Nano-sized formazan analogues: Synthesis, structure elucidation, antimicrobial activity and docking study for COVID-19.

Three series of nanosized-formazan analogues were synthesized from the reaction of dithiazone with various types of α-haloketones (ester and acetyl substituted hydrazonoyl chlorides and phenacyl bromides) in sodium ethoxide solution. The structure and the crystal size of the new synthesized derivatives were assured based on the spectral analyses, XRD and SEM data. The antibacterial and antifungal activities were evaluated by agar diffusion technique. The results showed mild to moderate antibacterial activities and moderate to potent antifungal activities. Significant antifungal activities were observed for four derivatives 3a, 3d, 5a and 5g on the pathogenic fungal strains; Aspergillus flavus and Candida albicans with inhibition zone ranging from 16 to 20 mm. Molecular docking simulations of the synthesized compounds into leucyl-tRNA synthetase editing domain of Candida albicans suggested that most formazan analogues can fit deeply forming stable complexes in the active site. Furthermore, we utilized the docking approach to examine the potential of these compounds to inhibit SARS-CoV-2 3CLpro. The results were very promising verifying these formazan analogues as a hopeful antiviral agents.

Synthesis, Molecular Docking Screening and Anti-Proliferative Potency Evaluation of Some New Imidazo[2,1-b]Thiazole Linked Thiadiazole Conjugates.

BACKGROUND: Imidazo[2,1-b]thiazole scaffolds were reported to possess various pharmaceutical activities. RESULTS: The novel compound named methyl-2-(1-(3-methyl-6-(p-tolyl)imidazo[2,1-b]thiazol-2-yl)ethylidene)hydrazine-1-carbodithioate 3 acted as a predecessor molecule for the synthesis of new thiadiazole derivatives incorporating imidazo[2,1-b]thiazole moiety. The reaction of 3 with the appropriate hydrazonoyl halide derivatives 4a-j and 7-9 had produced the respective 1,3,4-thiadiazole derivatives 6a-j and 10-12. The chemical composition of all the newly synthesized derivatives were confirmed by their microanalytical and spectral data (FT-IR, mass spectrometry, 1H-NMR and 13C-NMR). All the produced novel compounds were screened for their anti-proliferative efficacy on hepatic cancer cell lines (HepG2). In addition, a computational molecular docking study was carried out to determine the ability of the synthesized thiadiazole molecules to interact with active site of the target Glypican-3 protein (GPC-3). Moreover, the physiochemical properties of the synthesized compounds were derived to determine the viability of the compounds as drug candidates for hepatic cancer. CONCLUSION: All the tested compounds had exhibited good anti-proliferative efficacy against hepatic cancer cell lines. In addition, the molecular docking results showed strong binding interactions of the synthesized compounds with the target GPC-3 protein with lower energy scores. Thus, such novel compounds may act as promising candidates as drugs against hepatocellular carcinoma.

Synthesis, tautomeric structures, and antitumor activity of new perimidines.

New series of perimidine derivatives and fused perimidines were derived from the reaction of ketene aminals 1 and 2 with diazotized anilines or hydrazonoyl chlorides. In addition, 8,10-disubstituted-[1,2,4]triazolo[4,3-a]perimidines (20a-m) were prepared through the reaction of perimidine-2-thione (15) with hydrazonoyl chlorides. The structures of the newly synthesized compounds were established on the basis of spectral data and elemental analyses. Some products were investigated for their antitumor activities against the human breast cancer cell line MCF-7 and the liver carcinoma cell line HEPG-2, and the results of some derivatives showed promising activity.

Antiviral Activity of Pyrimidine Containing Compounds: Patent Review.

Viruses are still the most prevalent infectious pathogens on a worldwide scale, with many of them causing life-threatening illnesses in humans. Influenza viruses, because of their significant morbidity and mortality, continue to pose a major threat to human health. According to WHO statistics, seasonal influenza virus epidemics are predicted to cause over 2 million severe illness cases with high death rates yearly. The whole world has been suffering from the COVID-19 epidemic for two years and is still suffering so far, and the deaths from this virus have exceeded three million cases. Because the great majority of viral infections do not have a specific medication or vaccination, discovering novel medicines remains a vital task. This review covers reports in the patent literature from 1980 to the end of 2021 on the antiviral activities of pyrimidine moieties. The patent database, SciFinder, was used to locate patent applications. A large variety of pyrimidine molecules have been produced and tested for antiviral activity over the last decade. These molecules were reported to inhibit a wide range of viruses, including influenza virus, respiratory syncytial virus, rhinovirus, dengue virus, herpes virus, hepatitis B and C, and human immunodeficiency virus. The cytotoxicity of the developed pyrimidine derivatives was tested in almost all reported studies and the selectivity index was calculated to show the selectivity and safety of such molecules. From the remarkable activity of pyrimidine compounds as antivirals for several dangerous viruses, we expect that these derivatives will be used as potent drugs in the very near future.

Synthesis of New Thiazole Clubbed Imidazo[2,1-b]thiazole Hybrid as Antimycobacterial Agents.

AIMS: The study aims to synthesize bioactive hybrid pharmacophores (thiazole ring and imidazo[2,1-b]thiazole system) by incorporating them into one biological assessment molecular system. BACKGROUND: A literature survey revealed that various imidazo[2,1-b]thiazoles, thiazoles, and hydrazones have powerful antimycobacterial activity. OBJECTIVE: This study demonstrates the effectiveness of molecular hybridization and the scope for imidazo[2,1-b]thiazole-hydrazone-thiazoles to develop as promising antimycobacterial agents. METHODS: Several imidazo[2,1-b]thiazole-hydrazine-thiazoles 5a-g, 7a,b, 9a,b, 11a,b, 13, and 15a,b were generated using a molecular hybridization strategy and assessed against Mycobacterium tuberculosis (ATCC 25618) for their in vitro antituberculous activity. RESULTS: Derivative 7b (MIC = 0.98 µg/mL) has shown the most promising antimycobacterial activity among the series tested. Brief structure-activity relationship studies found that the thiazole of chlorophenyl or pyridine, or coumarin had a significant relation with the antimycobacterial activity. CONCLUSION: The promising antimycobacterial activity of compound 7b compared with the reference drug suggests that this compound may contribute as a lead compound in the search for new potential antimycobacterial agents.

Thiazole-Based Thiosemicarbazones: Synthesis, Cytotoxicity Evaluation and Molecular Docking Study.

INTRODUCTION: Hybrid drug design has developed as a prime method for the development of novel anticancer therapies that can theoretically solve much of the pharmacokinetic disadvantages of traditional anticancer drugs. Thus a number of studies have indicated that thiazole-thiophene hybrids and their bis derivatives have important anticancer activity. Mammalian Rab7b protein is a member of the Rab GTPase protein family that controls the trafficking from endosomes to the TGN. Alteration in the Rab7b expression is implicated in differentiation of malignant cells, causing cancer. METHODS: 1-(4-Methyl-2-(2-(1-(thiophen-2-yl) ethylidene) hydrazinyl) thiazol-5-yl) ethanone was used as building block for synthesis of novel series of 5-(1-(2-(thiazol-2-yl) hydrazono) ethyl) thiazole derivatives. The bioactivities of the synthesized compounds were evaluated with respect to their antitumor activities against MCF-7 tumor cells using MTT assay. Computer-aided docking protocol was performed to study the possible molecular interactions between the newly synthetic thiazole compounds and the active binding site of the target protein Rab7b. Moreover, the in silico prediction of adsorption, distribution, metabolism, excretion (ADME) and toxicity (T) properties of synthesized compounds were carried out using admetSAR tool. RESULTS: The results obtained showed that derivatives 9 and 11b have promising activity (IC50 = 14.6 ± 0.8 and 28.3 ± 1.5 µM, respectively) compared to Cisplatin (IC50 = 13.6 ± 0.9 µM). The molecular docking analysis reveals that the synthesized compounds are predicted to be fit into the binding site of the target Rab7b. In summary, the synthetic thiazole compounds 1-17 could be used as potent inhibitors as anticancer drugs. CONCLUSION: Promising anticancer activity of compounds 9 and 11 compared with cisplatin reference drug suggests that these ligands may contribute as lead compounds in search of new anticancer agents to combat chemo-resistance.

A New Reactive Ketenaminal: Synthesis, Coupling Reaction, Tautomeric Study, Docking and Antimicrobial Evaluation of the Products.

BACKGROUND: One of the most successful reagents used in the synthesis of the reactive enaminone is DMF-DMA, but it is very expensive with harmful effects on the human health and reacts with special compounds to generate the enaminone such as active methylene centers. AIM: In this article, we synthesized a new ketenaminal by simple method with inexpensive reagents (through desulfurization in diphenylether). METHODS: Thus, a novel reactive ketenaminal (enaminone) was synthesized from the desulfurization of 2-((2-(4-chlorophenyl)-2-oxoethyl)thio)-5,7-bis(4-methoxyphenyl)pyrido[2,3-d]pyrimidin- 4(3H)-one with diphenylether. The starting keteneaminal was coupled with diazotized anilines via the known coupling conditions to give a new series of 2-(4-chlorophenyl)-1-(2-(arylhydrazono)-2- oxoethyl)-5,7-bis(4-methoxy-phenyl)pyrido[2,3-d]pyrimidin-4(1H)-ones. RESULTS: The structures of the new compounds were elucidated based on their IR, 1H-NMR, 13CNMR, and Mass spectra. Moreover, the potency of these compounds as antimicrobial agents has been evaluated. The results showed that some of the products have high activity nearly equal to that of the used standard antibiotic. Additionally, the docking study was done to get the binding mode of the synthesized compounds with the binding site of the DHFR enzyme. The results of molecular docking of the synthesized arylhydrazono compounds are able to fit in DHFR binding site with binding energies ranging from -4.989 to -8.178 Kcal/mol. CONCLUSION: Our goal was achieved in this context by the synthesis of new ketenaminal from inexpensive reagents, which was utilized in the preparation of bioactive arylhydrazone derivatives.

Novel 2-indolinone thiazole hybrids as sunitinib analogues: Design, synthesis, and potent VEGFR-2 inhibition with potential anti-renal cancer activity.

Novel 2-indolinone thiazole hybrids were designed and synthesized as VEGFR-2 inhibitors based on sunitinib, an FDA-approved anticancer drug. The proposed structures of the prepared 2-indolinone thiazole hybrids were confirmed based on their spectral data and CHN analyses. The target compounds were screened in vitro for their anti-VEGFR-2 activity. All tested compounds exhibited a potent submicromolar inhibition of VEGFR-2 kinase with IC50 values ranging from 0.067 to 0.422 µM, relative to sunitinib reference drug (IC50 = 0.075 ± 0.002 µM). Compounds 5, 15a, 15b, 17, 19c displayed excellent VEGFR-2 inhibitory activity, comparable or nearly equipotent to sunitinib. Compound 13b stood out as the most potent against VEGFR-2 showing IC50 value of 0.067 ± 0.002 µM, lower than that of sunitinib. In addition, the most potent derivatives were assessed for their anticancer activity against two renal cancer cell lines. Compound 13b (IC50 = 3.9 ± 0.13 µM) was more potent than sunitinib (IC50 = 4.93 ± 0.16 µM) against CAKI-1 cell line. Moreover, thiazole 15b displayed excellent anticancer activity against CAKI-1 cell line (IC50 = 3.31 ± 0.11 µM), superior to that of sunitinib (IC50 = 4.93 ± 0.16 µM). Thiazole 15b was also equipotent to sunitinib (IC50 = 1.23 ± 0.04 µM) against A498 cell line. Besides, compound 15b revealed a safety profile much better than that of sunitinib against normal human renal cells. Furthermore, a docking study revealed a proper fitting of the most active compounds into the ATP binding site of VEGFR-2, rationalizing their potent anti-VEGFR-2 activity.

Indomethacin Analogs: Synthesis, Anti-inflammatory and Analgesic Activities of Indoline Derivatives.

BACKGROUND: Microwave assisted reactions offer a considerable advantages over conventional method reactions because the former results in substantial rate enhancement in a wide range of organic reactions. OBJECTIVE: we interested herein to prepare new anti-inflammatory and analgesic agents analogues to Indomethacin in short reaction time by using microwaves irradiation. METHOD: Synthesis of new hydrazonoindolines having thiazole moiety under microwave irradiation were achieved via the reaction of hydrazonoyl chlorides or halogenated active methylene derivatives with thiosemicarbazone derivatives. Also, the utility of the versatile indoline-2,3-dione derivatives in the design of new multifunctional building blocks using condensation with hydrazine derivatives was demonstrated. RESULTS: All products were formed in short reaction time and high yield. The information derived from the spectral data of the formed compounds was confirmed their structures. Also, the analgesic and antiinflammatory activities of the designed derivatives were screened and the results obtained indicated that six derivatives 4g, 9b, 4c, 10b, 4d and 11a revealed the highest anti-inflammatory and analgesic effects. CONCLUSION: we succeeded in this context to design and synthesis of new anti-inflammatory and analgesic agents analogues to Indomethacin in short reaction time and with high yield.