Letters in Drug Design & Discovery - Volume 17, Issue 2, 2020

Background: This paper reviews the research progress of pyrazoloquinazolines which widely used in the field of medicine and pesticide in recent years. Five types of pyrazoloquinazolines are introduced: pyrazolo [4,3-h]quinazolines, pyrazolo[1,5-c]quinazolines, pyrazolo[4,3-f]quinazolines, pyrazolo[1,5-a] quinazolines , pyrazolo[1,5-b]quinazolines, and their new progress in the synthesis methods and treatment of diseases. Methodology: The derivatives of pyrazoloquinazolines exhibit a wide range of pharmacological properties such as antibacterial, anticancer, antioxidants, anti-inflammatory, anti-diabetic, antiviral activities. Consequently, their syntheses have attracted significant interest. Various methodologies have been developed for the synthesis and functionalization of these class of compounds. Conclusion: In the present article, the relevant and recent advances in the field will be briefly covered.

Background: Mesalazine (5-aminosalicylic acid, 5-ASA) is a drug substance with an antiinflammatory activity, which is mainly used in the symptomatic treatment of diseases, such as Ulcerative Colitis, the Crohn's disease and the idiopathic inflammatory bowel disease. Mesalazine exerts its effect locally in the inflamed area of the intestine and not through systematic absorption, therefore the investigation of its release characteristics from solid pharmaceutical formulations is of great importance. Objective: The development of novel mesalazine modified release formulations with improved properties, regarding drug release in the gastrointestinal tract, by utilisation of the Design of Experiments (DoE) approach. Methods: D-optimal experimental design was applied. A Simplex Lattice mixture design was used for the development of suitable capsules containing 4 mini tablets and a D-optimal mixture design was used for compression-coated tablets, with the following characteristics: ≤10% release in 2 h, to minimize its degradation in the upper gastrointestinal tract, 20-40% release in 5 h for mesalazine administration in the small intestine, and quantitative release in 12 h for colonic delivery. The dissolution experiments were conducted in gastrointestinal-like fluids and pectinases to simulate the pectinolytic enzymes present in the colon. Results: The optimal compositions were reached via the desirability function, as a compromise to the different responses. The optimal solutions for both formulations led to colon-specific delivery of the active substance with minimal 5-ASA release in the upper gastrointestinal tract and appeared to conform with the pre-determined characteristics. Hard gelatin capsules, when filled with mini-tablets led to the aimed modified release profile, having sigmoidal characteristics and compression coated tablets led to colonic delivery. Conclusion: Two novel mesalazine formulations were developed with the desirable colonic release, by conducting a minimal number of experiments, as suggested by DoE experimental design.

Background: Perturbation of nucleic acids structures and confirmation by small molecules through intercalation binding is an intriguing application in anticancer therapy. The planar aromatic moiety of anticancer agents was inserted between DNA base pairs leading to change in the DNA structure and subsequent functional arrest. Objective: The final scaffold of the target compounds was annulated and linked to a benzotriazole ring. These new pharmacophoric features were examined as antiviral and anticancer agents against MCF7 and their effect on DNA damage was also assessed. Methods: A new series of fully substituted 2-oxopyridine/2-thioxopyridine derivatives tethered to a benzotriazole moiety (4a-h) was synthesized through Michael cyclization of synthesized α,β- unsaturated compounds (3a-e) with appropriate active methylene derivatives. The DNA damage study was assessed by comet assay. In silico DNA molecular docking was performed using Open Eye software to corroborate the experimental results and to understand molecule interaction at the atomic level. Results: The highest DNA damage was observed in Doxorubicin, followed by 4h, then, 4b, 4g, 4f, 4e, and 4d. The docking study showed that compound 4h formed Hydrogen Bonds (HBs) as a standard ligand with GSK-3. Compound 4h was the most active compound against rotavirus Wa, HAVHM175, and HSV strains with a reduction of 30%, 40%, and 70%, respectively. Conclusion: Compound 4h was the most active compound and could act as a prospective lead molecule for anticancer agent.

Background: Grindstone technique has been widely used as an efficient, consistent, more environmentally benign, solvent-free protocol for the preparation of many compounds with higher atom economy. Methods: A series of fourteen piperonal chalcone compounds were synthesized by this method and characterized by physical and spectral data (FT-IR, 1H NMR, Mass and elemental analysis). All chalcones were evaluated for their cytotoxic action against the cancer cell lines, MCF-7 and HepG2. One 2-pyridyl-substituted compound 14 with IC50 values 17.4±0.2 towards MCF-7 and 15.4±0.6μmol L-1 towards HepG2 cells. Results: The results demonstrated that the cytotoxic activity of 2-pyridyl-substituted compound shown higher activity as compared with the standard cisplatin towards HepG2 cells. Conclusion: Compound 14 showed good antioxidant activities in the DPPH test and H2O2 assay (IC50 = 17.23± 33/μg/mL and 20.17± 0.33μg/mL) when compared with the standard ascorbic acid (IC50=μg/mL 18.26 ± 0.22and 21.66± 1.06 μg/mL).

Background: Oxadiazole emerged as an important class of heterocyclic compound with diverse biological activities like anticancer, antitubercular, anticonvulsant, anti-tubulin, antimicrobial, anti-inflammatory, antioxidant etc. Objective: The objective of this study is to synthesis series of twelve substituted N-[(1,3,4-oxadiazol-2- yl)methyl]benzamines (6a-l) and their evaluation as antiproliferative and antioxidant agents. Methods: The substituted N-[(1,3,4-oxadiazol-2-yl)methyl]benzamines (6a-l) analogues were synthesized as per the reported procedure. The antiproliferative activity was tested against nine different panels cancer cell lines (leukemia, colon, renal, non-small cell lung, breast, CNS, melanoma, prostate, and ovarian cancer) at 10 μM drug concentrations as per the NCI US Protocol. Results: 2-(5-((3-Chloro-4-fluorophenylamino)methyl)-1,3,4-oxadiazol-2-yl)phenol (6e) revealed the significant antiproliferative activity among the series of title compounds (6a-l). The compound, 6e showed maximum sensitivity towards CCRF-CEM, MCF-7, MOLT-4, T-47D, and SR cell lines with percent growth inhibitions (%GIs) of 79.92, 56.67, 39.62, 34.71 and 33.35, respectively. Furthermore, the compounds, 6e and 6c showed promising antioxidant activity with an IC50 value of 15.09 and 19.02 μM, respectively in DPPH free radicals (FR) scavenging activity. Conclusion: The present study may support a significant value in cancer drug discovery programme.

Background: Cardiac troponin I-interacting kinase (TNNI3K) is a cardiac-specific kinase that belongs to MAPKKK family. It is a dual-function kinase with tyrosine and serine/threonine kinase activity. Over-expression of TNNI3K results in various cardiovascular diseases such as cardiomyopathy, ischemia/reperfusion injury, heart failure, etc. Since, it is a cardiac-specific kinase and expressed only in heart tissue, it is an ideal molecular target to treat cardiac diseases. The main objective of the work is to study and understand the structure-activity relationship of the reported deazapurine derivatives and to use the 3D-QSAR and docking results to design potent and novel TNNI3K inhibitors of this series. Methods: In the present study, we have used molecular docking 3D QSAR, and molecular dynamics simulation to understand the structure-activity correlation of reported TNNI3K inhibitors and to design novel compounds of deazapurine derivatives with increased activity. Results: Both CoMFA (q2=0.669, NOC=5, r2=0.944) and CoMSIA (q2=0.783, NOC=5, r2=0.965) have resulted in satisfactory models. The models were validated using external test set, Leave-out- Five, bootstrapping, progressive scrambling, and rm2 metrics calculations. The validation procedures showed the developed models were robust and reliable. The docking results and the contour maps analysis helped in the better understanding of the structure-activity relationship. Conclusion: This is the first report on 3D-QSAR modeling studies of TNNI3K inhibitors. Both docking and MD results were consistent and showed good correlation with the previous experimental data. Based on the information obtained from contour maps, 31 novel TNNI3K inhibitors were designed. These designed compounds showed higher activity than the existing dataset compounds.

Background: Azole antifungals are among the first-line drugs clinically used for the treatment of systemic candidiasis, a deadly type of fungal infection that threatens mostly immunecompromised and hospitalized patients. Some azole derivatives were also reported to have antiproliferative effects on cancer cells. Objective: In this study, 1-(4-trifluoromethylphenyl)-2-(1H-imidazol-1-yl)ethanone (3), its oxime (4), and a series of its novel oxime ester derivatives (5a-v) were synthesized and tested for their in vitro antimicrobial activities against certain ATCC standard strains of Candida sp. fungi and bacteria. The compounds were also tested for their cytotoxic effects against mouse fibroblast and human neuroblastoma cell lines. Molecular modeling studies were performed to provide insights into their possible mechanisms for antifungal and antibacterial actions. Methods: The compounds were synthesized by the reaction of various oximes with acyl chlorides. Antimicrobial activity of the compounds was determined according to the broth microdilution method. For the determination of cytotoxic effect, we used MTS assay. Molecular docking and QM/MM studies were performed to predict the binding mechanisms of the active compounds in the catalytic site of C. albicans CYP51 (CACYP51) and S. aureus flavohemoglobin (SAFH), the latter of which was created via homology modeling. Results: 5d, 5l, and 5t showed moderate antifungal activity against C. albicans, while 3, 5c, and 5r showed significant antibacterial activity against Staphylococcus aureus and Pseudomonas aeruginosa. Most of the compounds showed approximately 40-50% inhibition against the human neuroblastoma cells at 100 μM. In this line, 3 was the most potent with an IC50 value of 82.18 μM followed by 5a, 5o, and 5t. 3 and 5a were highly selective to the neuroblastoma cells. Molecular modelling results supported the hypothesis that our compounds were inhibitors of CAYP51 and SAFH. Conclusion: This study supports that oxime ester derivatives may be used for the development of new antimicrobial and cytotoxic agents.

Background: Untargeted studies led to the development of some pyrazolopyridine derivatives for the antiparasitic profile, particularly the derivatives containing the structural carbohydrazide subunit. In this work, we proceeded in the biological screening of 27 N’- (substitutedphenylmethylene)- 4-carbohydrazide-3-methyl-1-phenyl-1H-pyrazolo[3, 4-b]pyridine derivatives against T. cruzi as well as the cytotoxic evaluation. To obtain more information about the trypanocidal activity of this class of compounds, we carried out molecular docking simulations to get an insight into putative targets in T. cruzi. Methods: The assays were evaluated against both trypomastigote and amastigote forms of T. cruzi and cytotoxicity assays on LLCMK2 cells. The predominant conformational compounds were analyzed and molecular docking simulations performed. Results: The results from trypanocidal activity screening of this series showed that just the compounds with phenyl group at C-6 position exhibited activity and the N’-4-hydroxyphenylmethylene derivative presented the best profile against both trypomastigote and amastigote forms of T. cruzi. Docking simulation results showed that this compound has a binding affinity with both CYP51 and cruzain targets of T. cruzi. Conclusion: Our results indicate that the hydroxyl substituent at the N’-substituted-phenylmethylene moiety and the phenyl ring at C-6 of 1H-pyrazolo[3,4-b]pyridine system are relevant for the trypanocidal activity of this class of compounds. Also, docking simulations showed that activity presented can be related to more than one target of the parasite.

Background: Protoporphyrinogen oxidase (PPO, EC 1.3.3.4) is a key enzyme in the biosynthesis of chlorophyll and heme, also the target of different types of herbicides. Thiazole compounds shown excellent biological activity, can be designed by using active groups docking for new PPO inhibitors. Objective: The objective of this study was to synthsize a series of aryl thiazole compounds as PPO inhibitors. Methods: In this study, a series of aryl thiazole compounds derivatives 11a-l were obtained from 2- chloro-5-nitrobenzoic acid as the starting material via esterification, Iron powder reduction, diazotization, Hantzsch reaction and final acylation. All synthesized compounds have been tested for their herbicidal activities as a PPO inhibitors. Results: The Petri dish test indicated that all compounds exhibited good herbicidal activities at 200 mg/L using culture dish. And the post-emergence tests showed that at 150g.ai/ha on weed stem leaf spray treatment, some of the title compounds exhibited 80% inhibition rate against the dicotyledonou weeds Amaranthus retroflexus and Eclipta prostrate. Conclusion: Good activity was noted for some compounds that compounds 11a, 11b, 11c, 11g, 11h had 80% inhibition on stems and leaves of Amaranthus retroflexus at 150g.ai/ha.

Background: According to WHO, the 50 million people worldwide are suffering from epilepsy, making it one of the most common neurological diseases globally. Epilepsy is often characterized by neurobiological, cognitive, psychological and behavioral changes and that may enhance the susceptibility to seizures and affect the quality of life. Objectives: The aim of the present work was to develop 2, 3 disubstituted 4-(3H)-quinazolinone derivatives in order to find an effective and highly lipophilic compound with lesser side effects and to evaluate them for anticonvulsant and neurotoxic activity. Methods: A novel series of 3-{4-[2-amino-4-(substitutedphenyl)-2H-[1.3] oxazin/thiazin-6-yl} 2- phenyl-3H-quinazolin-4-one derivatives were synthesized and evaluated for their anticonvulsant activity. The structures of the compound have been confirmed by spectral analysis. The molecular docking study was performed for finding the binding affinity with GABAA receptor in order to rationalize their anticonvulsant activities in a qualitative way. Quantitative estimate of drug-likeness was also performed which calculate the molecular properties and screen the molecules based on drug-likeness rules. Anticonvulsant activities of synthesized compounds were done by using (Maximal electroshock) MES induced seizures and subcutaneous pentylenetetrazole (scPTZ) induced seizure models in Wistar rats of either sex. None of the compounds demonstrated any sign of neurotoxicity. Results: Compounds 3-{4-[2-amino-4-(fluorophenyl)-2H- [1, 3] oxazin-6-yl} 2-phenyl-3H quinazolin-4-one (5i) and 3-{4-[2-amino-4-(fluorophenyl)-2H- [1, 3] thiazin -6-yl} 2-phenyl-3H quinazolin-4-one (5n) have shown significant activity against tonic seizure by the MES model and clonic seizure by scPTZ induced seizure model. Conclusion: These ten novels synthesized compounds had significant anticonvulsant activity. As a result, the compound (5i) and (5n) emerged out as the pilot molecule with a better anticonvulsant activity without any neurotoxicity, while the other compounds have moderate activity. QED analysis of compounds (5i) and (5n) also indicated that these compounds will have good oral absorption. The proposed work is to make efforts towards the development and identification of novel molecules as anticonvulsant agents by the synthesis of some novel quinazolinone derivatives with improved biological activity.

Background: Nitro-derivatives of heterocyclic compounds were used as active agents against pathogenic microorganisms. A set of 4- and 5-nitroimidazole derivatives exhibiting antimicrobial activity was analyzed with the use of Quantitative Structure-Activity Relationships (QSAR) method. The study included compounds used both in documented treatment and those described as experimental. Objective: The purpose of this study was to demonstrate the common and differentiating characteristics of the above-mentioned chemical compounds alike physicochemically as well as pharmacologically based on the quantum chemical calculations and microbiological activity data. Methods: During the study PCA and MLR analysis were performed, as the types of proposed chemometric approach. The semi-empirical and ab initio level of in silico molecular modeling was performed for calculations of molecular descriptors. Results: QSAR models were proposed based on chosen descriptors. The relationship between the nitro-derivatives structure and microbiological activity data was able to class and describe the antimicrobial activity with the use of statistically significant molecular descriptors. Conclusion: The applied chemometric approaches revealed the influential features of the tested structures responsible for the antimicrobial activity of studied nitro-derivatives.