Mohammed I. El-Gamal

New diarylureas and diarylamides containing 1,3,4-triarylpyrazole scaffold: Synthesis, antiproliferative evaluation against melanoma cell lines, ERK kinase inhibition, and molecular docking studies.

Synthesis of a new series of diarylureas and diarylamides possessing 1,3,4-triarylpyrazole scaffold is described. Their in vitro antiproliferative activities against 9 human melanoma cell lines were tested. Compounds 12, 13, 15, and 21-23 showed the highest potency against A375P melanoma cell line. In addition, compounds 10-15 and 19-24 showed high potency over the NCI 8 tested melanoma cell-lines panel. The IC(50) values for compound 23 were 0.36 μM and 0.84 μM over LOX IMVI and M14 cell lines, respectively. Compounds 21 and 23 showed high, dose-dependent inhibition of ERK kinase. Virtual screening was carried out through docking of compound 21 into the domain of V600E-B-RAF and the binding mode was studied.

Synthesis of pyrrolo[2,3-d]pyrimidine derivatives and their antiproliferative activity against melanoma cell line

Synthesis of a new series of diarylureas and amides having pyrrolo[2,3-d]pyrimidine scaffold is described. Their in vitro antiproliferative activities against A375 human melanoma cell line and HS 27 fibroblast cell line were tested and the effect of substituents on pyrrolo[2,3-d]pyrimidine was investigated. The newly synthesized compounds, except N-acetyl derivatives (Id, Ie, and Im), generally showed superior or similar activity against A375 to Sorafenib. Among all of these derivatives, compounds Iq and Ir having imidazole and morpholine moieties, respectively, showed the most potent antiproliferative activity against A375.

New imidazo[2,1-b]thiazole derivatives: Synthesis, in vitro anticancer evaluation, and in silico studies

A series of 18 new imidazo[2,1-b]thiazole derivatives was synthesized. Their in vitro antiproliferative activities against A375P human melanoma cell line and NCI-60 cell line panel were tested. Compounds 15, 16, 18, 22, 26-28, and 31 showed superior potency against A375P to sorafenib. In addition, compounds 26 and 27 showed selectivity toward melanoma cell lines than for other cancer types. Both compounds exerted sub-micromolar IC(50) values over 7 (including A375P) and 6 melanoma cell lines, respectively. In silico studies are also reported. ADME profiling, in silico toxicity, drug-likeness, and drug-score data of compounds 26 and 27 are promising.

New diarylureas and diarylamides possessing acet(benz)amidophenyl scaffold: design, synthesis, and antiproliferative activity against melanoma cell line.

A series of new diarylurea and diarylamide derivatives possessing acet(benz)amidophenyl scaffold was synthesized. Their in vitro antiproliferative activity was tested against A375P human melanoma cell line. Compounds 1c,d and 2c,d showed the highest potencies with IC(50) values in sub-micromolar scale. In addition, compounds 1b,e,l and 2e,l were more potent than Sorafenib but with IC(50) values in micromolar range. Moreover, compound 2c was equipotent to Vemurafenib, and 2d showed higher potency than Vemurafenib against A375P. Molar refractometry calculation and ADME profiling of the highest potent four derivatives 1c,d and 2c,d are also reported.

Synthesis and in vitro antiproliferative activity of new 1,3,4-oxadiazole derivatives possessing sulfonamide moiety

Synthesis of a new series of 1,3,4-oxadiazole derivatives possessing sulfonamide moiety is described. Their in vitro antiproliferative activities against NCI-58 human cancer cell lines of nine different cancer types were tested. Compound 1k with p-methoxybenzenesulfonamido moiety showed the highest mean %inhibition value over the 58 cell line panel at 10 μM concentration. It showed broad-spectrum antiproliferative activity over many cell lines of different cancer types. For instance, compound 1k inhibited the growth of T-47D breast cancer cell line by 90.47% at 10 μM. And it inhibited growth of SR leukemia, SK-MEL-5 melanoma, and MDA-MB-468 breast cancer cell lines by more than 80% at the same test concentration. Compound 1k showed superior activity than Paclitaxel and Gefitinib against the most sensitive cell lines.

FMS Kinase Inhibitors: Current Status and Future Prospects.

FMS, first discovered as the oncogene responsible for Feline McDonough Sarcoma, is a type III receptor tyrosine kinase that binds to the macrophage or monocyte colony‐stimulating factor (M‐CSF or CSF‐1). Signal transduction through that binding results in survival, proliferation, and differentiation of monocyte/macrophage lineage. Overexpression of CSF‐1 and/or FMS has been implicated in a number of disease states such as the growth of metastasis of certain types of cancer, in promoting osteoclast proliferation in bone osteolysis, and many inflammatory disorders. Inhibition of CSF‐1 and/or FMS may help treat these pathological conditions. This article reviews FMS gene, FMS kinase, CSF‐1, IL‐34, and their roles in bone osteolysis, cancer biology, and inflammation. Monoclonal antibodies, FMS crystal structure, and small molecule FMS kinase inhibitors of different chemical scaffolds are also reviewed.

Design, synthesis, and antiproliferative activity of new 1H-pyrrolo[3,2-c]pyridine derivatives against melanoma cell lines. Part 2

A new series of diarylureas and diarylamides possessing 1H-pyrrolo[3,2-c]pyridine scaffold was designed and synthesized. Their in vitro antiproliferative activities against A375P human melanoma cell line and NCI-9 human melanoma cell line panel were tested. All the target compounds, except three amino derivatives 8g, h and 9h, demonstrated superior potencies against A375P to Sorafenib. In addition, compounds 8a and 9b-f demonstrated higher potencies than Vemurafenib against A375P. Compounds 8c and 9b were 7.50 and 454.90 times, respectively, more selective towards A375P melanoma cells over NIH3T3 fibroblasts. Furthermore, compounds 8d, e and 9a-d, f demonstrated very high potencies against the nine tested melanoma cell lines at the NCI. The bisamide derivatives 9a-c, f showed 2-digit nanomolar IC(50) values over different cell lines of the NCI-9 melanoma cell lines.

Synthesis and anti-inflammatory activity of novel (substituted)benzylidene acetone oxime ether derivatives: Molecular modeling study

Herein, we report the design, synthesis, and pharmacological properties of a series of substituted benzylidene acetone oxime ether derivatives from the corresponding oxime derivatives. All the newly synthesized compounds were investigated in vivo for their anti-inflammatory activities using carrageenin-induced rat paw oedema model. Among the compounds examined, compounds 5b and 7a showed the highest activity, nearly equivalent to that of the standard drug diclofenac sodium. Hence, they were screened for their analgesic activities using acetic acid-induced writhing model in mice and also, their ulcerogenic effects were studied. Compound 7a was found to possess significant anti-inflammatory and analgesic activities with negligible ulcerogenic effect. Docking study of the synthesized compound 7a into the active site of COX-1 and COX-2 revealed a similar binding mode to SC-558, a selective COX-2 inhibitor.

Synthesis, in vitro antiproliferative activity, and in silico studies of fused tricyclic coumarin sulfonate derivatives.

A series of fused tricyclic coumarin sulfonate derivatives was synthesized. Their in vitro antiproliferative activities against a panel of 57 human cancer cell lines of nine different cancer types were tested at the NCI. Compounds 1e, 1f, 1h, 1i, and 1o showed the highest mean percentage of inhibition values over the 57 cell line panel at 10 μM, and they were further tested in 5-dose testing mode to determine their IC50 values. Compounds 1e, 1f, and 1o were more selective against leukemia and colon cancer subpanels, while compounds 1h and 1i showed broad-spectrum anticancer activities. Compounds 1e, 1f, 1h, 1i, and 1o demonstrated high selectivity towards cancer cell lines than RAW 264.7 macrophages. Compound 1h exerted lethal effect over NCI-H522 NSCLC, SK-MEL-5 melanoma, and A498 renal cancer cell lines with percentage of inhibition values of 114.10%, 103.23%, and 100.52% at 10 μM concentration, respectively. Moreover, the IC50 value of compound 1o against HT29 colon cancer cell line was 532 nM. Compounds 1e, 1f, 1h, 1i, and 1o were tested for inhibitory effect over cyclooxygenase-2 (COX-2) enzyme as a possible mechanism of action. Furthermore, in silico studies were conducted to check the compliance of those five compounds with Lipinskis rule of five, and hence estimate their oral bioavailability.

Current Status of Carbapenem Antibiotics

β-Lactam antibiotics are the most prescribed antibacterial agents. They comprise more than half of all antibiotics. They are considered as the cornerstone of the antibiotic armamentarium. By inhibiting bacterial cell wall biosynthesis, they are highly effective against Gram-positive and Gram-negative bacteria. Antibiotic resistance among Gram-negative pathogens in hospitals represents a dangerous threat to public health. Since many bacteria have developed resistance to older agents, new β-lactam antibiotics have been continuously developed. In the late 1970s, a new class of exceptionally broad-spectrum non-traditional β-lactams, carbapenems, was developed. This review article focuses on the new developments related to the field of carbapenems for treatment of bacterial infections, especially those caused by Gram-negative bacteria. The structural features, principal characteristics, and clinical implications of carbapenems including thienamycin, imipenem/cilastatin, panipenem/betamipron, biapenem, tebipenem, tebipenem pivoxil, meropenem, ertapenem, doripenem, lenapenem, and tomopenem are discussed herein.