Promising Antibacterial and Antifungal Agents Based on Thiolated Vitamin K3 Analogs: Synthesis, Bioevaluation, Molecular Docking

Abstract

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.

New Insights into the Structural Requirements of Isatin-derived Pro-apoptotic Agents against Acute Myeloid Leukemia

“…The 3D X-ray crystal structure of ERK2 co-crystalized with SCH772984 was downloaded from the protein data bank, PDB, (PDB ID: 6GDM). Docking of the target ligands as a conformations database was performed inside SCH772984 binding site using MOE 2019 as described before [58,59]. A scoring function, London dG, was employed for comparison of different conformers, poses with lower values are more beneficial.…”

Analysis of Quinolinequinone Analogs with Promising Cytotoxic Activity against Breast Cancer

“…[39] In our previous studies, our group has introduced to the literature the aminated and/or thiolated lead structures as anticancer and/or antibacterial agents based on 1,4-quinone scaffolds, also named as Plastoquinone and quinolinequinone analogs. [40][41][42][43][44] Encouraged by all these good results and in continuation of our studies on the generation of new lead structures, we herein undertake to carry out extensive studies aiming at the identification of new lead molecules for the treatment of cancer. Five target quinolinequinones containing electron-withdrawing groups were synthesized and submitted to the National Cancer Institute of Bethesda within the Developmental Therapeutics Program [45] with the protocol of the Drug Evaluation Branch, NCI [46] to be tested at a single-dose concentration of 10 μM on nine different cancer types including leukemia, lung, colon, CNS, melanoma, ovarian, renal, prostate, and breast cancer cell lines.…”

“…In our previous studies, our group has introduced to the literature the aminated and/or thiolated lead structures as anticancer and/or antibacterial agents based on 1,4‐quinone scaffolds, also named as Plastoquinone and quinolinequinone analogs [40–44] . Encouraged by all these good results and in continuation of our studies on the generation of new lead structures, we herein undertake to carry out extensive studies aiming at the identification of new lead molecules for the treatment of cancer.…”

Aminated Quinolinequinones as Privileged Scaffolds for Antibacterial Agents: Synthesis, In Vitro Evaluation, and Putative Mode of Action

“…In the past 10 years or so, we have been developing potential drug candidates in our laboratory to fight cancer and antimicrobial resistance and have primarily modified a 1,4-quinone moiety with different side groups to find out the structure–activity relationships (SARs) around this moiety as shown in Figure . − The insertion of primary or secondary amines and/or aromatic/alkyl chain thiols into the 1,4-quinone moiety is our primary goal. Besides, we have also tuned the biological activity of quinones through the modification of this moiety, fused with benzene named as naphthoquinone analogues (vitamin K analogues), or fused with pyridine named as quinolinequinone analogues, ,, or attached to the dimethoxy groups named as Coenzyme Q analogues, or attached to the dimethyl groups named as Plastoquinone analogues. , Our initial structure–activity relationship (SAR) studies focused on exploring the effect of 1,4-quinone moiety, in addition to the type of amino moiety, the substituent(s) within amino moiety, and the type of halogen (bromine or chlorine atom) as the side chains. The antimicrobial activity and structures of these molecules are shown in Figure .…”

“… 13 − 15 The insertion of primary or secondary amines and/or aromatic/alkyl chain thiols into the 1,4-quinone moiety is our primary goal. Besides, we have also tuned the biological activity of quinones through the modification of this moiety, fused with benzene named as naphthoquinone analogues (vitamin K analogues), 16 or fused with pyridine named as quinolinequinone analogues, 13 , 17 , 18 or attached to the dimethoxy groups named as Coenzyme Q analogues, 19 or attached to the dimethyl groups named as Plastoquinone analogues. 14 , 20 Our initial structure–activity relationship (SAR) studies focused on exploring the effect of 1,4-quinone moiety, in addition to the type of amino moiety, the substituent(s) within amino moiety, and the type of halogen (bromine or chlorine atom) as the side chains.…”