were all higher than those in doxorubicin-treated cells (Bcl-2, B-cell lymphoma 2, encoded in humans by the Bcl-2 gene). Additionally, compounds 6a and 8a appeared to exhibit higher selectivity against MCF-10 human breast normal cell line. The synthesized congeners could be considered as potent apoptotic inducers interfering with extrinsic and intrinsic apoptotic pathways. Moreover, compound 6a was able to form complex with zinc ions as indicated by UV spectrophotometry which revealed its ability for being caspase activator. Molecular docking studies expected the interactions and binding modes of the synthesized inhibitors in the caspase-3 active site.

Synthesis, molecular modeling studies and anticonvulsant activity of certain (1-(benzyl (aryl) amino) cyclohexyl) methyl esters.

A series of (1-(benzyl (aryl) amino) cyclohexyl) methyl esters 7a-n were prepared and screened for their anticonvulsant profile. Screening of these esters 7a-n and their starting alcohols 6a and 6b revealed that compound 7k was the most potent one in the scPTZ screening test with an ED50 value of 0.0056mmol/kg being about 10- and 164-fold more potent than phenobarbital (ED50=0.056mmol/kg) and ethosuximide (ED50=0.92mmol/kg) as reference drugs, respectively. Meanwhile, in the MES test, compounds 7b and 7k at doses 0.0821mmol/kg and 0.0334mmol/kg, exerted 66% and 50% protection of the tested mice, respectively, compared with diphenylhydantoin, which exerted 100% protection at dose 0.16mmol/kg. In the neurotoxicity screen test, almost all esters 7a-n did not show any minimal motor impairment at the maximum administrated dose. The anticonvulsant effectiveness of esters 7a-n was higher than their corresponding alcohols 6a and 6b. Compounds 7b and 7k exhibited pronounced anticonvulsant activity devoid of neurotoxicity in minimal motor impairment test and hepatotoxicity in the serum enzyme activity assay. 3D pharmacophore model using Discovery Studio 2.5 programs showed high fit value. The obtained experimental results of sc-PTZ activity of compounds 7a-n was consistent with the molecular modeling study.