Medicinal Chemistry - Volume 15, Issue 3, 2019

Background: Noncoding RNAs (ncRNAs) which play an important role in various cellular processes are important in medicine as well as in drug design strategies. Different studies have shown that ncRNAs are dis-regulated in cancer cells and play an important role in human tumorigenesis. Therefore, it is important to identify and predict such molecules by experimental and computational methods, respectively. However, to avoid expensive experimental methods, computational algorithms have been developed for accurately and fast prediction of ncRNAs. Objective: The aim of this review was to introduce the experimental and computational methods to identify and predict ncRNAs structure. Also, we explained the ncRNA’s roles in cellular processes and drugs design, briefly. Method: In this survey, we will introduce ncRNAs and their roles in biological and medicinal processes. Then, some important laboratory techniques will be studied to identify ncRNAs. Finally, the state-of-the-art models and algorithms will be introduced along with important tools and databases. Results: The results showed that the integration of experimental and computational approaches improves to identify ncRNAs. Moreover, the high accurate databases, algorithms and tools were compared to predict the ncRNAs. Conclusion: ncRNAs prediction is an exciting research field, but there are different difficulties. It requires accurate and reliable algorithms and tools. Also, it should be mentioned that computational costs of such algorithm including running time and usage memory are very important. Finally, some suggestions were presented to improve computational methods of ncRNAs gene and structural prediction.

Background: Cancer is an important cause of human death worldwide. During the last decades, many anticancer agents with anti-tubulin mechanism have been synthesized or extracted from nature and some of them also entered clinical use. Indibulin is one of the most potent tubulin polymerization inhibitors with minimal peripheral neuropathy, which is a big problem by some of the antimitotic agents such as taxanes and vinka alkaloids. With respect to this giant benefit, herein we decided to design and synthesize novel indibulin related compounds and investigate their anticancer activity against HT-29, Caco-2 and T47-D cancerous cell lines as well as NIH-T3T as normal cell line. Objective: The aim of this study was to synthesize new anti-cancer agents and evaluates their cytotoxic activity on diverse cancerous and normal cell lines. Method: Target compounds were synthesized in multistep reaction and cytotoxic activity was investigated by MTT cell viability assay. Results: Herein, nine novel target compounds were synthesized in moderate to good yield. Some of the compounds exerted good cytotoxic activity against cancerous cell lines. Annexin V/PI staining showed that compound 4g could induce apoptosis and necrosis in HT-29 cell line. Conclusion: It is valuable to do further investigation on compound 4g which showed the highest activity against HT-29 and Caco-2 (IC50 values are 6.9 and 7 μM respectively). Also, synthesis of new derivatives of current synthesized compounds is suggested.

Background: Chagas disease, also known as American trypanosomiasis, is classified as one of the 17 most important neglected diseases by the World Health Organization. The only drugs with proven efficacy against Chagas disease are benznidazole and nifurtimox, however both show adverse effects, poor clinical efficacy, and development of resistance. For these reasons, the search for new effective chemical entities is a challenge to research groups and the pharmaceutical industry. Objective: Synthesis and evaluation of antitrypanosomal activities of a series of thiosemicarbazones and semicarbazones containing 1,2,3-1H triazole isatin scaffold. Method: 5'-(4-alkyl/aryl)-1H-1,2,3-triazole-isatins were prepared by Huisgen 1,3-dipolar cycloaddition and the thiosemicarbazones and semicarbazones were obtained by the 1:1 reactions of the carbonylated derivatives with thiosemicarbazide and semicarbazide hydrochloride, respectively, in methanol, using conventional reflux or microwave heating. The compounds were assayed for in vitro trypanocidal activity against Trypanosoma cruzi, the aetiological agent of Chagas disease. Beyond the thio/semicarbazone derivatives, isatin and triazole synthetic intermediates were also evaluated for comparison. Results: A series of compounds were prepared in good yields. Among the 37 compounds evaluated, 18 were found to be active, in particular thiosemicarbazones containing a non-polar saturated alkyl chain (IC50 = 24.1, 38.6, and 83.2 μM; SI = 11.6, 11.8, and 14.0, respectively). To further elucidate the mechanism of action of these new compounds, the redox behaviour of some active and inactive derivatives was studied by cyclic voltammetry. Molecular docking studies were also performed in two validated protein targets of Trypanosoma cruzi, i.e., cruzipain (CRZ) and phosphodiesterase C (TcrPDEC). Conclusion: A class of thio/semicarbazones structurally simple and easily accessible was synthesized. Compounds containing thiosemicarbazone moieties showed the best results in the series, being more active than the corresponding semicarbazones. Our results indicated that the activity of these compounds does not originate from an oxidation-reduction pathway but probably from the interactions with trypanosomal enzymes.

Background: 2-Aminochromene derivatives display important pharmacological properties, including mainly antibiotic and anticancer activities. Objective: The study aims to synthesize new chromene derivatives via a new approach using Grignard reagents, for the evaluation of their antibiotic and antifungal properties. Method: A series of novel 3-cyano-4-aminochromene derivatives bearing alkyl substituents at the 4-position was prepared for biological evaluation. Results: These compounds were obtained by the addition of various Grignard reagents into Nethoxycarbonyl- 3-cyanoiminocoumarines in moderate to good yields (72-96%). The reaction is completely regioselective. The new chromene derivatives were screened for their in vitro antimicrobial activities against a panel of six bacterial and three fungal strains using agar dilution method. Conclusion: The antibacterial activity of the chromene derivatives was more pronounced on Gram-positive bacteria than on Gram-negative bacteria with a significant activity observed against Staphylococcus aureus. An interesting antifungal activity against Fusarium sp. and Fusarium oxysporum was also noticed.

Background: Chagas disease affects about 7 million people worldwide. Only two drugs are currently available for the treatment for this parasite disease, namely, benznidazol (Bzn) and nifurtimox (Nfx). Both drugs have limited curative power in the chronic phase of the disease. Therefore, continuous research is an urgent need so as to discover novel therapeutic alternatives. Objective: The development of safer and more efficient therapeutic anti-T. cruzi drugs continues to be a major goal in trypanocidal chemotherapy. Method: Synthesis, 2D-QSAR and drug-like physicochemical properties of a set of quinazolinone and quinazoline derivatives were studied as trypanocidal agents. All compounds were screened in vitro against Trypanosoma cruzi (Tulahuen strain, Tul 2 stock) epimastigotes and bloodstream trypomastigotes. Results: Out of 34 compounds synthesized and tested, six compounds (5a, 5b, 9b, 9h, 13f and 13p) displayed significant activity against both epimastigotes and tripomastigotes, without exerting toxicity on Vero cells. Conclusion: The antiprotozoal activity of these quinazolinone and quinazoline derivatives represents an interesting starting point for a medicinal chemistry program aiming at the development of novel chemotherapies for Chagas disease.

Background: Pyrimidines emerged as a remarkable class of heterocyclic compounds that have reinforced the pharmaceutical chemistry with various bioactive antitumor agents. Moreover, pyrimidine scaffold displayed VEGFR-2 inhibitory activity. Also, nano-sized catalysts are used in organic reactions in order to speed up the catalytic process. Objective: We were interested herein to synthesize a new series of fused pyrimidines using ZnO(NPs) to investigate their antitumor efficiency against breast MCF7 cancer and their VEGFR- 2 inhibition properties. Method: A simple and efficient method for the synthesis of fused pyrimidines was developed using zinc oxide nanoparticles ZnO(NPs) in refluxing ethanol. Results: The proposed structures of all new fused pyrimidines are in agreement with their spectral data. Antitumor evaluation of newly fused pyrimidine derivatives against breast MCF-7 cancer was performed. It was apparent that the 2-phenylpyrazolo[1,5-a]pyrimidine derivatives 9a (IC50 = 9.12±1.16 μg/ml), 9c (IC50 = 9.10±1.07 μg/ml) and 9d (IC50 = 9.60±1.22 μg/ml) exhibited equipotent antitumor activity as Tamoxifen (IC50 = 9.11±0.90 μg/ml). Also, the inhibitory activity of the novel fused pyrimidine derivatives on VEGFR-2 as well as Tamoxifen was determined using breast cancer cell line MCF-7. The data was obvious that 2-phenylpyrazolo[1,5-a]pyrimidine derivatives 9a, 9c and 9d exhibited noticeable VEGFR-2 inhibitory effect with % inhibition ranging from 80-84 % versus Tamoxifen 93.5%. Conclusion: We succeeded in this context to synthesize new fused pyrimidines using ZnO(NPs) as anti-breast cancer agents targeting VEGFR-2.

Background: The benzazole nucleus is found in many promising small molecules such as anticancer and antibacterial agents. Bendamustine (Alkylating agent), Nocodazole (Mitotic inhibitor), Veliparib (PARP inhibitor), and Glasdegib (SMO inhibitor) are being clinically used as anticancer therapeutic which bear benzimidazole moiety. Based on the principle of bioisosterism, in the present work, 23 compounds belonging to 2-(3,4-dimethoxyphenyl)benzazoles and imidazopyridine series were synthesized and evaluated for their anticancer and antimicrobial activities. Objective: A series of new 2-(3,4-dimethoxyphenyl)-1H-benz(or pyrido)azoles were synthesized and evaluated for their anticancer and antimicrobial activities. Method: N-(5-chloro-2-hdroxyphenyl)-3,4-dimethoxybenzamide 1, was obtained by the amidation of 2-hydroxy-5-chloroaniline with 3,4-dimethoxybenzoic acid by using 1,1'-carbonyldiimidazole. Cyclization of 1 to benzoxazole derivative 2, was achieved by p-toluenesulfonic acid. Other 1H-benz(or pyrido)azoles were prepared by the reaction between 2-aminothiophenol, ophenylenediamine, o-pyridinediamine with sodium metabisulfite adduct of 3,4-dimethoxybenzaldehyde. The NMR assignments of the dimethoxy groups were established by the NOESY spectra. Results: Compound 12, bearing two chlorine atoms at the 5(4) and 7(6) positions of the benzene moiety of benzimidazole was found the most potent analogue against A549 cells with the GI50 value of 1.5 μg/mL. Moreover, 24 showed remarkable cell growth inhibition against MCF-7 and HeLa cells with the GI50 values of 7 and 5.5 μg/mL, respectively. The synthesized compounds have no important antibacterial and antifungal activities. Conclusion: It could be concluded that the introduction of di-chloro atoms at the phenyl ring of 2-(3,4-dimethoxyphenyl)-1H-benzimidazoles increases significant cytotoxicity to selected human tumor cell lines in comparison to other all benzazoles synthesized. Unsubstituted 2-(3,4- dimethoxyphenyl)-imidazopyridines also gave good inhibitory profile against A549 and HeLa cells.

Background: The over-expression of the carbonic anhydrases results in some specific carcinomas including pancreatic, gastric and brain tumor. Tumors are distinguished under hypoxic conditions and various investigations are being carried out to target the known hypoxic areas of the tumors to increase the sensitivity towards standard therapeutic treatment. Objective: Herein, we have designed and synthesized some biologically important esters, hydrazides, thiocarbamates, 1,2,4-triazole-3-thiones and Schiff bases. The purpose of the research was to evaluate the derivative against carbonic anhydrase and to assess the toxicity of the same compounds. Method: The structures of all the compounds were characterized by FT-IR, mass spectrometry, elemental analysis, 1H and 13C NMR spectroscopy. The synthetic derivatives were screened for their inhibitory potential against carbonic anhydrase II by in vitro assay. Double reciprocal plots for inhibition kinetics of the potent compounds were constructed and mode of inhibition was determined. Furthermore, to check the cytotoxicity, these derivatives were tested against human breast adenocarcinoma by MTT method. Results: X-ray diffraction analysis of the compounds 10, 14 and 15 showed that they did not have any π-π or C-H…π interactions. The experimental results were validated by molecular docking and dynamic simulations of the potent compounds in the active pocket of enzyme. Important binding interactions of potent compounds with the key residues in the active site of the carbonic anhydrase enzyme were revealed. Drug likeness profile of the derivatives was evaluated to determine the physicochemical properties. Conclusion: The proposed synthetic approach provides a suitable platform for the generation of a new library of compounds which could potentially be employed in the future testing and optimization of inhibitor potencies.

Background: Benzothiazole derivatives are known for anti-TB properties. Based on the known anti-TB benzothiazole pharmacophore, in the present study, we described the synthesis, structural elucidation, and anti-tubercular screening of a series of novel benzothiazole (BNTZ) derivatives (BNTZ 1–7 and BNTZ 8–13). Objective: The study aims to carry out the development of benzothiazole based anti-TB compounds. Methods: Title compounds are synthesized by microwave method and purified by column chromatography. Characterization of the compounds is achieved by FT-IR, NMR (1H and 13C), LCMS and elemental analysis. Screening of test compounds for anti-TB activity is achieved by Resazurin Microplate Assay (REMA) Plate method. Results: It was noted that the BNTZ compound with an isoquinoline nucleus (BNTZ 9) exhibited remarkable anti-tubercular activity at 8 μg/mL against both the susceptible strain H37Rv and the multi-drug resistant tuberculosis strains of Mycobacterium tuberculosis. On the other hand, the BNTZ compound with a naphthalene nucleus (BNTZ 2) revealed anti-tubercular activity at 6 μg/mL and 11 μg/mL against both the susceptible strain H37Rv and the multi-drug resistant tuberculosis strains of M. tuberculosis, respectively. One of the selected BNTZ derivatives BNTZ 13 was used for single crystal X-ray studies. Conclusion: To identify the appropriate target for potent BNTZ compounds from the series, molecular modeling studies revealed the multiple strong binding of several BNTZs with mycobacterium lysine-ε-aminotransferase and decaprenyl-phosphoryl-β-D-ribose 2'-oxidase. The interaction is derived by forming favorable hydrogen bonds and stacking interactions. This new class of BNTZ compounds gave promising anti-tubercular actions in the low micromolar range, and can be further optimized on a structural basis to develop promising, novel, BNTZ pharmacophore-based anti-tubercular drugs.