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Design and synthesis of new barbituric- and thiobarbituric acid derivatives as potent urease inhibitors: Structure activity relationship and molecular modeling studies

Rauf A, Shahzad S, Bajda M, Yar M, Ahmed F, Hussain N, et al.

Bioorg Med Chem, 2015 Sep 1;23(17):6049-58.
PMID: 26081763 DOI: 10.1016/j.bmc.2015.05.038

In this study 36 new compounds were synthesized by condensing barbituric acid or thiobarbituric acid and respective anilines (bearing different substituents) in the presence of triethyl orthoformate in good yields. In vitro urease inhibition studies against jack bean urease revealed that barbituric acid derived compounds (1-9 and 19-27) were found to exhibit low to moderate activity however thiobarbituric acid derived compounds (10-18 and 28-36) showed significant inhibition activity at low micro-molar concentrations. Among the synthesized compounds, compounds (15), (12), (10), (36), (16) and (35) showed excellent urease inhibition with IC50 values 8.53 ± 0.027, 8.93 ± 0.027, 12.96 ± 0.13, 15 ± 0.098, 18.9 ± 0.027 and 19.7 ± 0.63 μM, respectively, even better than the reference compound thiourea (IC50 = 21 ± 0.011). The compound (11) exhibited comparable activity to the standard with IC50 value 21.83 ± 0.19 μM. In silico molecular docking studies for most active compounds (10), (12), (15), (16), (35) and (36) and two inactive compounds (3) and (6) were performed to predict the binding patterns.
Fulltext Erratum: pH Sensitive Hydrogels in Drug Delivery: Brief History, Properties, Swelling, and Release Mechanism, Material Selection and Applications. Polymers 2017, 9, 137

Rizwan M, Yahya R, Hassan A, Yar M, Azzahari AD, Selvanathan V, et al.

Polymers (Basel), 2017 06 14;9(6).
PMID: 30970902 DOI: 10.3390/polym9060225

The authors wish to make a change to their published paper [1]. [...].
Novel chitosan derivative based composite scaffolds with enhanced angiogenesis; potential candidates for healing chronic non-healing wounds

Rizwan M, Yahya R, Hassan A, Yar M, Abd Halim AA, Rageh Al-Maleki A, et al.

J Mater Sci Mater Med, 2019 Jun 11;30(6):72.
PMID: 31187295 DOI: 10.1007/s10856-019-6273-3

The success of wound healing depends upon the proper growth of vascular system in time in the damaged tissues. Poor blood supply to wounded tissues or tissue engineered grafts leads to the failure of wound healing or rejection of grafts. In present paper, we report the synthesis of novel organosoluble and pro-angiogenic chitosan derivative (CSD) by the reaction of chitosan with 1,3-dimethylbarbituric acid and triethylorthoformate (TEOF). The synthesized material was characterized by FTIR and 13C-NMR to confirm the incorporated functional groups and new covalent connectivities. Biodegradability of the synthesized chitosan derivative was tested in the presence of lysozyme and was found to be comparable with CS. The cytotoxicity and apoptosis effect of new derivative was determined against gastric adenocarcinoma (AGS) cells and was found to be non-toxic. The CSD was found to be soluble in majority of organic solvents. It was blended with polycaprolactone (PCL) to form composite scaffolds. From an ex ovo CAM assay, it was noted that CSD stimulated the angiogenesis.
Novel approaches for the development of direct KRAS inhibitors: structural insights and drug design

Haider K, Sharma A, Yar MS, Yakkala PA, Shafi S, Kamal A

Expert Opin Drug Discov, 2022 Jan 27.
PMID: 35084268 DOI: 10.1080/17460441.2022.2029842

INTRODUCTION: Hyperactivated RAS signaling is reported in 13% of all human cancers, in which ~80% resulted due to KRAS mutations alone. Direct inhibition of KRAS is an important aspect in treating KRAS-related tumors. Despite the efforts of more than four decades, not many KRAS inhibitors have been successful in obtaining clinical approval, except the very recent FDA approval for sotorasib. In recent years, the understanding of structural insights and allosteric pocket identification at catalytic sites of KRAS are likely to provide an excellent opportunity for the development of much more effective clinical candidates.
AREA COVERED: The presented review article mainly summarizes the developments of small molecule KRAS inhibitors as drug candidates and rational approaches that are being utilized for the selective targeting of KRAS signaling in the mutant cancer cells.
EXPERT OPINION: After the initial success in targeting the mutant KRAS G12C variants, the search has been shifted to address the challenges concerning the resistance and efficacy of small molecule KRAS inhibitors. However, the contribution of other KRAS mutations at G12V, G13C, and G13D variants causing cancers is much higher than the mutations at G12C. In view of this aspect, specific attention is required to target all other mutations as well. Accordingly, for the development of KRAS targeted therapies, the design of small molecule inhibitors that can inhibit KRAS signaling and as well as target inhibition of other signaling pathways like RAS-SOS and RAS-PI3K has to be explored extensively.
Design and synthesis of newer 1,3,4-oxadiazole and 1,2,4-triazole based Topsentin analogues as anti-proliferative agent targeting tubulin

Naaz F, Ahmad F, Lone BA, Pokharel YR, Fuloria NK, Fuloria S, et al.

Bioorg Chem, 2020 01;95:103519.
PMID: 31884140 DOI: 10.1016/j.bioorg.2019.103519

A set of two series of 1,3,4-oxadiazole (11a-n) and 1,2,4-Triazole (12a, c, e, g, h, j-n) based topsentin analogues were prepared by replacing imizadole moiety of topsentin through a multistep synthesis starting from indole. All the compounds synthesized were submitted for single dose (10 µM) screening against a NCI panel of 60-human cancer cell lines. Among all cancer cell lines, colon (HCC-2998) and Breast (MCF-7, T-47D) cancer cell lines were found to be more susceptible for this class of compounds. Among the compounds tested, compounds 11a, 11d, 11f, 12e and 12h, were exhibited good anti-proliferative activity against various cancer cell lines. Compounds 11d, 12e and 12h demonstrated better activity with IC50 2.42 µM, 3.06 µM, and 3.30 µM respectively against MCF-7 human cancer cell line than that of the standard drug doxorubicin IC50 6.31 µM. Furthermore, 11d induced cell cycle arrest at G0/G1 phase and also disrupted mitochondrial membrane potential with reducing cell migration potential of MCF-7 cells in dose dependent manner. In vitro microtubule polymerization assays found that compound 11d disrupt tubulin dynamics by inhibiting tubulin polymerization with IC50 3.89 μM compared with standard nocodazole (IC50 2.49 μM). In silico docking studies represented that 11d was binding at colchicine binding site of β-tubulin. Compound 11d emerged as lead molecule from the library of compounds tested and this may serve as a template for further drug discovery.
Novel 9-(2-(1-arylethylidene)hydrazinyl)acridine derivatives: Target Topoisomerase 1 and growth inhibition of HeLa cancer cells

Haider MR, Ahmad K, Siddiqui N, Ali Z, Akhtar MJ, Fuloria N, et al.

Bioorg Chem, 2019 07;88:102962.
PMID: 31085373 DOI: 10.1016/j.bioorg.2019.102962

A series of 9-(2-(1-arylethylidene)hydrazinyl)acridine and its analogs were designed, synthesized and evaluated for biological activities. Various biochemical assays were performed to determine the free radical scavenging capacity of synthesized compounds (4a-4j). Anticancer activity of these compounds was assessed against two different human cancer cell lines viz cervical cancer cells (HeLa) and liver cancer cells (HepG2) as well as normal human embryonic kidney cell line (HEK 293). Compounds 4b, 4d and 4e showed potential anti-proliferative effects on HeLa cells. Based on results obtained from antioxidant and cytotoxicity studies, 4b, 4d and 4e were further studied in detail for different biological activities. 4b, 4d and 4e reduced the cell growth, inhibited metastatic activity and declined the potential of cell migration in HeLa cell lines. Topoisomerase1 (Top1) treated with compounds 4b, 4d and 4e exhibited inhibition of Top1 and prevented DNA replication. Molecular docking results validate that interaction of compounds 4b, 4d and 4e with Top1-DNA complex, which might be accountable for their inhibitory effects. Further it was concluded that compounds 4b, 4d and 4e arrests the cells at S phase and consequently induces cell death through DNA damage in HeLa cells.