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A series of 2-arylamino-3-chloro-1,4-naphthoquinone derivatives (3a–h) by the reaction of 2,3-dichloro-1,4-naphthoquinone with aryl amines (2a–h) and benzo[b]phenazine-6,11-dione derivatives (4a–c) by the treatment of 2-arylamino-3-chloro-1,4-naphthoquinone derivatives (3a–h) with sodium azide were synthesized and tested for their in vitro antibacterial and antifungal activities. The results suggest that compounds 3d and 3g had potent antifungal activity against Candida albicans (MIC = 78.12 μg/mL). All synthesized compounds (3a–h, 4a–c) possessed activity against E. faecalis with MIC values of between 312.5 and 1250 μg/mL. Benzo[b]phenazine-6,11-dione derivatives (4a–c) were mostly active against Gram-positive bacteria. The structures of the new members of the series were established on the basis of their spectral properties (IR, 1H NMR, 13C NMR, and mass spectrometry).

The evaluation of in vitro biological activity of several previously reported quinolinequinones (AQQ1–5) against 60 human cancer cell lines (NCI-60) used by the National Cancer Institute’s Developmental Therapeutics Program (DTP) contributed to our earlier research on possible anticancer and/or antibacterial agents. Of interest, NCI-60 screening revealed that two quinolinequinones (AQQ1 and AQQ2) significantly reduced the proliferation of several cancer genotypes. Following the administration of a single dose and five additional doses, all quinolinequinones demonstrated a significant inhibitory effect on the growth of leukemia and other cancer cell lines. Hence, a series of subsequent in vitro biological assessments were performed to further understand the mechanistic impact of the compounds. In MTT assays, it was found that AQQ1 and AQQ2 exhibited higher efficacy against DU-145 cells (IC50 4.18 µM and 4.17 µM, respectively) compared to MDA-MB-231 (IC50 8.27 and 13.33 µM, respectively) and HCT-116 cells (IC50 5.83 and 9.18 µM, respectively). Additionally, AQQ1 demonstrated greater activity in this context. Further investigations revealed that AQQ1 inhibited DU-145 cell growth and migration dose-dependently. Remarkably, arrest of the DU-145 cell cycle at G0/G1 phase and ROS elevation were observed. Pharmacokinetic (PK) studies revealed that AQQ1 has better PK parameters than AQQ2 with %F of 9.83 in rat. Considering the data obtained with human liver microsomal stability studies, AQQ1 should have a better PK profile in human subjects. In silico studies (molecular dynamics) with three kinases (CDK2, CDK4, and MAPK) leading to cell cycle arrest at G0/G1 identified MAPK as a probable target for AQQ1. Taken together, our results showed that AQQ1 could be a potential chemotherapeutic lead molecule for prostate cancer.

The development of new anticancer drugs is still ongoing as a solution to the unsatisfactory results obtained by chemotherapy patients. Our previous studies on natural product-based anticancer agents led us to synthesize a new series of Plastoquinone (PQ) analogs and study their anticancer effects. Four members of PQ analogs (PQ1–4) were designed based on the scaffold hopping strategy; the design was later completed with structural modification. The obtained PQ analogs were synthesized and biologically evaluated against different cancer genotypes according to NCI-60 screening in vitro. According to the NCI results, bromo and iodo-substituted PQ analogs (PQ2 and PQ3) showed remarkable anticancer activities with a wide-spectrum profile. Among the two selected analogs (PQ2 and PQ3), PQ2 showed promising anticancer activity, in particular against leukemia cell lines, at both single- and five-dose NCI screenings. This compound was also detected by MTT assay to reveal significant selectivity between Jurkat cells and PBMC (healthy) compared to imatinib. Further in silico studies indicated that PQ2 was able to occupy the ATP-binding cleft of Abl TK, one of the main targets of leukemia, through key interactions similar to dasatinib and imatinib. PQ2 is also bound to the minor groove of the double helix of DNA. Based on computational pharmacokinetic studies, PQ2 possessed a remarkable drug-like profile, making it a potential anti-leukemia drug candidate for future studies.

Colorectal cancer (CRC), breast cancer, and chronic myeloid leukemia (CML) are life-threatening malignancies worldwide. Although potent therapeutic and screening strategies have been developed so far, these cancer types are still major public health problems. Therefore, the exploration of more potent and selective new agents is urgently required for the treatment of these cancers. Quinones represent one of the most important structures in anticancer drug discovery. We have previously identified a series of quinone-based compounds (ABQ-1-17) as anti-CML agents. In the current work, ABQ-3 was taken to the National Cancer Institute (NCI) for screening to determine its in vitro antiproliferative effects against a large panel of human tumor cell lines at five doses. ABQ-3 revealed significant growth inhibition against HCT-116 CRC and MCF-7 breast cancer cells with 2.00 µM and 2.35 µM GI50 values, respectively. The MTT test also showed that ABQ-3 possessed anticancer effects towards HCT-116 and MCF-7 cells with IC50 values of 5.22 ± 2.41 μM and 7.46 ± 2.76 μM, respectively. Further experiments indicated that ABQ-3 induced apoptosis in both cell lines, and molecular docking studies explicitly suggested that ABQ-3 exhibited DNA binding in a similar fashion to previously reported compounds. Based on in silico pharmacokinetic prediction, ABQ-3 might display drug-like features enabling this compound to become a lead molecule for future studies.

Quinolinequinones, which are bicyclic heterocycles and quinone derivatives due to their broad range of biological activities, which include strong antifungal, antibacterial, antimalarial, and anticancer, have long been the subject of numerous investigations. After successful synthesis and characterization of aminated quinolinequinones (AQQ) and antimicrobial evaluation by our group, compounds were subjected to the NCI-60 Human Tumor Cell Lines Screen to determine anticancer activity. According to the NCI report, we further investigated the cytotoxic effects of selected compounds, AQQ6 and AQQ9, on the growth of DU-145 prostate cancer, MDA-MB-231 breast cancer, and HCT-116 colon cancer lines after 24 h treatment by MTT assay at 1–100 μM concentrations. HUVEC human umbilical vein endothelial cells were used as a non-cancerous cell line to determine the cancer selectivity of the compounds. Doxorubicin was used as a positive control drug. AQQ6 was more cytotoxic than AQQ9 and showed good cytotoxicity against DU-145 prostate cancer cells. Then, molecular pathways related to the cytotoxic effects of AQQ6 were investigated with analysis of cell cycle distribution, measurements of cellular ROS levels, and apoptosis/necrosis rate with flow cytometry at 1, 2.5, and 5 μM AQQ6 concentrations. According to our findings, AQQ6 induces G0/G1 cell cycle arrest dose-dependently. Additionally, apoptotic and necrotic cell populations significantly increased with 2.5 and 5 μM AQQ6 concentrations. AQQ6 did not affect cellular ROS levels. In conclusion, AQQ6 shows antiproliferative effects against DU-145 prostate cancer cells, which are mediated through cell cycle arrest and apoptotic and necrotic cell death. Potentially, AQQ6 can be a promising drug candidate for further anticancer research.

Microorganisms are responsible for hospital infections, and methicillin-resistant Staphylococcus aureus is one of them. In looking for the most effective lead structures to cope with the rise of antimicrobial (antibiotic) resistance, we evaluated the antimicrobial profile of quinolinequinones for potential antimicrobial applications. 1,4-quinone molecules fused with heteroatom have been studied extensively for many years as a source of drugs and lead structures. The aims of this study were to evaluate the antimicrobial activity of quinolinequinones against bacterial and fungal strains, and to probe for potential lead structures. For this reason, the activity of these compounds against three different strains of Candida fungi (C. albicans, C. parapsilosis, and C. tropicalis) and Gram-positive and Gram-negative pathogenic bacteria were investigated, searching for potential lead compounds. Five of nine quinolinequinones showed activity mainly against the Gram-positive strains with a minimal inhibitory concentration within the Clinical and Laboratory Standards Institute (CLSI) levels. The results revealed that quinolinequinones have significant activity against bacteria including Staphylococcus aureus and Staphylococcus epidermidis, and fungi including Candida albicans and Candida parapsilosis. QQ1, QQ2, QQ3, QQ5, and QQ6 exhibited the highest growth inhibition against two essential species of the Gram-positive strains (Staphylococcus epidermidis and Staphylococcus aureus). Among these, four molecules (QQ2, QQ3, QQ5, and QQ6) were also active against Enterococcus faecalis, the other member of the Gram-positive strains. The antifungal profile of two quinolinequinones (QQ7 and QQ8) indicated that they were as effective as the reference drug Clotrimazole against Candida albicans. The same molecules also have potential inhibitory antifungal activity against Candida tropicalis. For better understanding, the most active two quinolinequinones (QQ2 and QQ6) were examined for biofilm inhibition and a time-kill kinetic study.

The HIV-1 Gag protein binds to the host cell membrane and assembles into immature particles. Then, in the course of immature virion budding, activated protease cleaves Gag into its main components: MA, CA, NC, and p6 proteins. The highly basic residues of MA predominantly interact with the acidic head of phosphatidyl-inositol-4,5-bisphosphate (PI(4,5)P2) inserted into the membrane. Our research group developed L-Heptanoylphosphatidyl Inositol Pentakisphosphate (L-HIPPO) and previously confirmed that this compound bound to the MA more strongly than PI(4,5)P2 and inositol hexakisphosphate (IP6) did. Therefore, herein we rationally designed eight new L-HIPPO derivatives based on the fact that the most changeable parts of L-HIPPO were two acyl chains. After that, we employed molecular docking for eight compounds via Maestro software using high-resolution crystal structures of MA in complex with IP6 (PDB IDs: 7E1I, 7E1J, and 7E1K), which were recently elucidated by our research group. The most promising docking scores were obtained with benzene-inserted compounds. Thus, we generated a library containing 213 new aromatic group-inserted L-HIPPO derivatives and performed the same molecular docking procedure. According to the results, we determined the nine new L-HIPPO derivatives most effectively binding to the MA with the most favorable scoring functions and pharmacokinetic properties for further exploration.

Colorectal cancer (CRC) and breast cancer are leading causes of death globally, due to significant challenges in detection and management. The late-stage diagnosis and treatment failures require the discovery of potential anticancer agents to achieve a satisfactory therapeutic effect. We have previously reported a series of plastoquinone analogues to understand their cytotoxic profile. Among these derivatives, three of them (AQ-11, AQ-12, and AQ-15) were selected by the National Cancer Institute (NCI) to evaluate their in vitro antiproliferative activity against a panel of 60 human tumor cell lines. AQ-12 exhibited significant antiproliferative activity against HCT-116 CRC and MCF-7 breast cancer cells at a single dose and further five doses. MTT assay was also performed for AQ-12 at different concentrations against these two cells, implying that AQ-12 exerted notable cytotoxicity toward HCT-116 (IC50 = 5.11 ± 2.14 μM) and MCF-7 (IC50 = 6.06 ± 3.09 μM) cells in comparison with cisplatin (IC50 = 23.68 ± 6.81 μM and 19.67 ± 5.94 μM, respectively). This compound also augmented apoptosis in HCT-116 (62.30%) and MCF-7 (64.60%) cells comparable to cisplatin (67.30% and 78.80%, respectively). Molecular docking studies showed that AQ-12 bound to DNA, forming hydrogen bonding through the quinone scaffold. In silico pharmacokinetic determinants indicated that AQ-12 demonstrated drug-likeness with a remarkable pharmacokinetic profile for future mechanistic anti-CRC and anti-breast cancer activity studies.

Plastoquinone analogs are privileged structures among the known antiproliferative natural product-based compound families. Exploiting one of these analogs as a lead structure, we report the investigation of the brominated PQ analogs (BrPQ) in collaboration with the National Cancer Institute of Bethesda within the Developmental Therapeutics Program (DTP). These analogs exhibited growth inhibition in the micromolar range across leukemia, non-small cell lung cancer (EKVX, HOP-92, and NCI-H522), colon cancer (HCT-116, HOP-92), melanoma (LOX IMVI), and ovarian cancer (OVCAR-4) cell lines. One brominated PQ analog (BrPQ5) was selected for a full panel five-dose in vitro assay by the NCI’s Development Therapeutic Program (DTP) division to determine GI50, TGI, and LC50 parameters. The brominated PQ analog (BrPQ5) displayed remarkable activity against most tested cell lines, with GI50 values ranging from 1.55 to 4.41 µM. The designed molecules (BrPQ analogs) obeyed drug-likeness rules, displayed a favorable predictive Absorption, Distribution, Metabolism, and Excretion (ADME) profile, and an in silico simulation predicted a possible BrPQ5 interaction with proteasome catalytic subunits. Furthermore, the in vitro cytotoxic activity of BrPQ5 was assessed, and IC50 values for U-251 glioma, MCF-7 and MDA-MB-231 breast cancers, DU145 prostate cancer, HCT-116 colon cancer, and VHF93 fibroblast cell lines were evaluated using an MTT assay. MCF-7 was the most affected cell line, and the effects of BrPQ5 on cell proliferation, cell cycle, oxidative stress, apoptosis/necrosis induction, and proteasome activity were further investigated in MCF-7 cells. The in vitro assay results showed that BrPQ5 caused cytotoxicity in MCF-7 breast cancer cells via cell cycle arrest and oxidative stress induction. However, BrPQ5 did not inhibit the catalytic activity of the proteasome. These results provide valuable insights for further discovery of novel antiproliferative agents.

Two subseries of aminated quinolinequinones (AQQs, AQQ1–16) containing electron-withdrawing group (EWG) or electron-donating group (EDG) in aryl amine moiety were successfully synthesized. Antimicrobial activity assessment indicates that some of the AQQs (AQQ8–10 and AQQ12–14) with an EDG in aryl amine exhibited strong antibacterial activity against Gram-positive bacterial strains, including Staphylococcus aureus (ATCC® 29213) and Enterococcus faecalis (ATCC® 29212). In contrast, AQQ4 with an EWG in aryl amine displayed excellent antifungal activity against fungi Candida albicans (ATCC® 10231) with a MIC value of 1.22 μg/mL. To explore the mode of action, the selected AQQs (AQQ4 and AQQ9) were further evaluated in vitro to determine their antimicrobial activity against each of 20 clinically obtained resistant strains of Gram-positive bacteria by performing antibiofilm activity assay and time-kill curve assay. In addition, in silico studies were carried out to determine the possible mechanism of action observed in vitro. The data obtained from these experiments suggests that these molecules could be used to target pathogens in different modes of growth, such as planktonic and biofilm.

In the present study, we designed and synthesized thiolated VK3 analogs (VK3a–g) along with an extensive antimicrobial study. After the evaluation of the antibacterial and antifungal activity against various bacterial and fungal strains, we presented an initial structure–activity relationship study on these VK3 analogs. In particular, four thiolated VK3 analogs exhibited superior biological potency against some Gram-positive bacterial strains, including Staphylococcus aureus (ATCC® 29213) and Enterococcus faecalis (ATCC® 29212). Next, all thiolated VK3 analogs were evaluated for their potential of cell growth inhibition on the NCI-60 cancer cell lines panel. This screening underlined that the thiolated VK3 analogs have no visible cytotoxicity on different cancer cell lines. The selected two thiolated VK3 analogs (VK3a and VK3b), having minimal hemolytic activity, which also have the lowest MIC values on S. aureus and E. faecalis, were further evaluated for their inhibition capacities on biofilm formation after evaluating their potential in vitro antimicrobial activity against each of the 20 clinically obtained resistant strains of Staphylococcus aureus. VK3b showed excellent antimicrobial activity against clinically resistant S. aureus isolates. Furthermore, the tested molecules showed nearly two log10 reduction in the viable cell count at six hours according to the time kill curve studies. Although these molecules decreased biofilm attachment about 50%, when sub-MIC concentrations were used these molecules increased the percentage of biofilm formation. The molecular docking of VK3a and VK3b in S. aureus thymidylate kinase was conducted in order to predict their molecular interactions. VK3a and VK3b exhibited excellent lead-likeness properties and pharmacokinetic profiles that qualify them for further optimization and development. In conclusion, since investigating efficient novel antimicrobial molecules is quite difficult, these studies are of high importance, especially in the present era of antimicrobial resistance.

Plants have paved the way for the attainment of molecules with a wide-range of biological activities. However, plant products occasionally show low biological activities and/or poor pharmacokinetic properties. In that case, development of their derivatives as drugs from the plant world has been actively performed. As plant products, plastoquinones (PQs) have been of high importance in anticancer drug design and discovery; we have previously evaluated and reported the potential cytotoxic effects of a series of PQ analogs. Among these analogs, PQ2, PQ3 and PQ10 were selected for National Cancer Institute (NCI) for in vitro screening of anticancer activity against a wide range of cancer cell lines. The apparent superior anticancer potency of PQ2 on the HCT-116 colorectal cancer cell line than that of PQ3 and PQ10 compared to other tested cell lines has encouraged us to perform further mechanistic studies to enlighten the mode of anti-colorectal cancer action of PQ2. For this purpose, its apoptotic effects on the HCT-116 cell line, DNA binding capacity and several crucial pharmacokinetic properties were investigated. Initially, MTT assay was conducted for PQ2 at different concentrations against HCT-116 cells. Results indicated that PQ2 exhibited significant cytotoxicity in HCT-116 cells with an IC50 value of 4.97 ± 1.93 μM compared to cisplatin (IC50 = 26.65 ± 7.85 μM). Moreover, apoptotic effects of PQ2 on HCT-116 cells were investigated by the annexin V/ethidium homodimer III staining method and PQ2 significantly induced apoptosis in HCT-116 cells compared to cisplatin. Based on the potent DNA cleavage capacity of PQ2, molecular docking studies were conducted in the minor groove of the double helix of DNA and PQ2 presented a key hydrogen bonding through its methoxy moiety. Overall, both in vitro and in silico studies indicated that effective, orally bioavailable drug-like PQ2 attracted attention for colorectal cancer treatment. The most important point to emerge from this study is that appropriate derivatization of a plant product leads to unique biologically active compounds.