Letters in Drug Design & Discovery - Volume 19, Issue 12, 2022

Alzheimer's is a neurodegenerative disease (NDs) found in old age people with associated most common symptom dementia. MTDLs (Multi-Target Direct Ligand strategy) is based on a combination of two or more bioactive pharmacophores into a single molecule and this phenomenon has received a great attention in the new era of modern drug discovery and emerging as a choice to treat this complex Alzheimer’s disease (AD). In last fifteen years, many research groups designed, and synthesized new carbazole integrated molecules linked with other bioactive pharmacophores like thiazoles, carvedilol, α- naphthylaminopropan-2-ol, tacrine, ferulic acid, piperazine, coumarin, chalcones, stilbene, benzyl piperidine, adamantane, quinoline, phthalocyanines, α-amino phosphonate, thiosemicarbazones, hydrazones, etc. derivatives using MTDLs approach to confront AD. The present review entails the scientific data on carbazole hybrids as potential Anti-Alzheimer activities from 2007 to 2021 that have shown potential anti-Alzheimer activities through multiple target pathways thereby promising hope for new drug development to confront AD.

Background: The search for novel and potent anticancer drugs is imperative. This present study aims to unravel the mechanisms of action of 2-alkoxyecarbonyl esters using robust model(s) that can accurately predict the bioactivity of novel compounds. Twenty-four potential anticancer 2- alkoxycarbonylallyl ester compounds obtained from the literature were employed in building a 3D-QSAR model. Objectives: The objective of this study is to determine the predictive ability of the GFA-based QSAR models and extreme machine learning models and compare them. The lead compounds and newly designed compounds were docked at the active site of a human epidermal growth factor receptor (EGFR) kinase domain to determine their binding modes and affinity. Methods: QikProp program and Spartan packages were employed for screening compounds for druglikeness and toxicity. QSAR models were equally used to predict the bioactivities of these molecules using the Material Studio package. Molecular docking of the molecules at the active site of an EGFR receptor, 1M17, was done using Auto dock tools. Results: The model of choice, with r²pred (0.857), satisfied the recommended standard for a stable and reliable model. The low value of r², Q² for several trials and cRp2 (0.779 ≥ 0.5) and the high value of correlation coefficient r² for the training set (0.918) and test set (0.849) provide credence to the predictability of the model. The superior inhibition of EGFR displayed by the lead compounds (20 and 21) with binding energies of 6.70 and 7.00 kcalmol-1, respectively, is likely due to the presence of double bonds and α-ester groups. ADMET screening showed that these compounds are highly druggable. The designed compounds (A and B) displayed better inhibition of EGFR. Conclusion: The QSAR model used here performed better than the Random Forest Regression model for predicting the bioactivity of these anticancer compounds, while the designed compounds (A and B) performed better with higher binding affinity than the lead compounds.

Background: Lung cancer is a leading cause of cancer death globally. Platinum-based chemotherapeutic medications are essential for treating advanced NSCLC, despite that drug resistance severely limits its effectiveness. Objective: In this study, we investigated the cytotoxic effect of metformin on cisplatin-resistant NSCLC cells (A549/DDP) and its potential mechanisms. Methods: Anti-lung cancer efficacy of metformin, cisplatin, and metformin combined with cisplatin was examined in A549 and A549/DDP cells. The cell counting kit-8 (CCK-8) assay was applied for measuring cell proliferation. CalcuSyn software was used to calculate the combination index and estimate the synergistic effect of metformin and cisplatin on cell proliferation. The cell apoptosis was analyzed by flow cytometry and the expression of apoptosis-related proteins, Bcl-2, Bax and caspase-3 were analyzed using Western blot. Futhermore, the expression of key nucleotide excision repair (NER) proteins, ERCC1, XPF, and XPA, was also analyzed using Western blot. Results: We found that metformin had dose-dependent antiproliferative effects on A549/DDP and A549 cells. The combination of metformin and cisplatin had higher effectiveness in inhibiting A549/DDP and A549 cell growth than either of the two drugs alone. Flow cytometry analysis indicated that the combined treatment could cause more cell apoptosis than the single-drug treatment. Consistently, the combined treatment decreased the expression of Bcl-2 protein and elevated the expression of Bax, and cleaved caspase-3 proteins. The expression level of ERCC1, XPF, and XPA proteins were lower in the combined treatment than in either of metformin and cisplatin treatment alone. Conclusion: Our study suggested that metformin and cisplatin had synergistic antitumorigenic effects in A549/DDP cells. The combination of cisplatin and metformin could be promising drug candidates to sensitize cisplatin-induced apoptosis through regulating nucleotide excision repair pathways in lung cancer.

Background: Despite the fact that anticonvulsant drugs targeting multiple targets have been used in the health center, their effectiveness and tolerability in the treatment of seizures have not improved much. As a result, innovative anticonvulsant medicines are still needed urgently to overcome the significant toxicity of currently existing medications. Objective: This study aimed to synthesize 2-aminobenzothiazole derivatives as anticonvulsant agents, compute physicochemical parameters, and conduct a docking investigation. Methods: Condensing 4-(2-(benzo[d]thiazole-2-ylamino) acetamido) benzoyl chloride with substituted phenols in acetone in anhydrous potassium carbonate in the presence of potassium iodide in dry acetone yielded benzothiazole derivatives. IR and NMR spectroscopy were used to characterize the structures of freshly synthesized substances. To estimate their drug-like candidates, a number of molecular attributes of these derivatives were computed. The carbonic anhydrase enzyme was used to perform molecular docking on these synthesized compounds. The synthetic compounds were tested for biological activity, such as anticonvulsant activity and enzyme inhibitor activity for carbonic anhydrase.. Results: The findings showed that V-5 (4-chlorophenyl 4-(2-(benzo[d]thiazol-2-ylamino)acetamido)benzoate) had the strongest anticonvulsant effect out of all the eight target compounds. Conclusion: The outcome of this research was that V-5 could be a promising new lead molecule for the development of anticonvulsant drugs.

Background: An enzyme called urease assists highly pathogenic bacteria in colonizing and maintaining themselves. Accordingly, inhibiting urease enzymes has been shown to be a promising strategy for preventing ureolytic bacterial infections. Objective: This study aimed to synthesize and evaluate the bioactivity of a series of semicarbazone derivatives. Methods: A series of piperazine-based semicarbazone derivatives 5a-o were synthesized and isolated, and their structures were elucidated by ¹H-NMR and ¹³C-NMR spectroscopic techniques besides MS and elemental analysis. The urease inhibition activity of these compounds was evaluated using the standard urease enzyme inhibition kit. An MTT assay was performed on two different cell lines (NIH-3T3 and MCF-7) to investigate the cytotoxicity profile. Results: All semicarbazone 5a-o exhibited higher urease inhibition activity (3.95–6.62 μM) than the reference standards thiourea and hydroxyurea (IC50: 22 and 100 μM, respectively). Derivatives 5m and 5o exhibited the best activity with the IC50 values of 3.95 and 4.05 μM, respectively. Investigating the cytotoxicity profile of the target compound showed that all compounds 5a-o have IC50 values higher than 50 μM for both tested cell lines. Conclusion: The results showed that semicarbazone derivatives could be highly effective as urease inhibitors.

Background: Antimicrobial resistance has been rising continuously in the past few years due to the overuse and exploitation of existing antimicrobials. This has motivated the search for a novel scaffold that has the capability of rapid antimicrobial action. The hybridized pyrimidines have attracted us due to their widespread biological activities, such as anti-bacterial and antifungal activities. Objective: The present study incorporates a series of pyrimidine-based antimicrobial agents for the 2D quantitative structure-activity relationship analysis (2D QSAR) and docking analysis. Methods: The exploration of the chemical structures in combination with the biological activity in CPMLR led to the detection of six descriptors (Constitutional descriptors, Topological descriptors, Modified Burden Eigenvalues and 2D autocorrelations) for modeling the activity. The resulted QSAR model has been validated using a combinatorial protocol in multiple linear regression (CP-MLR) and partial least squares (PLS) analysis. Results: The best QSAR model displays the r²t value of 0.594, Q²LOO value of 0.779, Q²L5O value of 0.767. Further docking study was executed using Autodock Vina against Penicillin-binding protein (PBP2a). Conclusion: From the results, Compounds 4, 11and 24 were found to possess a good binding affinity towards PBP2a.