New tetrahydropyrimidine-1,2,3-triazole clubbed compounds: Antitubercular activity and Thymidine Monophosphate Kinase (TMPKmt) inhibition.

Two series of new tetrahydropyrimidine (THPM)-1,2,3-triazole clubbed compounds were designed, synthesized and screened for their antitubercular (anti-TB) activity against M. tuberculosis H37Rv strain using microplate alamar blue assay (MABA). The most active compounds 5c, 5d, 5e and 5f were further examined for their cytotoxicity against the growth of RAW 264.7 mouse macrophage cells using MTT assay. The four compounds showed safety profiles better than or comparable to that of ethambutol (EMB). These compounds were evaluated for their inhibition activity against mycobacterium tuberculosis thymidine monophosphate kinase (TMPKmt). Compounds 5c and 5e were the most potent exhibiting comparable inhibition activity to that of the natural substrate deoxythymidine monophosphate (dTMP). An in silico study was performed including docking of the most active compounds 5c and 5e into the TMPKmt (PDB: ID 1G3U) binding pocket in addition to prediction of their physicochemical and pharmacokinetic properties to explore the overall activity of these anti-TB candidates. Compounds 5c and 5e are promising anti-TB agents and TMPKmt inhibitors with acceptable oral bioavailability, physicochemical and pharmacokinetic properties.

Antiproliferative activity, enzymatic inhibition and apoptosis-promoting effects of benzoxazole-based hybrids on human breast cancer cells.

New benzoxazole derivatives containing 1,3,4-oxadiazole, 1,2,4-triazole or triazolothiadiazine rings were synthesized and screened for their in vitro antiproliferative activities against MCF-7 and MDA-MB-231 breast cancer cell lines using MTT assay. Doxorubicin, cisplatin and 2-(4-aminophenyl)benzothiazole (CJM 126) were used as references. The most active compounds 7a, 8d, 8e and 10c were screened for their antiproliferative activities against MCF-10A normal breast cells where compounds 8e and 7a were the most selective towards MCF-7 and MDA-MB-231 cell lines, respectively compared to CJM 126. In vitro enzymatic inhibition assays of epidermal growth factor receptor (EGFR) and aromatase (ARO) enzymes were performed. Compound 7a showed inhibition of EGFR comparable to that of erlotinib while compound 8e exhibited nearly half the inhibitory activity of erlotinib towards EGFR and was more potent inhibitor of ARO than letrozole. Caspase-9 activation assay, cell cycle analysis and Annexin-V/ Propidium iodide assay performed for compounds 7a, 8d, 8e and 10c demonstrated over expression of caspase-9 protein level, pre G1 apoptosis and high annexin V binding affinity. Therefore, these compounds are considered as potent apoptosis-promoting agents. The predicted docking studies and in silico chemo-informatic properties of compounds 7a and 8e were appropriate. Compounds 7a and 8e are promising anti-breast cancer agents exhibiting potent apoptosis-promoting properties.

Benzoxazole derivatives as new generation of anti-breast cancer agents.

New 2-substituted benzoxazole derivatives were synthesized and screened for their in vitro anti-proliferative activities against MCF-7 and MDA-MB-231 cell lines. Compounds 4b, 4d and 11c eliciting the highest activity against MCF-7 cells were further assayed for their cytotoxic activities against A431 and HCC827 cancer cells in addition to their in vitro inhibition of wild and mutated epidermal growth factor receptor (EGFR) enzymes. Compound 11c was the most active against A431 cells and it displayed a potent inhibition of EGFRWT while compounds 4b and 4d elicited higher potencies than erlotinib against mutated EGFRL858R. Compounds 4a, 6c and 8a showed the most potent cytotoxic activity against MDA-MB-231 cancer cells where compounds 4a and 6c were slightly less potent aromatase (ARO) inhibitors than letrozole. MCF-7 cells treated with compounds 4b, 4d, 11c and MDA-MB-231 cells treated with compounds 4a, 6c and 8a showed remarkable over-expression of caspase-9 protein level and elicited pre G1 apoptosis and cell cycle arrest at G2/M phase in addition to high annexin V binding affinity indicating significant apoptosis. Chemo-informatic and docking properties were also predicted. Docking results revealed that docked compounds displayed binding modes with EGFR and ARO enzymes comparable to that of the reference ligands. The benzoxazole derivatives 11c and 6c possessing amide and dithiocarbamate moieties respectively were found to be potent apoptosis-inducing anti-breast cancer agents with acceptable physicochemical properties. They exert their activity via inhibition of EGFR and ARO enzymes respectively.

Pyrazoles containing thiophene, thienopyrimidine and thienotriazolopyrimidine as COX-2 selective inhibitors: Design, synthesis, in vivo anti-inflammatory activity, docking and in silico chemo-informatic studies.

New thiophene and annulated thiophene pyrazole hybrids were synthesized and screened for their in vitro COX-1/COX-2 enzymatic inhibition and in vivo anti-inflammatory activities. All compounds were more COX-2 selective inhibitors than COX-1 with compound 13 exhibiting the highest COX-2 selectivity index. Compounds 3, 6a, 9 and 11 were the most promising in the acute anti-inflammatory assay while compounds 3, 5, 6a, 6c, 9, 10, 11 and 13 exerted promising anti-inflammatory activity in the sub-acute anti-inflammatory assay. Compounds 3, 6a, 6c, 9, 10 and 11 were evaluated for their ED50 values and were more potent than diclofenac sodium while compounds 6a, 6c and 9 were of greater potency than celecoxib with compound 6a being the most potent showing ED50 = 0.033 mmol/kg. These compounds were non-toxic and proved to be gastrointestinal safe compared to indomethacin, diclofenac sodium and celecoxib. Docking studies into COX-2 active site (PDB code 3LN1) revealed that compounds 3, 6a, 6c, 9, 10, 11 and 13 had binding modes and energies comparable to that of celecoxib. Compounds 3, 9, 10 and 11 complied with Lipinski's RO5 while compounds 6a and 6c showed one violation whereas compound 13 deviated by 2 violations. Compounds 6a, 6c and 13 showed 100% plasma protein binding (PPB) and showed no aqueous solubility while compounds 3, 10 and 11 demonstrated the best drug likeness model scores. Therefore, the thiophene analog 3 and the thienopyrimidine derivatives 10 and 11 are promising anti-inflammatory candidates that exert moderate selective COX-2 inhibition with acceptable physicochemical properties.

Synthesis, biological evaluation and molecular modeling of novel thienopyrimidinone and triazolothienopyrimidinone derivatives as dual anti-inflammatory antimicrobial agents.

New thienopyrimidinone and triazolothienopyrimidinone derivatives have been synthesized. These compounds were subjected to anti-inflammatory and antimicrobial activity screening aiming to identify new candidates that have dual anti-inflammatory and antimicrobial activities. Compounds 5, 7 and 10a showed minimal ulcerogenic effect and high selectivity towards human recombinant COX-2 over COX-1 enzyme. Their docking outcome correlated with their biological activity and assured the high selectivity binding towards COX-2. In addition, they could act safely up to 80 mg/kg orally or 40 mg/kg parentrally. The antimicrobial screening showed that compound 10a displayed distinctive inhibitory effect on the growth of Escherichia coli comparable to that of ampicillin. Moreover, compounds 5, 7, 9 and 12a possessed 50% of the inhibitory activity of ampicillin against E. coli. Thus, compounds 5, 7 and 10a represent promising dual acting anti-inflammatory and antimicrobial agents. This work provides rewarding template enriching the chemical space for dual anti-inflammatory anti-microbial activities.

Design, synthesis, anticancer screening, docking studies and in silico ADME prediction of some ß-carboline derivatives.

BACKGROUND: Medicinal interest has focused on ß-carbolines as anticancer agents. METHODOLOGY/RESULTS: Several ß-carbolines were designed, synthesized and evaluated for their cytotoxic activity against MCF-7 and A-549 cancer cell lines using MTT assay. Compounds 13a, 13c, 13d and 20a were the most promising showing high selectivity indices. Compounds 13c and 20a showed potent inhibition of topoisomerase (topo-I) and kinesin spindle protein (KSP/Eg5 ATPase) which was confirmed by their docking results into the active site of both enzymes. In silico physicochemical calculations predicted that compounds 13a, 13d and 20a obeyed Lipinski's rule of five. CONCLUSION: Compounds 13c and 20a are multitarget anticancer leads that act as potent inhibitors for both topo-I and/or KSP ATPase.

Design and synthesis of some ß-carboline derivatives as multi-target anticancer agents.

AIM: Some anticancer ß-carbolines exhibited dual inhibition of topo-I and KSP. METHODOLOGY/RESULTS: Novel ß-carbolines were synthesized and screened for their anticancer activity according to the NCI protocol. Five dose assays results indicated that compounds 9, 10, 12, 17 and 20 were potent and non selective anticancer agents; the sulfanyltriazole 12 was the most potent. Compounds 10, 12 and 20 showed dual topo-I and KSP inhibition with compound 12 being the most potent. Active compounds elicited Pre-G1 apoptosis and cell cycle arrest at G2/M phase of melanoma MDA-MB-435 cells. Docking results, in silico physicochemical and absorption, distribution, metabolism, excretion (ADME) properties were appropriate. CONCLUSION: Compounds 10, 12 and 20 are potent apoptosis-inducing multitarget anticancer agents that act via dual inhibition of topo-I and KSP-ATPase.

Design, facile synthesis and anthelmintic activity of new O-substituted 6-methoxybenzothiazole-2-carbamates. Part II.

In the framework of pursuing the design and synthesis of a new series of substituted 6-methoxybenzothiazole-2-carbamates as potential anthelmintics, and as a continuation of the expended efforts in part I, we have set out to develop novel compounds with enhanced anthelmintic activity by blocking the 6-position of benzothiazole with side chains of different polarities. Guided by the findings in part I, and reporting the paramphistomicidal activity of oxadiazoline derivatives V and VI, we aimed to synthesize target benzothiazoles designed to comprise some planar heterocyclic ring systems, namely, 1,3,4-oxadiazoles and 1,2,4-triazoles, bearing a variety of hydrophobic and hydrophilic components. The synthesis of the desired compounds was primarily achieved by cyclization of 6-acetohydrazide, 1. The in vitro paramphistomicidal activity of all synthesized carbamates was evaluated. Four synthesized carbamates exhibited notable activity. Compound 24, methyl 6-[(5-(4-bromophenacylsulfanyl)-[1,3,4]-oxadiazol-2-yl)methoxy]benzothiazole-2-carbamate, displayed an equipotent effect to the reference drug oxyclozanide at a concentration of 80 µg mL-1; compounds 9, 10 and 23 showed high orders of anthelmintic effect. A structural computational study on the polar nature and hydrophilic-lipophilic properties of the synthesized carbamates was undertaken to discuss their structure-activity relationship (SAR). Besides, pharmacophore mapping was performed using eight active compounds as a training set. The generated pharmacophore model revealed five common features and was validated using fenbendazole, triclabendazole and triclabendazole sulfoxide.

Synthesis, evaluation and modeling of some triazolothienopyrimidinones as anti-inflammatory and antimicrobial agents.

AIM: New triazolotetrahydrobenzothienopyrimidinone derivatives were synthesized. EXPERIMENTAL: Their structures were confirmed, and their anti-inflammatory, antimicrobial activities and ulcerogenic potentials were evaluated. RESULTS: Compounds 7a, 10a and 11a showed minimal ulcerogenic effect and high selectivity toward human recombinant COX-2 over COX-1 enzyme with IC50 values of 1.39, 1.22 and 0.56 µM, respectively. Their docking outcome correlated with their biological activity and confirmed the high selectivity binding toward COX-2. Compound 12b displayed antimicrobial activity comparable to that of ampicillin against Escherichia coli while compounds 6 and 11c were similar to ampicillin against Staphylococcus aureus. In addition, compounds 7a, 9a, 10b and 11c showed dual anti-inflammatory/antimicrobial activities. CONCLUSION: This work represents a promising matrix for developing new potential anti-inflammatory, antimicrobial and dual antimicrobial/anti-inflammatory candidates. [Formula: see text].