Novel tropane analogues as Hsp90 inhibitors targeting colon cancer: Synthesis, biological estimation, and molecular docking study.

New derivatives of tropane scaffold were prepared from the reaction of their thione or thioamide derivatives with α-halocarbonyl compounds. The structures of all new derivatives were assured and proved with their spectral data. The novel tropane derivatives were examined for their cytotoxicity on two colon tumor cell lines; Caco2 and HCT116 cells. The most active compounds 3, 4, 5, 9d and 14a displayed significant antitumor activities with IC50 range of 9.50 - 30.15 µM compared to doxorubicin. Moreover, they revealed reduced cytotoxic effect on WI-38 normal ones, signifying their great safety. With the aim of better understanding the inhibitory potential of such compounds on heat-shock protein 90 (Hsp90), there activities were assessed against such enzyme demonstrating high inhibitory activities with IC50 range of 56.58-78.85 nM. Western blotting was carried out to ensure the inhibitory activity on Hsp90, results showed that 3 markedly suppressed Hsp90 expression on Caco2 cell line. Additionally, a molecular docking analysis of the most potent derivatives at the Hsp90 binding site was carried out in order to approve the performed in vitro assays.

Novel 6,7,8-trihydrobenzo[6',7']cyclohepta[2',1'-e]pyrazolo[2,3-a]pyrimidine derivatives as Topo IIα inhibitors with potential cytotoxic activity.

Novel tetracyclic pyrazolo[1,5-a]pyrimidine derivatives; namely benzo[3,4]cyclohepta[1,2-e]pyrazolo[1,5-a]pyrimidin-2-amines 6a-e and benzo[3,4]cyclohepta[1,2-e]pyrazolo[1,5-a]pyrimidin-2(6H)-ones 15a-d, were designed and synthesized as topoisomerase IIα inhibitors with potential anticancer activity. The structure and their mechanistic pathway were discussed and confirmed based on spectral data and DFT calculations. Compounds 6a, 6c, 15b, 15c and 15d exhibited potent Topo II inhibitory activity at one-digit IC50 values (2.35 - 7.18 µM). Among the tested compounds, aminopyrazolopyrimidine derivatives 6a (IC50 = 3.44 µM) and 6c (IC50 = 2.35 µM) were comparable/ equipotent to Doxorubicin (IC50 = 2.71 µM) against Topo II. The most active compounds in Topo II assay were further investigated in vitro for their cytotoxic potential. The oxo-pyrazolopyrimidine derivative 15c; was the most potent possessing one-digit IC50 values (HCT116 IC50 = 2.32 ± 0.13 µM, MCF7 IC50 = 1.137 ± 0.06 µM). Compound 15c was two times more potent than Doxorubicin against MCF7 breast cancer cells. 15c exhibited a safety profile much better than that of Doxorubicin against non-cancerous cells. Compound 15c was also found to be a good apoptotic inducer. Moreover, docking result revealed well-fitting and proper orientation of 15c into Topo II-DNA complex.

Synthesis of a new series of pyrazolo[1,5-a]pyrimidines as CDK2 inhibitors and anti-leukemia.

Based on the structural study of previously known CDK2 inhibitors, a new series of pyrazolo[1,5-a]pyrimidine derivatives was designed and synthesized. The target compounds were biologically assessed as potent CDK2 inhibitors and promising anti-leukemia hits. The 7-(4-Bromo-phenyl)-3-(3-chloro/2-chloro-phenylazo)-pyrazolo[1,5-a]pyrimidin-2-ylamines 5 h and 5i revealed the best CDK2 inhibitory activity with comparable potency (IC50 = 22 and 24 nM, respectively) to that of dinaciclib (IC50 = 18 nM). Additionally, both analogues showed potent activities against CDK1, CDK5 and CDK9 at nanomolar concentrations (IC50 = 28-80 nM). The anti-leukemia screening of the target compounds showed strong to moderate cytotoxicity against the used leukemia cell lines (MOLT-4 and HL-60). Compound 5 h inhibited MOLT-4 and HL-60 by 1.4 and 2.3 folds (IC50 = 0.93 and 0.80 µM), respectively, compared to dinaciclib (IC50 = 1.30 and 1.84 µM). Furthermore, compound 5i was comparable to dinaciclib against MOLT-4 and exhibited twice its activity against HL-60. Besides, the cytotoxicity of the promising analogues on normal human blood cells indicated the safety of 5h and 5i as compared to the reference dinaciclib. The pharmacokinetic properties of 5h and 5i were predicted using ADME calculations revealing good oral bioavailability and high GI absorption. The molecular docking simulations indicated, as expected, that the dinaciclib analogues can well-accommodate the CDK2 binding site, forming a variety of interactions.

Synthesis and Antimicrobial Evaluation of Novel Pyrazolopyrimidines Incorporated with Mono- and Diphenylsulfonyl Groups.

A novel series of pyrazolo[1,5-a]pyrimidine ring systems containing phenylsulfonyl moiety have been synthesized via the reaction of 2-(phenylsulfonyl)-1-(4-(phenylsulfonyl) phenyl)ethan-1-one, 2-benzenesulfonyl-1-(4-benzenesulfonyl-phenyl)-3-dimethylamino-propenone and 3-(dimethylamino)-1-(4-(phenylsulfonyl)phenyl)prop-2-en-1-one each with various substituted aminoazopyrazole derivatives in one pot reaction strategy. The proposed structure as well as the mechanism of their reactions were discussed and proved with all possible spectral data. The results of antimicrobial activities of the new sulfone derivatives revealed that several derivatives showed activity exceeding the activity of reference drug. Contrary to expectations, we found that derivatives containing one sulfone group are more effective against all bacteria and fungi used than those contain two sulfone groups.

Design and Synthesis of New bis-oxindole and Spiro(triazole-oxindole) as CDK4 Inhibitors with Potent Anti-breast Cancer Activity.

BACKGROUND: Since CDKs have been demonstrated to be overexpressed in a wide spectrum of human malignancies, their inhibition has been cited as an effective technique for anticancer drug development. METHODS: In this context, new bis-oxindole/spiro-triazole-oxindole anti-breast cancer drugs with potential CDK4 inhibitory effects were produced in this work. The novel series of bis-oxindole/spirotriazole- oxindole were synthesized from the reaction of bis-oxindole with the aniline derivatives then followed by 1,3-dipolar cycloaddition of hydrazonoyl chloride. RESULTS: The structure of these bis-oxindole/spiro-triazole-oxindole series was proven based on their spectral analyses. Most bis-oxindole and bis-spiro-triazole-oxindole compounds effectively inhibited the growth of MCF-7 (IC50 = 2.81-17.61 µM) and MDA-MB-231 (IC50 = 3.23-7.98 µM) breast cancer cell lines with low inhibitory activity against normal WI-38 cells. While the reference doxorubicin showed IC50 values of 7.43 µM against MCF-7 and 5.71 µM against the MDA-MB-231 cell line. Additionally, compounds 3b, 3c, 6b, and 6d revealed significant anti-CDK4 activity (IC50 = 0.157- 0.618 µM) compared to palbociclib (IC50 = 0.071 µM). Subsequent mechanistic investigations demonstrated that 3c was able to trigger tumor cell death through the induction of apoptosis. Moreover, it stimulated cancer cell cycle arrest in the G1 phase. Furthermore, western blotting disclosed that the 3c-induced cell cycle arrest may be mediated through p21 upregulation. CONCLUSION: According to all of the findings, bis-oxindole 3c shows promise as a cancer treatment targeting CDK4.

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.

Anti-viral activity of thiazole derivatives: an updated patent review.

INTRODUCTION: Several viral infections cause life-threatening consequences in humans, making them the most serious public health concerns. Despite the fact that several antiviral medicines are available on the market, there is no full treatment for many important viral infections. To date, antiviral medicines have significantly reduced the spread of epidemics, but their continued use has resulted in the creation of drug-resistant variants throughout time. As a result, the development of new, safe, and efficient antiviral drugs is critical. AREAS COVERED: This review covered reports in the patent literature in the period 2014 to the first quarter of 2021 on the antiviral activities of thiazole derivatives. These molecules were reported to inhibit a wide range of viruses including influenza viruses, coronaviruses, herpes viruses, hepatitis B and C, bovine viral diarrhea virus, chikungunya virus and human immunodeficiency viruses. EXPERT OPINION: The most bioactive molecules can be used as lead structures for the development of new thiazole compounds with potent and selective antiviral activity. In addition, more efforts are needed to better understand the host-virus interactions for the discovery and development of new therapeutic agents and creative treatment strategies that are supposed to improve rates of clinical cure of the serious viruses.