Hamdy M. Abdel-Rahman

Design, synthesis and molecular modeling study of acylated 1,2,4-triazole-3-acetates with potential anti-inflammatory activity

The present investigation is concerned with the synthesis of different acylated 1,2,4-triazole-3-acetates with the objective of discovering novel and potent anti-inflammatory agents. Structures of the synthesized compounds were elucidated by spectral and elemental analyses. The obtained compounds were evaluated for their anti-inflammatory activites as well as gastric ulcerogenic effects and acute toxicity. Results showed that 1-acylated-5-amino-1,2,4-triazole-3-acetates 3a-e showed higher anti-inflammatory activity than the corresponding 5-acylamino derivatives 4a-e in carageenan-induced rat paw edema test with low gastric ulcerogenicity compared with indomethacin. Furthermore, molecular modeling studies were performed in order to rationalize the obtained biological results.

HIV Protease Inhibitors: Peptidomimetic Drugs and Future Perspectives

A literature review on the human immunodeficiency virus (HIV), the causative agent of acquired immune deficiency syndrome (AIDS). This review includes its life cycle, HIV protease structure, function, and substrates, as well as the mechanism and the design of inhibitors including the clinically approved drugs. Moreover the review mentioned the problems that hindered the development of peptidomimetic drug candidates as HIV protease inhibitors and the different approaches used by medicinal chemists to overcome these problems. A special attention was made to the design rationale as well as the lead optimization processes that provided inhibitors that possess high potency, reduced molecular weight and lower lipophilicity of the allophenylnorstatine (Apns) containing HIV protease inhibitors.

Design of inhibitors against HIV, HTLV-I, and Plasmodium falciparum aspartic proteases

Abstract Aspartic proteases have emerged as targets for substrate-based inhibitor design due to their vital roles in the life cycles of the organisms that cause AIDS, malaria, leukemia, and other infectious diseases. Based on the concept of mimicking the substrate transition-state, we designed and synthesized a novel class of aspartic protease inhibitors containing the hydroxymethylcarbonyl (HMC) isostere. An unnatural amino acid, allophenylnorstatine [Apns; (2S,3S)-3-amino-2-hydroxy-4-phenylbutyric acid], was incorporated at the P1 site in a series of peptidomimetic compounds that mimic the natural substrates of the HIV, HTLV-I, and malarial aspartic proteases. From extensive structure-activity relationship studies, we were able to identify a series of highly potent peptidomimetic inhibitors of HIV protease. One highly potent inhibitor of the malarial aspartic protease (plasmepsin II) was identified. Finally, a promising lead compound against the HTLV-I protease was identified.

Synthesis of some pyrazolyl benzenesulfonamide derivatives as dual anti-inflammatory antimicrobial agents

Four series of pyrazolylbenzenesulfonamide derivatives were synthesized and evaluated for their anti-inflammatory activity using cotton pellet induced granuloma and carrageenan-induced rat paw edema bioassays. Moreover, COX-1 and COX-2 inhibitory activity, ulcerogenic effect and acute toxiCIT000y were also determined. Furthermore, the target compounds were screened for their in-vitro antimicrobial activity against Eischerichia coli, Staphylococcus aureus and Candida albicans. Compounds 4-(3-Phenyl-4-cyano-1H-pyrazol-1-yl)benzenesulfonamide 9a and 4-(3-Tolyl-4-cyano-1H-pyrazol-1-yl)benzenesulfonamide 9b were not only found to be the most active dual anti-inflammatory antimicrobial agents in the present study with good safety margin and minimal ulcerogenic effect but also exhibited good selective inhibitory activity towards COX-2. A docking pose for 9a and 9b separately in the active site of the human COX-2 enzyme was also obtained. Therefore, these compounds would represent a fruitful matrix for the development of dual anti-inflammatory antimicrobial candidates with remarkable COX-2 selectivity.

Synthesis and anti-inflammatory activity of some pyrazole derivatives

A novel series of pyrazoles containing benzenesulfonamides, 1,3,4-oxadiazole-2-thiones, 4-substituted-1,2,4-triazole-3-thiones, and 2-substituted-1,3,4-thiadiazoles has been synthesized. Anti-inflammatory activity of some synthesized compounds was evaluated in vivo utilizing a standard acute carrageenan-induced paw edema method. The most active anti-inflammatory agents 3, 8f, and 10f were evaluated for ulcerogenic liability in rats compared to indomethacin and celecoxib as reference standards. Molecular modeling studies were initiated herein to validate the attained pharmacological data and provide understandable evidence for the observed anti-inflammatory behavior.

Synthesis and anti-mycobacterial evaluation of some pyrazine-2-carboxylic acid hydrazide derivatives

A series of pyrazine-2-carboxylic acid hydrazide derivatives were synthesized and screened for their activity against Mycobacterium tuberculosis. The results show that pyrazine-2-carboxylic acid hydrazide-hydrazone derivatives 3a-l were less active than pyrazinamide. In contrast, the N(4)-ethyl-N(1)-pyrazinoyl-thiosemicarbazide 4 showed the highest activity against M. tuberculosis H(37)Rv (IC(90) = 16.87 microg/mL). Details of the structure-activity and structure-cytotoxicity relationships are discussed.

Fluorinated 1,2,4-Triazolo[1,5-a]pyrimidine-6-carboxylic Acid Derivatives as Antimycobacterial Agents

A series of fluorinated 1,2,4‐triazolo[1,5‐a]pyrimidine‐6‐carboxylic acid derivatives was designed and synthesized as fluoroquinolone analogues. The synthesized compounds were screened against Mycobacterium tuberculosis H37Rv strain at 6.25 μg/mL concentration. Compound 4, the 7‐oxo‐2‐(trifluoromethyl)‐4,7‐dihydro‐1,2,4‐triazolo[5,1‐a]pyrimidine‐6‐carboxylic acid was found to be a very potent inhibitor, being able to inhibit 92% growth of M. tuberculosis H37Rv at 6.25 μg/mL concentration. At the same time, it proofed to be nontoxic to mammalian cells (IC50 > 62.5 μg/mL in VERO cells).

Synthesis and Biological Evaluation of Colchicine B‑Ring Analogues Tethered with Halogenated Benzyl Moieties

Deacetylcolchicine was reacted with substituted benzyl halides to provide a library of compounds for biological analysis. Compound 7 (3,4-difluorobenzyl-N-aminocolchicine) was shown to possess cytotoxicity in cancer cell lines in the low nanomolar range. Significantly, it showed no loss of activity in the resistant A2780AD ovarian carcinoma cell line known to overexpress the ABCB1 drug transporter and was also unaffected by overexpression of class III β-tubulin in HeLa transfected cells.

Novel benzothiazolyl urea and thiourea derivatives with potential cytotoxic and antimicrobial activities.

A novel series of benzothiazole urea and thiourea derivatives was synthesized and evaluated for its in vitro cytotoxicity against MCF-7 breast cancer cells. The N1-(benzothiazol-2-yl)-N3-morpholinourea 3 displayed the highest cytotoxic activity in this series. A docked pose of 3 was obtained bound to G-quadruplex of human telomere DNA active site using the Molecular Operating Environment (MOE) module. Moreover, the synthesized compounds were screened for their antimicrobial activity against Mycobacterium tuberculosis H37Rv, E. coli, S. aureus and C. albicans. Again, 3 showed the best activity against M. tuberculosis H37Rv while other compounds were equipotent with ampicillin against S. aureus and E. coli.

Synthesis and biological evaluation of colchicine C-ring analogues tethered with aliphatic linkers suitable for prodrug derivatisation

Colchicine was modified at the 10-OCH(3) position of the C-ring by reaction with heterocyclic amines or commercially available amines to afford a library of target colchicinoids in high yields (62-99%). Molecular modeling revealed that the incorporation of the linker groups led to a reduction in entropy and therefore binding affinity when compared with colchicine. Some colchicinoids were shown to be equicytotoxic with colchicine when evaluated in the DLD-1 colon cancer cells and retained activity in resistant A2780AD or HeLa cells with mutant Class III β-tubulin. Importantly, unlike colchicine, the analogues in this study are amenable for prodrug derivatisation and with potential for tumor-selective delivery.