New Phenylthiazoles: Design, Synthesis, and Biological Evaluation as Antibacterial, Antifungal, and Anti-COVID-19 Candidates.

The combination of antibacterial and antiviral agents is becoming a very important aspect of dealing with resistant bacterial and viral infections. The N-phenylthiazole scaffold was found to possess significant anti-MRSA, antifungal, and anti-COVID-19 activities as previously published; hence, a slight refinement was proposed to attach various alkyne lipophilic tails to this promising scaffold, to investigate their effects on the antimicrobial activity of the newly synthesized compounds and to provide a valuable structure-activity relationship. Phenylthiazole 4 m exhibited the most potent anti-MRSA activity with 8 µg/mL MIC value. Compounds 4 k and 4 m demonstrated potent activity against Clostridium difficile with MIC values of 2 µg/mL and moderate activity against Candida albicans with MIC value of 4 µg/mL. When analyzed for their anti-COVID-19 inhibitory effect, compound 4 b emerged with IC50 =1269 nM and the highest selectivity of 138.86 and this was supported by its binding score of -5.21 kcal mol-1 when docked against SARS-CoV-2 M pro . Two H-bonds were formed, one with His164 and the other with Met49 stabilizing phenylthiazole derivative 4 b, inside the binding pocket. Additionally, it created two arene-H bonds with Asn142 and Glu166, through the phenylthiazole scaffold and one arene-H bond with Leu141 via the phenyl ring of the lipophilic tail.

The Anti-MRSA Activity of Phenylthiazoles: A Comprehensive Review.

Antimicrobial resistance is an aggravating global issue therefore it has been under extensive research in an attempt to reduce the number of antibiotics that are constantly reported as obsolete jeopardizing the lives of millions worldwide. Thiazoles possess a reputation as one of the most diverse biologically active nuclei, and phenylthiazoles are no less exceptional with an assorted array of biological activities such as anthelmintic, insecticidal, antimicrobial, antibacterial, and antifungal activity. Recently phenyl thiazoles came under the spotlight as a scaffold having strong potential as an anti-MRSA lead compound. It is a prominent pharmacophore in designing and synthesizing new compounds with antibacterial activity against multidrug-resistant bacteria such as MRSA, which is categorized as a serious threat pathogen, that exhibited concomitant resistance to most of the first-line antibiotics. MRSA has been associated with soft tissue and skin infections resulting in high death rates, rapid dissemination, and loss of millions of dollars of additional health care costs. In this brief review, we have focused on the advances of phenylthiazole derivatives as potential anti-MRSA from 2014 to 2021. The review encompasses the effect on biological activity due to combining this molecule with various synthetic pharmacophores. The physicochemical aspects were correlated with the pharmacokinetic properties of the reviewed compounds to reach a structure-activity relationship profile. Lead optimization of phenyl thiazole derivatives has additionally been outlined where the lipophilicity of the compounds was balanced with the metabolic stability and oral solubility to aid the researchers in medicinal chemistry, design, and synthesizing effective anti- MRSA phenylthiazoles in the future.

Development of Semisynthetic Apoptosis-Inducing Agents Based on Natural Phenolic Acids Scaffold: Design, Synthesis and In-Vitro Biological Evaluation.

A crucial target in drug research is magnifying efficacy and decreasing toxicity. Therefore, using natural active constituents as precursors will enhance both safety and biological activities. Despite having many pharmacological activities, caffeic and ferulic acids showed limited clinical usage due to their poor bioavailability and fast elimination. Therefore, semisynthetic compounds from these two acids were prepared and screened as anticancer agents. In this study, CA and FA showed very potent anticancer activity against Caco-2 cells. Consequently, eighteen derivatives were tested against the same cell line. Four potent candidates were selected for determination of the selectivity index, where compound 10 revealed a high safety margin. Compound 10 represented a new scaffold and showed significant cytotoxic activity against Caco-2. Cell-cycle analysis and evaluation of apoptosis showed that derivatives 10, 7, 11, 15 and 14 showed the highest proportion of cells in a late apoptotic stage.

Evaluation of N-phenyl-2-aminothiazoles for treatment of multi-drug resistant and intracellular Staphylococcus aureus infections.

The increasing emergence of antibiotic-resistant bacterial pathogens calls for additional urgency in the development of new antibacterial candidates. N-Phenyl-2-aminothiazoles are promising candidates that possess potent anti-MRSA activity and could potentially replenish the MRSA antibiotic pipeline. The initial screen of a series of compounds in this novel class against several bacterial strains revealed that the aminoguanidine analogues possessed promising activities and superior safety profiles. The determined MICs of these compounds were comparable to, if not better than, those of the control drugs (linezolid and vancomycin). Remarkably, compounds 3a, 3b, and 3e possessed potent activities against multidrug resistant staphylococcal isolates and several clinically important pathogens, such as vancomycin-resistant enterococci (VRE) and Streptococcus pneumoniae. In addition, the compounds were superior to vancomycin in the rapid killing of MRSA and the longer post-antibiotic effects. Furthermore, low concentrations of compounds 3a, 3b, and 3e reduced the intracellular burden of MRSA by greater than 90%. Initial in vitro PK/toxicity assessments revealed that compound 3e was highly tolerable and possessed a low metabolic clearance rate and a highly acceptable half-life.

Synthesis, anticancer activity and effects on cell cycle profile and apoptosis of novel thieno[2,3-d]pyrimidine and thieno[3,2-e] triazolo[4,3-c]pyrimidine derivatives.

Motivated by the widely reported anticancer activity of thieno[2,3-d]pyrimidines a series of 24 new 2-substitutedhexahydrocycloocta[4,5] thieno[2,3-d]pyrimidines with different substituents at C-4 position and hexahydrocycloocta[4,5]thieno[3,2-e]-1,2,4-triazolo[4,3-c]pyrimidines were synthesized. The anticancer activity of 17 compounds were evaluated by National Cancer Institute (USA) using a two stage process utilizing 59 different human tumor cell lines representing leukemia, melanoma, cancers of lung, colon, central nervous system (CNS), ovary, kidney, prostate as well as breast. Compound 9c showed broad spectrum potent anticancer activity in nano molar to micro molar range against 56 human tumor cell lines with GI50 less than 10 µM ranging from 0.495 to 5.57 µM, also it is worth mentioning that compound 9c had the marked highest selectivity against the two cell lines T-47D and MDA-MB-468 belonging to breast cancer with GI50 = 0.495 and 0.568 µM respectively, and its effect was further studied on cell cycle progression and induction of apoptosis in the MDA-MB-468 cell line. Results showed that compound 9c induced cell cycle arrest at G2/M phase and also, showed accumulation of cells in pre-G1 phase which may result from, degradation or fragmentation of the genetic materials indicating a possible role of apoptosis in compound 9c-induced cancer cell death and cytotoxicity and verifying this compound as promising selective anticancer lead. Compound 6c was selective against K-562, SR and MOLT-4 cell lines belonging to leukemia showing growth inhibition percentages 86.38, 65.76 and 60.40 at a single dose test, at the same time it showed lethal activity against HOP-92 representing non-small cell lung cancer. Interestingly, leukemia SR, CNS cancer SNB-75 and renal cancer UO-31 cell lines proved to be sensitive to compound 6d with growth inhibition percentages 52.86, 50.94 and 53.99 respectively. Additionally, compound 6d demonstrated lethal activity to HOP-92 belonging non-small cell lung cancer.