A. M. Farghaly

Synthesis and 5-HT2A antagonist activity of derivatives of the novel heterocycles indolo[3,2-d]pyrrolo[3,2-g]azecine and benzo[d]pyrrolo[3,2-g]azecine compared to the benz[d]indolo[2,3-g]azecine derivative LE 300.

An indolo[3,2‐d]pyrrolo[3,2‐g]azecine and a benzo[d]pyrrolo[3,2‐g]azecine analogue of the potent dopamine receptor antagonist LE 300 (7‐methyl‐6,7,8,9,14,15‐hexahydro‐5H‐benz‐[d]indolo[2,3‐g]azecine) have been prepared in multi‐step reactions via C‐N bond cleavage of corresponding quaternary N‐methylquinolizinium iodides. LE 300, the target compounds and two precursor quinolizines have been tested in vitro for antagonist activity at 5‐HT2A receptors (rat tail artery) and H1 receptors (guinea‐pig ileum), respectively. LE 300 and compound 19 (3,6‐dimethyl‐ 4,5,6,7,8,13‐hexahydro‐3H‐benzo[d]pyrrolo[3,2‐g]azecine) competitively inhibited 5‐HT‐induced contractions with similar nanomolar potency (pA2 = 8.32 and 8.01, respectively) but were less active than the reference antagonist ketanserin (pA2 = 9.55). Compound 19 displayed moderate H1‐antihistaminic activity in the guinea‐pig ileum assay (pA2 = 7.37).

Synthesis of Some Triazolophthalazine Derivatives for Their Anti-Inflammatory and Antimicrobial Activities

Several novel series of triazolophthalazine derivatives namely; pyrazolylethenyltriazolophthalazinones (4a–d), styryltriazolophthalazinones (5a,b), aryloxopropenyltriazolophthalazinones (7a,b), pyrazolinyl‐ (8a,b), (9a,b) and (10a–f), pyrazolyl‐ (11a–d), (1,2‐oxazol‐5‐yl)‐1,2,4‐triazolo[3,4‐a]phthalazin‐6(5H)‐ones (14a,b), triazolo[3,4‐a]phthalazin‐3‐yl‐pyridine‐3‐carbonitriles (12a,b), triazolo[3,4‐a]phthalazin‐3‐yl)ethylthioacetic acids (13a,b) and 2‐aryl‐5‐arylamino‐1H,5H‐pyrazolo[2″,3″‐1′,5′]imidazo[3′,4′‐1,5]‐1,2,4‐triazolo[3,4‐a]phthalazin‐12(13H)‐ones (15a–c) have been synthesized. The anti‐inflammatory activity of representative compounds has been studied. Compounds 8b, 10c, 10f, 11b, 12a, 13b, and 15a showed anti‐inflammatory activities comparable to that of the reference standard, indomethacin. They exhibit also minimal ulcerogenic effect relevant to the reference standard and were found to be non‐toxic up to 120 mg/kg orally or up to 75 mg/kg through parenteral route. Concerning the antimicrobial activity; compounds 12b and 13b were found to be equipotent to ampicillin against Staphylococcus aureus, while compounds 10a and 10f were found to be as potent as ampicillin against E. coli, whereas compound 14b exhibited equipotency to clotrimazole against Candida albicans. Compounds 8b, 10f, 11b, 12a, and 13b exhibited, besides their antimicrobial activity, moderate to potent anti‐inflammatory profiles. This represents a fruitful matrix for the development of a new class of dual non‐acidic anti‐inflammatory/antimicrobial agents.

Synthesis and biological evaluation of novel N3-substituted dihydropyrimidine derivatives as T-type calcium channel blockers and their efficacy as analgesics in mouse models of inflammatory pain

Low-voltage-activated calcium channels are important regulators of neurotransmission and membrane ion conductance. A plethora of intracellular events rely on their modulation. Accordingly, they are implicated in many disorders including epilepsy, Parkinsons disease, pain and other neurological diseases. Among different subfamilies, T-type calcium channels, and in particular the CaV3.2 isoform, were shown to be involved in nociceptive neurotransmission. The role of CaV3.2 in pain modulation was supported by demonstrating selective antisense oligonucleotide-mediated CaV3.2 knockdown, in vivo antinociceptive effects of T-type blockers, and pain attenuation in CaV3.2 knockout formalin-induced pain model. These Emerging investigations have provided new insights into targeting T-type calcium channels for pain management. Within this scope, various T-type calcium channel blockers have been developed such as mibefradil and ethosuximide. Although being active, most of these molecules interact with other receptors as well. This addresses the need for T-selectivity. Few selective T-type channel blockers of diverse chemical classes were developed such as ABT-639 and TTA-P2. Interestingly, R(-) efonidipine which is a dihydropyridine (DHP) showed T-channel selectivity. Systematic modification of 1,4-dihydropyridine scaffold introduced novel derivatives with 40-fold T-type selectivity over L-type calcium channels. Along these lines, substitution of the DHP core with various analogues favored T-selectivity and may serve as novel pharmacophores. Several dihydropyrimidine (DHPM) mimics were introduced by Squibb as potential candidates. As a continuation of this approach, the current study describes the synthesis of Novel N3 substituted DHPMs with structure similarities to the active DHPs. Different functional groups were introduced to the N3 position through a spacer to gain more information about activity and selectivity. Furthermore, the spacer aims at improving the metabolic stability of the molecules. Initial screening data by whole patch clamp technique showed a robust inhibition of Cav3.2 T-type channels by eleven compounds. Interestingly, four compounds of these were efficient selective T-type blockers. Based on selectivity and efficiency, two compounds were selected for in vivo evaluation in mouse models of inflammatory pain. Results showed effective attenuation of nociception and mechanical hypersensitivity.

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].

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.

Ethyl 5-methyl-7-phenyl-1,2,4-triazolo[4,3-a]pyrimidine-6-carboxyl­ate

In the title compound, C15H14N4O2, the triazolopyrimidine ring system is almost planar (r.m.s. deviation = 0.02 Å) and the phenyl ring is inclined to its mean plane by 42.45 (9)°. The carboxyl group is inclined to the triazolopyrimidine ring mean plane by 57.8 (3)°. In the molecule, there is a short C—H⋯O contact involving the carbonyl O atom and an H atom of the adjacent methyl substituent. In the crystal, neighbouring molecules are linked by C—H⋯O hydrogen bonds, forming chains propagating along [010]. There are also weak π–π interactions present involving the pyridine and phenyl rings of neighbouring chains [intercentroid distance = 3.8580 (16) Å].