Quinazoline-tethered hydrazone: A versatile scaffold toward dual anti-TB and EGFR inhibition activities in NSCLC.

Globally, lung cancer and tuberculosis are considered to be very serious and complex diseases. Evidence suggests that chronic infection with tuberculosis (TB) can often lead to lung tumors; therefore, developing drugs that target both diseases is of great clinical significance. In our study, we designed and synthesized a suite of 14 new quinazolinones (5a-n) and performed biological investigations of these compounds in Mycobacterium tuberculosis (MTB) and cancer cell lines. In addition, we conducted a molecular modeling study to determine the mechanism of action of these compounds at the molecular level. Compounds that showed anticancer activity in the preliminary screening were further evaluated in three cancer cell lines (A549, Calu-3, and BT-474 cells) and characterized in an epidermal growth factor receptor (EGFR) binding assay. Cytotoxicity in noncancerous lung fibroblast cells was also evaluated to obtain safety data. Our theoretical and experimental studies indicated that our compounds showed a mechanism of action similar to that of erlotinib by inhibiting the EGFR tyrosine kinase. In turn, the antituberculosis activity of these compounds would be produced by the inhibition of enoyl-ACP-reductase. From our findings, we were able to identify two potential lead compounds (5i and 5l) with dual activity and elevated safety toward noncancerous lung fibroblast cells. In addition, our data identified three compounds with excellent anti-TB activities (compounds 5i, 5l, and 5n).

Quinazolinone dimers as a potential new class of safer Kv1 inhibitors: Overcoming hERG, sodium and calcium channel affinities.

The discovery of more selective and safer voltage-gated potassium channel blockers is an extremely demanding approach. Designing selective Kv1.5 inhibitors is very challenging as only limited data is available on this target due to a lacking crystal structure for this ion channel receptor. Herein, we synthesized a series of 21 novel quinazolinone dimers 3a-i, 5a-i and 10a-c. We tried to avoid structural features responsible for non-selectivity and for most potassium channel blockers' side effects in our design. In contrast to other works, which lack investigation over wide ranges of potassium and sodium channels, we screened the inhibitory activity of our synthesized compounds over multiple voltage-gated potassium channels, including six different human Kv1 channel subtypes Kv1.1, Kv1.2, Kv1.3, Kv1.4, Kv1.5 and Kv1.6 channels as well as Kv2.1, Kv3.1, Kv4.3, Kv7.2, Kv7.3, Kv10.1, hERG, and Shaker IR. Moreover, these compounds' selectivity was investigated on sodium channels Nav1.2, Nav1.4 and Nav1.5 and calcium channels Cav3.1-Cav3.3. The results revealed two compounds (3a and 3e) with low micromolar Kv1.5 inhibition activity with EC50 values of 5.1 ± 0.9 µM and 12.5 ± 1.1 µM, respectively. However, at higher concentrations, they also showed inhibitory activity on Kv1.3 and Kv1.1 channels. This might be due to structural similarities between these three Kv1 channel isoforms. Compound 3a shows a slight preference for Kv1.5. Interestingly, they lack any activity on other potassium channels (including hERG), sodium channels, and calcium channels. Our findings recommend quinazolinone dimers with ethylene linker as a potential new class of safer Kv1 inhibitors and a good start for designing more selective and potent Kv1.5 inhibitors.

Q fever in Egypt: Epidemiological survey of Coxiella burnetii specific antibodies in cattle, buffaloes, sheep, goats and camels.

Q fever is a zoonotic disease caused by the bacterium Coxiella burnetii. Clinical presentation in humans varies from asymptomatic to flu-like illness and severe sequelae may be seen. Ruminants are often sub-clinically infected or show reproductive disorders such as abortions. In Egypt, only limited data on the epidemiology of Q fever in animals are available. Using a stratified two stage random sampling approach, we evaluated the prevalence of Coxiella burnetii specific antibodies among ruminants and camels in 299 herds. A total of 2,699 blood samples was investigated using enzyme-linked-immunosorbent assay (ELISA). Coxiella burnetii specific antibodies were detected in 40.7% of camels (215/528), 19.3% of cattle (162/840), 11.2% of buffaloes (34/304), 8.9% of sheep (64/716) and 6.8% of goats (21/311), respectively. Odds of seropositivity were significantly higher for cattle (aOR: 3.17; 95% CI: 1.96-5.13) and camels (aOR: 9.75; 95% CI: 6.02-15.78). Significant differences in seropositivity were also found between domains (Western Desert, Eastern Desert and Nile Valley and Delta) and 25 governorates (p < 0.001), respectively. Animal rearing in the Eastern Desert domain was found to be a significant risk factor (aOR: 2.16; 95% CI: 1.62-2.88). Most seropositive animals were older than four years. No correlation between positive titers and husbandry practices or animal origin were found (p > 0.05). Only 8.7% of the interviewed people living on the farms consumed raw camel milk and none reported prior knowledge on Q fever. Findings from this nationwide study show that exposure to Coxiella burnetii is common in ruminants and camels. Disease awareness among physicians, veterinarians and animal owners has to be raised. Future epidemiological investigations have to elucidate the impact of Q fever on human health and on the economy of Egypt.